Interstitial lung disease 1 (ILD1) is a rare, gene-defined fibrosing lung disease caused by germline missense variants in SFTPA1, which encodes surfactant protein A1 (SP-A1), a collectin secreted by alveolar type II cells. The reported variants cluster in the carbohydrate-recognition domain of SP-A1; cell studies show that the mutant protein is made but not secreted, and patient lung tissue shows an abnormal SP-A staining pattern. Disease ranges from severe respiratory insufficiency in infancy to adult idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis, and is frequently accompanied by lung adenocarcinoma in carriers and their relatives. Inheritance is usually autosomal dominant with incomplete, age-dependent penetrance; a single consanguineous family with a homozygous variant has also been reported. Lung transplantation is the established treatment for end-stage disease. ClinGen classifies SFTPA1 as Moderate for autosomal dominant ILD1.
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name: Interstitial Lung Disease 1
creation_date: "2026-10-15T14:36:39Z"
category: Mendelian
description: >-
Interstitial lung disease 1 (ILD1) is a rare, gene-defined fibrosing lung
disease caused by germline missense variants in SFTPA1, which encodes
surfactant protein A1 (SP-A1), a collectin secreted by alveolar type II
cells. The reported variants cluster in the carbohydrate-recognition domain
of SP-A1; cell studies show that the mutant protein is made but not
secreted, and patient lung tissue shows an abnormal SP-A staining pattern.
Disease ranges from severe respiratory insufficiency in infancy to adult
idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis, and is
frequently accompanied by lung adenocarcinoma in carriers and their
relatives. Inheritance is usually autosomal dominant with incomplete,
age-dependent penetrance; a single consanguineous family with a homozygous
variant has also been reported. Lung transplantation is the established
treatment for end-stage disease. ClinGen classifies SFTPA1 as Moderate for
autosomal dominant ILD1.
disease_term:
preferred_term: interstitial lung disease 1
term:
id: MONDO:0030608
label: interstitial lung disease 1
synonyms:
- ILD1
- SFTPA1-related interstitial lung disease
parents:
- Inherited Interstitial Lung Disease
categories:
- Interstitial Lung Disease
- Surfactant Dysfunction Disorder
mappings:
mondo_mappings:
- term:
id: MONDO:0030608
label: interstitial lung disease 1
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: Primary MONDO identifier for the SFTPA1-defined interstitial lung disease (OMIM 619611).
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
penetrance: INCOMPLETE
expressivity: VARIABLE
description: >-
Heterozygous SFTPA1 missense variants segregate with disease in
multigenerational families. Young carriers can be asymptomatic, and the
clinical picture among affected carriers ranges from infant-onset
respiratory insufficiency to adult fibrosis with or without lung
adenocarcinoma. The only penetrance estimate pools SFTPA1 and SFTPA2
carriers as a single locus, so it is not given as a number here.
evidence:
- reference: PMID:26792177
reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified, in a multigenerational family, nine members carrying a
heterozygous missense mutation with evidence of pathogenicity in SFTPA1
that encodes the surfactant protein (SP)-A1.
explanation: >-
Nine heterozygous carriers in one multigenerational family establish
dominant transmission of the disease allele.
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Moreover, this variant was also found by Sanger sequencing in one other
symptomatic family member and one young asymptomatic family member.
explanation: >-
A second, independent family carrying p.Val178Met shows dominant
segregation and an asymptomatic young carrier, consistent with
age-dependent penetrance.
- reference: CGGV:assertion_3c3d8e40-6ec1-4fb0-8a30-ce4f1e33dbdf-2025-01-28T170000.000Z
reference_title: "SFTPA1 / interstitial lung disease 1 (Moderate)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Lung disease associated with SFTPA1 variants is characterized by
pulmonary fibrosis, interstitial pneumonia, and/or lung adenocarcinoma,
with variability in presentation.
explanation: >-
ClinGen's summary records variable expressivity among SFTPA1 carriers.
- reference: CGGV:assertion_3c3d8e40-6ec1-4fb0-8a30-ce4f1e33dbdf-2025-01-28T170000.000Z
reference_title: "SFTPA1 / interstitial lung disease 1 (Moderate)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Due to these reasons the ILD disease entity is curated in the autosomal
dominant mode of inheritance only.
explanation: >-
ClinGen curates this gene-disease pair as autosomal dominant.
- name: Autosomal recessive (single family)
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
One consanguineous Japanese family had three brothers homozygous for
SFTPA1 p.Tyr208His, with both parents heterozygous. OMIM lists both modes
for ILD1, but ClinGen judged the evidence that this family's disease is
monogenic insufficient and did not score it, so recessive inheritance
rests on one report.
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we describe the identification of a homozygous missense mutation
in SFTPA1 in patients of a consanguineous Japanese family.
explanation: >-
A homozygous SFTPA1 variant in affected members of a consanguineous
family supports recessive inheritance in this family; the paper also
reports both parents as heterozygous.
- reference: CGGV:assertion_3c3d8e40-6ec1-4fb0-8a30-ce4f1e33dbdf-2025-01-28T170000.000Z
reference_title: "SFTPA1 / interstitial lung disease 1 (Moderate)"
supports: REFUTE
evidence_source: OTHER
snippet: >-
At this time, the data asserting an autosomal recessive inheritance
pattern are limited, and sufficient evidence has not been provided in
published reports regarding the monogenic nature of the lung disease
found in the probands (PMID 31601679).
explanation: >-
ClinGen does not accept the recessive family as sufficient evidence for
an autosomal recessive form of ILD1.
pathophysiology:
- name: SFTPA1 Carbohydrate-Recognition Domain Missense Variant
description: >-
Disease-associated SFTPA1 variants are germline missense changes in the
C-terminal carbohydrate-recognition domain (CRD) of SP-A1, including
p.Trp211Arg (a residue invariant across CRD-containing proteins),
p.Val178Met and p.Tyr208His.
biological_scale: MOLECULAR
genes:
- preferred_term: SFTPA1
term:
id: hgnc:10798
label: SFTPA1
genetic_context:
variant_origin: GERMLINE
molecular_functions:
- preferred_term: SP-A1 carbohydrate-recognition domain carbohydrate binding
term:
id: GO:0030246
label: carbohydrate binding
notes: >-
The molecular function is bound without a modifier. The variants lie in
the carbohydrate-recognition domain, but the cited studies measure loss
of secretion, not loss of carbohydrate binding, so no change in this
activity is asserted. GO:0120153 calcium-dependent carbohydrate binding
was not used because no cited source states the calcium dependence.
evidence:
- reference: CGGV:assertion_3c3d8e40-6ec1-4fb0-8a30-ce4f1e33dbdf-2025-01-28T170000.000Z
reference_title: "SFTPA1 / interstitial lung disease 1 (Moderate)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
SP-A binds specific carbohydrate moieties found on lipids and on the
surface of microorganisms, playing an essential role in the defense
against respiratory pathogens
explanation: >-
ClinGen's summary of SP-A function supports the carbohydrate-binding
molecular function, the activity of the domain in which every reported
ILD1 variant lies.
- reference: PMID:26792177
reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mutation (p.Trp211Arg), which segregates with a disease phenotype
characterized by either isolated IIP/IPF, or IPF associated with lung
adenocarcinoma, is located in the carbohydrate recognition domain (CRD)
of SP-A1 and involves a residue invariant throughout evolution
explanation: >-
The founding p.Trp211Arg variant lies in the CRD at an evolutionarily
invariant residue.
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This variant encodes the substitution p.(Val178Met), localized within the
carbohydrate recognition domain of surfactant protein A
explanation: >-
A second family's variant also lies in the CRD.
- reference: CGGV:assertion_3c3d8e40-6ec1-4fb0-8a30-ce4f1e33dbdf-2025-01-28T170000.000Z
reference_title: "SFTPA1 / interstitial lung disease 1 (Moderate)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Variants reported in this gene are all missense variants in exon 6
encoding the carbohydrate-binding domain, which do not affect the
expression of the protein but interfere with its secretion.
explanation: >-
ClinGen's summary of all reported variants: missense, exon 6, CRD.
downstream:
- target: Defective SP-A1 Secretion From Alveolar Type II Cells
causal_link_type: DIRECT
description: >-
Each CRD missense variant tested in cells abolishes secretion of SP-A1
while leaving its production intact.
evidence:
- reference: PMID:26792177
reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
As shown through functional studies, the p.Trp211Arg mutation impairs
SP-A1 secretion.
explanation: >-
Cell-based functional assays link the p.Trp211Arg variant to impaired
secretion.
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: The mutation in SFTPA1 disturbed the secretion of SFTPA1 protein.
explanation: >-
The recessive p.Tyr208His variant also disturbs SP-A1 secretion in
expression studies.
- name: Defective SP-A1 Secretion From Alveolar Type II Cells
description: >-
Mutant SP-A1 is produced but is not secreted from the cell, and patient
alveolar epithelium shows an altered, largely intracellular SP-A staining
pattern. The mutant protein can still associate with SP-A2, so wild-type
SP-A may also be retained, but a dominant-negative mechanism has not been
shown directly.
biological_scale: CELLULAR
cell_types:
- preferred_term: alveolar type II cell
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
biological_processes:
- preferred_term: protein secretion
term:
id: GO:0009306
label: protein secretion
modifier: DECREASED
genes:
- preferred_term: SFTPA1
term:
id: hgnc:10798
label: SFTPA1
evidence:
- reference: PMID:32855221
reference_title: Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for
SP-A secretion in cell models and in lung tissue immunostaining
explanation: >-
In this series production was preserved but secretion abolished for all
11 variants tested in cell models. The variants include both SFTPA1 and
SFTPA2 alleles; the tissue immunostaining is covered by the separate
human item below.
- reference: PMID:26792177
reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Immunohistochemistry studies on patient alveolar epithelium showed an altered SP-A expression pattern.
explanation: >-
Altered SP-A immunostaining in alveolar epithelium of a p.Trp211Arg
carrier.
downstream:
- target: Alveolar Type II Cell Endoplasmic Reticulum Stress
causal_link_type: DIRECT
description: >-
In Sftpa1 p.Tyr208His knock-in mice, secretion but not intracellular
expression of SP-A1 was disturbed and ER stress was induced in type II
cells. Whether dominant alleles act the same way has not been tested.
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
As the secretion but not intracellular expression of Sftpa1 was
disturbed in Sftpa1-KI mice, we sought to determine whether ER stress
was induced in Sftpa1-KI mice.
explanation: >-
The authors test ER stress as the consequence of intracellular
retention of non-secreted SP-A1 and then find it; the retention-to-ER
stress link is their reasoning rather than a separate experiment.
- reference: PMID:38575158
reference_title: High risk of lung cancer in surfactant-related gene variant carriers.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
snippet: >-
Dominant-negative SFTPC BRICHOS variants as well as SFTPA1 and SFTPA2
variants may be considered toxic gain-of-function variants resulting
in endoplasmic reticulum stress
explanation: >-
Discussion-level synthesis that SFTPA1 variants act through ER stress;
stated as a hypothesis, citing other work.
- name: Alveolar Type II Cell Endoplasmic Reticulum Stress
description: >-
Retained mutant SP-A1 is accompanied by ER stress in type II cells, with
increased IRE1alpha phosphorylation. Shown only in the homozygous
p.Tyr208His knock-in mouse.
biological_scale: CELLULAR
cell_types:
- preferred_term: alveolar type II cell
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
biological_processes:
- preferred_term: IRE1-mediated unfolded protein response
term:
id: GO:0036498
label: IRE1-mediated unfolded protein response
modifier: INCREASED
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: ER stress was induced in AEII cells in Sftpa1-KI mice, resulting in activation of the JNK-Ripk3 pathway.
explanation: ER stress in type II cells of the knock-in mouse.
downstream:
- target: JNK-Mediated RIPK3 Upregulation
causal_link_type: DIRECT
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We also found that increased phosphorylation of IRE1α (a component of
ER stress responses) led to phosphorylation of JNK in AEII cells in
Sftpa1-KI mice, which up-regulated Ripk3.
explanation: >-
IRE1alpha activation leads to JNK phosphorylation and Ripk3
upregulation in knock-in type II cells.
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: ER stress was induced in AEII cells in Sftpa1-KI mice, resulting in activation of the JNK-Ripk3 pathway.
explanation: States the ER stress to JNK-Ripk3 link directly.
- name: JNK-Mediated RIPK3 Upregulation
description: >-
JNK activation downstream of IRE1alpha raises Ripk3 expression in type II
cells. A JNK inhibitor reduced fibrosis in knock-in mice, and forced Ripk3
expression reversed that benefit.
biological_scale: CELLULAR
cell_types:
- preferred_term: alveolar type II cell
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
biological_processes:
- preferred_term: JNK cascade
term:
id: GO:0007254
label: JNK cascade
modifier: INCREASED
genes:
- preferred_term: RIPK3
term:
id: hgnc:10021
label: RIPK3
modifier: INCREASED
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The inhibition of JNK ameliorated pulmonary fibrosis in Sftpa1-KI mice,
and overexpression of Ripk3 in Sftpa1-KI mice treated with a JNK
inhibitor worsened pulmonary fibrosis.
explanation: >-
Pharmacological and genetic manipulation places JNK upstream of Ripk3 in
the knock-in mouse.
downstream:
- target: Alveolar Type II Cell Necroptosis
causal_link_type: DIRECT
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
JNK signaling in AEII cells up-regulated Ripk3 expression, leading to
an increased sensitivity to necroptosis in AEII cells, which
contributed to the development of pulmonary fibrosis.
explanation: States that JNK-driven Ripk3 upregulation sensitizes type II cells to necroptosis.
- name: Alveolar Type II Cell Necroptosis
description: >-
Type II cells in knock-in mice die by RIPK3- and MLKL-dependent
necroptosis rather than apoptosis: active caspase-3 was not increased, and
deleting Ripk3 or Mlkl protected against fibrosis. Increased
phosphorylated MLKL was seen in type II cells of one homozygous patient.
biological_scale: CELLULAR
cell_types:
- preferred_term: alveolar type II cell
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
biological_processes:
- preferred_term: necroptotic process
term:
id: GO:0070266
label: necroptotic process
modifier: INCREASED
genes:
- preferred_term: MLKL
term:
id: hgnc:26617
label: MLKL
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: The deletion of Ripk3 or Mlkl from Sftpa1-KI mice ameliorated the pulmonary fibrosis, indicating that necroptosis is involved in cell death.
explanation: Genetic epistasis in the knock-in mouse places necroptosis in the pathway.
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
To assess whether necroptosis was enhanced in IPF patients with SFTPA1
mutations, we evaluated a patient's expression of phosphorylated MLKL.
Although we could assess a lung specimen from only one patient, we
detected increased levels of phosphorylated MLKL expression in AEII
cells of the IPF patient
explanation: >-
A single patient lung specimen shows the necroptosis marker in type II
cells; the authors note the sample size.
downstream:
- target: Progressive Fibrotic Remodeling of the Distal Lung
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Loss of type II cells by necroptosis is followed by collagen
accumulation, hypoxaemia and death in knock-in mice; the steps between
epithelial death and fibroblast activation were not dissected.
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In the present study, although we did not evaluate the roles of RIPK1,
deletion of Ripk3 or Mlkl suppressed the progression of pulmonary
fibrosis in Sftpa1-KI mice, demonstrating that RIPK3-mediated MLKL
activation is a crucial determinant for pulmonary fibrosis in Sftpa1-KI
mice.
explanation: >-
Blocking necroptosis suppresses fibrosis progression, supporting a
causal edge from necroptosis to fibrosis in the model.
- target: Pulmonary fibrosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Type II cell necroptosis contributes to the pulmonary fibrosis of the
knock-in mouse.
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: The deletion of Ripk3 or Mlkl from Sftpa1-KI mice ameliorated the pulmonary fibrosis, indicating that necroptosis is involved in cell death.
explanation: >-
Removing the necroptosis machinery reduces pulmonary fibrosis in the
knock-in mouse.
- name: Progressive Fibrotic Remodeling of the Distal Lung
description: >-
Collagen accumulates in the lung parenchyma, distorting the alveolar
architecture. In patients this appears as idiopathic interstitial
pneumonia with usual or nonspecific interstitial pneumonia patterns; in
knock-in mice, Col1a1 mRNA and lung hydroxyproline rise with age.
biological_scale: TISSUE
cell_types:
- preferred_term: lung fibroblast
term:
id: CL:0002553
label: fibroblast of lung
biological_processes:
- preferred_term: collagen metabolic process
term:
id: GO:0032963
label: collagen metabolic process
modifier: INCREASED
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as
patients spontaneously developed pulmonary fibrosis that was accelerated
by influenza virus infection.
explanation: >-
Knock-in mice develop spontaneous fibrosis; the paper measures it as
rising lung Col1a1 mRNA and hydroxyproline with age.
- reference: PMID:26792177
reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mutation (p.Trp211Arg), which segregates with a disease phenotype
characterized by either isolated IIP/IPF, or IPF associated with lung
adenocarcinoma
explanation: Human carriers develop fibrosing interstitial pneumonia.
downstream:
- target: Nonspecific interstitial pneumonia
causal_link_type: DIRECT
description: >-
In the p.Val178Met proband the fibrosis took a nonspecific interstitial
pneumonia pattern on biopsy.
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Video-assisted thoracoscopic (VATS) lung biopsy revealed pulmonary
fibrosis with a nonspecific interstitial pneumonia pattern.
explanation: The biopsy shows the fibrosis expressed as an NSIP pattern.
- target: Respiratory insufficiency
causal_link_type: DIRECT
description: >-
Progressive fibrosis, with acute exacerbation, ends in fatal respiratory
failure.
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: He died of respiratory failure due to acute exacerbation of pulmonary fibrosis 11 years after diagnosis.
explanation: Attributes the proband's fatal respiratory failure to exacerbation of his fibrosis.
phenotypes:
- name: Pulmonary fibrosis
category: Respiratory
description: >-
Fibrosing lung disease, frequently meeting criteria for idiopathic
pulmonary fibrosis, is the core manifestation in both dominant and
recessive families.
phenotype_term:
preferred_term: Pulmonary fibrosis
term:
id: HP:0002206
label: Pulmonary fibrosis
evidence:
- reference: PMID:26792177
reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall, this first report of a germline molecular defect in SFTPA1
unveils the key role of SP-A1 in the occurrence of several chronic
respiratory diseases, ranging from severe respiratory insufficiency
occurring early in life to the association of lung fibrosis and cancer
in adult patients.
explanation: Lung fibrosis in adult carriers of the p.Trp211Arg family.
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Here, we show that a homozygous missense mutation in SFTPA1 caused IPF in a consanguineous Japanese family.
explanation: Idiopathic pulmonary fibrosis in the homozygous family.
- name: Interstitial pneumonitis
category: Respiratory
description: >-
Idiopathic interstitial pneumonia is the clinical label under which most
families were ascertained.
phenotype_term:
preferred_term: Idiopathic interstitial pneumonia
term:
id: HP:0006515
label: Interstitial pneumonitis
evidence:
- reference: PMID:26792177
reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mutation (p.Trp211Arg), which segregates with a disease phenotype
characterized by either isolated IIP/IPF, or IPF associated with lung
adenocarcinoma
explanation: Idiopathic interstitial pneumonia segregates with p.Trp211Arg.
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Here, we report a novel, rare SFTPA1 variant in a family with idiopathic interstitial pneumonia (IIP).
explanation: Idiopathic interstitial pneumonia in the p.Val178Met family.
- name: Usual interstitial pneumonia
category: Respiratory
description: >-
A usual interstitial pneumonia pattern was found on biopsy in the
p.Val178Met family and is the predominant histological pattern across
adults with surfactant-gene ILD.
phenotype_term:
preferred_term: Usual interstitial pneumonia
term:
id: HP:0031950
label: Usual interstitial pneumonia
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, a VATS lung biopsy and histological examination revealed a
pattern of typical interstitial pneumonia.
explanation: >-
Biopsy of the proband's mother showed a typical (usual) interstitial
pneumonia pattern.
- reference: PMID:42784242
reference_title: "Adulthood interstitial lung disease due to variants in surfactant related genes: A systematic review."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: usual interstitial pneumonia was the predominant histological pattern except in ABCA3-related disease
explanation: >-
Pooled review of 162 adults with surfactant-gene variants, 61 of them in
SFTPA1 or SFTPA2; the pattern is not broken out by gene in the abstract.
- name: Nonspecific interstitial pneumonia
category: Respiratory
description: >-
A nonspecific interstitial pneumonia pattern was found on biopsy of the
p.Val178Met proband, showing that histology varies within one family.
phenotype_term:
preferred_term: Nonspecific interstitial pneumonia
term:
id: HP:0033584
label: Nonspecific interstitial pneumonia
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Video-assisted thoracoscopic (VATS) lung biopsy revealed pulmonary
fibrosis with a nonspecific interstitial pneumonia pattern.
explanation: NSIP pattern on the proband's biopsy.
- name: Ground-glass opacification
category: Respiratory
phenotype_term:
preferred_term: Ground-glass opacities on HRCT
term:
id: HP:0025179
label: Ground-glass opacification
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
High-resolution computed tomography (HRCT) of the patient's chest showed
interlobular septal thickening and ground glass opacities, especially in
the lower lung areas
explanation: Ground-glass opacities on the proband's HRCT.
- name: Interlobular septal thickening
category: Respiratory
phenotype_term:
preferred_term: Interlobular septal thickening
term:
id: HP:0030879
label: Interlobular septal thickening
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
An HRCT of her thorax showed ventral and dorsobasal subpleural
interlobular septal thickening.
explanation: Interlobular septal thickening in an affected carrier.
- name: Traction bronchiectasis
category: Respiratory
phenotype_term:
preferred_term: Traction bronchiectasis
term:
id: HP:0032969
label: Traction bronchiectasis
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Inter- and intralobular septal thickening and irregular reticular lines
(blue arrows), ground glass opacities arrows, and crazy paving and
traction bronchiectasis without honeycombing (red arrows) are shown
explanation: >-
Figure legend describing traction bronchiectasis on chest HRCT of the
p.Val178Met proband and his mother.
- name: Restrictive ventilatory defect
category: Respiratory
phenotype_term:
preferred_term: Restrictive ventilatory defect
term:
id: HP:0002091
label: Restrictive ventilatory defect
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Lung function testing showed a restrictive syndrome with a mild reduction in diffuse lung capacity.
explanation: Restrictive physiology in the proband.
- name: Decreased DLCO
category: Respiratory
phenotype_term:
preferred_term: Reduced diffusing capacity
term:
id: HP:0045051
label: Decreased DLCO
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Lung function testing showed a restrictive syndrome with a mild reduction in diffuse lung capacity.
explanation: Mildly reduced diffusing capacity in the proband.
- name: Dyspnea
category: Respiratory
phenotype_term:
preferred_term: Dyspnea
term:
id: HP:0002094
label: Dyspnea
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The proband presented with dyspnea and a dry cough.
explanation: Dyspnea in a heterozygous p.Val178Met proband.
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The youngest brother also began to develop dyspnea at the age of 40 yr.
explanation: Dyspnea in a homozygous p.Tyr208His patient.
- name: Cough
category: Respiratory
phenotype_term:
preferred_term: Dry cough
term:
id: HP:0031246
label: Nonproductive cough
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The proband presented with dyspnea and a dry cough.
explanation: Dry cough in the proband.
- name: Clubbing
category: Musculoskeletal
phenotype_term:
preferred_term: Digital clubbing
term:
id: HP:0001217
label: Clubbing
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: (II-2), a nonsmoker with digital clubbing, developed dyspnea at the age of 44 years.
explanation: Digital clubbing in an affected heterozygous carrier.
- name: Respiratory insufficiency
category: Respiratory
description: >-
Disease can cause severe respiratory insufficiency in infancy and fatal
respiratory failure in adults, sometimes after an acute exacerbation.
phenotype_term:
preferred_term: Respiratory insufficiency
term:
id: HP:0002093
label: Respiratory insufficiency
evidence:
- reference: PMID:26792177
reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall, this first report of a germline molecular defect in SFTPA1
unveils the key role of SP-A1 in the occurrence of several chronic
respiratory diseases, ranging from severe respiratory insufficiency
occurring early in life to the association of lung fibrosis and cancer
in adult patients.
explanation: Early-life respiratory insufficiency within the SFTPA1 spectrum.
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: He died of respiratory failure due to acute exacerbation of pulmonary fibrosis 11 years after diagnosis.
explanation: Fatal respiratory failure in an adult carrier.
- name: Lung adenocarcinoma
category: Neoplasm
description: >-
Lung adenocarcinoma occurs in carriers and their relatives, sometimes
diagnosed together with the fibrosis. Smoking strongly raises
the odds, and four of the seven SFTPA1-associated cancers in that cohort
came from one family, so the cancer risk of an individual SFTPA1 variant is
not known. No frequency is given because the available counts come from
referral cohorts.
phenotype_term:
preferred_term: Lung adenocarcinoma
term:
id: HP:0030078
label: Lung adenocarcinoma
evidence:
- reference: PMID:26792177
reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mutation (p.Trp211Arg), which segregates with a disease phenotype
characterized by either isolated IIP/IPF, or IPF associated with lung
adenocarcinoma
explanation: Lung adenocarcinoma is part of the segregating phenotype in the founding family.
- reference: PMID:38575158
reference_title: High risk of lung cancer in surfactant-related gene variant carriers.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified 99 SRG adult variant carriers (SFTPA1 (n=18), SFTPA2
(n=31), SFTPC (n=24), ABCA3 (n=14) and NKX2-1 (n=12)), including 20
(20.2%) with lung cancer (SFTPA1 (n=7), SFTPA2 (n=8), SFTPC (n=3), NKX2-1
(n=2) and ABCA3 (n=0)).
explanation: Seven of 18 adult SFTPA1 carriers in the OrphaLung cohort had lung cancer.
- reference: PMID:38575158
reference_title: High risk of lung cancer in surfactant-related gene variant carriers.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The association of SRG mutations and lung cancer in this cohort may be
driven by a few highly penetrant variants in addition to unmeasured
environmental exposures because four out of seven SFTPA1-associated lung
cancer cases belonged to the same family.
explanation: >-
The authors caution that the SFTPA1 cancer count is concentrated in one
family, which limits generalising the risk to every variant.
genetic:
- name: SFTPA1
gene_term:
preferred_term: SFTPA1
term:
id: hgnc:10798
label: SFTPA1
association: Defining gene; ClinGen Moderate for autosomal dominant ILD1
variant_origin: GERMLINE
gene_disease_validity:
- validity_classification: MODERATE
classified_by: CLINGEN
external_id: CGGV:assertion_3c3d8e40-6ec1-4fb0-8a30-ce4f1e33dbdf-2025-01-28T170000.000Z
evidence:
- reference: CGGV:assertion_3c3d8e40-6ec1-4fb0-8a30-ce4f1e33dbdf-2025-01-28T170000.000Z
reference_title: "SFTPA1 / interstitial lung disease 1 (Moderate)"
supports: SUPPORT
evidence_source: OTHER
snippet: "SFTPA1 | HGNC:10798 | interstitial lung disease 1 | MONDO:0030608 | AD | Moderate"
explanation: >-
ClinGen Interstitial Lung Disease GCEP classifies SFTPA1 and
autosomal dominant ILD1 as Moderate.
notes: >-
relationship_type is deliberately left unset. The schema defines CAUSATIVE
as ClinGen Definitive or Strong, and ClinGen rates this pair Moderate. Common
SP-A1 haplotypes and polymorphisms studied in association analyses are not
evidence for this Mendelian disease and are not recorded here.
variants:
- name: SFTPA1 p.Trp211Arg
description: >-
Heterozygous CRD missense variant carried by nine members of a
multigenerational French family with IIP/IPF and lung adenocarcinoma;
impairs SP-A1 secretion.
evidence:
- reference: PMID:26792177
reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mutation (p.Trp211Arg), which segregates with a disease phenotype
characterized by either isolated IIP/IPF, or IPF associated with lung
adenocarcinoma
explanation: Segregation of p.Trp211Arg with disease.
- name: SFTPA1 c.532G>A (p.Val178Met)
description: >-
Heterozygous CRD missense variant found by exome sequencing in a Czech
family with autosomal dominant idiopathic interstitial pneumonia.
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A heterozygous single nucleotide variant c.532 G > A in the SFTPA1 gene has been identified.
explanation: Identification of the variant in the affected family.
- name: SFTPA1 c.622T>C (p.Tyr208His)
description: >-
Homozygous variant in three brothers of a consanguineous Japanese family,
two of whom were diagnosed with IPF in their twenties. The basis of the
Sftpa1 knock-in mouse model. ClinGen did not score this family.
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a single Japanese family with consanguineous marriage, two of the
sons were diagnosed with IPF at the ages of 24 and 27 yr and died at 32
and 34 yr, respectively
explanation: Early-onset fatal IPF in the homozygous brothers.
evidence:
- reference: PMID:26792177
reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall, this first report of a germline molecular defect in SFTPA1
unveils the key role of SP-A1 in the occurrence of several chronic
respiratory diseases
explanation: First report establishing germline SFTPA1 variants as a cause of lung disease.
- reference: PMID:32855221
reference_title: Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Interstitial lung diseases (ILDs) can be caused by mutations in the
SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex
SP-A.
explanation: Independent cohort confirming SFTPA1 as an ILD gene.
environmental:
- name: Influenza A virus infection
description: >-
In Sftpa1 p.Tyr208His knock-in mice, influenza A infection accelerated
fibrosis and death without changing viral susceptibility. Not studied in
patients.
exposure_term:
preferred_term: exposure to influenza A virus
term:
id: ECTO:3000107
label: exposure to Influenza A virus
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as
patients spontaneously developed pulmonary fibrosis that was accelerated
by influenza virus infection.
explanation: Influenza infection accelerates fibrosis in the knock-in mouse.
influences_mechanisms:
- target: Alveolar Type II Cell Necroptosis
environmental_effect: EXACERBATES
causal_link_type: DIRECT
description: >-
After influenza infection, deleting Ripk3 normalised type II cell death
in knock-in mice.
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In Sftpa1-KI; Ripk3−/− mice, the number of AEII cells positive for 7AAD
after infection with IAV was equivalent to the WT
explanation: >-
Infection-induced type II cell death in knock-in mice depends on Ripk3,
placing the infection effect on the necroptosis node.
- name: Tobacco smoking
description: >-
Smoking was strongly associated with lung cancer among adult carriers of
surfactant-related gene variants. The estimate pools SFTPA1, SFTPA2,
SFTPC, ABCA3 and NKX2-1 carriers.
exposure_term:
preferred_term: tobacco smoking
term:
id: ECTO:6000029
label: exposure to tobacco smoking
evidence:
- reference: PMID:38575158
reference_title: High risk of lung cancer in surfactant-related gene variant carriers.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among SRG variant carriers, the odds of lung cancer was associated with
age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2) and
SFTPA1/SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2).
explanation: Smoking is associated with lung cancer among surfactant-gene variant carriers.
influences_mechanisms:
- target: Lung adenocarcinoma
environmental_effect: PREDISPOSES
description: >-
Association with lung cancer among surfactant-gene carriers; no
mechanism was studied.
evidence:
- reference: PMID:38575158
reference_title: High risk of lung cancer in surfactant-related gene variant carriers.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among SRG variant carriers, the odds of lung cancer was associated with
age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2)
and SFTPA1/SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2).
explanation: >-
Smoking is associated with higher odds of lung cancer among
surfactant-gene variant carriers (pooled across genes).
diagnosis:
- name: Surfactant gene sequencing
description: >-
Diagnosis rests on finding a germline SFTPA1 CRD missense variant in a
person with fibrosing ILD, typically by exome or panel sequencing with
Sanger confirmation and family segregation testing.
diagnosis_term:
preferred_term: whole exome sequencing
term:
id: NCIT:C101295
label: Whole Exome Sequencing
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The c.532 G > A variant was further validated using Sanger sequencing of
the amplicons, confirming the diagnosis in all symptomatic family
members.
explanation: Exome sequencing with Sanger confirmation established the diagnosis in the family.
- reference: PMID:32855221
reference_title: Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In the framework of ILD molecular diagnosis, we identified 14
independent patients with pathogenic SFTPA1 or SFTPA2 mutations.
explanation: SFTPA1 variants are found through routine ILD molecular diagnosis.
- name: High-resolution chest CT
description: >-
HRCT shows ground-glass opacities, septal thickening, reticulation and
traction bronchiectasis.
diagnosis_term:
preferred_term: high-resolution computed tomography of the chest
term:
id: NCIT:C20644
label: High Resolution Computed Tomography
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
High-resolution computed tomography (HRCT) of the patient's chest showed
interlobular septal thickening and ground glass opacities, especially in
the lower lung areas
explanation: HRCT findings in an SFTPA1 proband.
- name: Pulmonary function testing
description: >-
Spirometry and gas-transfer measurement show a restrictive defect with
reduced diffusing capacity.
diagnosis_term:
preferred_term: pulmonary function test
term:
id: NCIT:C38081
label: Pulmonary Function Test
evidence:
- reference: PMID:30854216
reference_title: A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Lung function testing showed a restrictive syndrome with a mild reduction in diffuse lung capacity.
explanation: Pulmonary function findings in the p.Val178Met proband.
treatments:
- name: Lung Transplantation
description: >-
Transplantation is the treatment for end-stage disease. In a French
multicentre series, recipients with an SFTPA1 variant survived better
after transplantation than recipients with other surfactant-gene
variants. Some SFTPA1 recipients had lung cancer before transplantation,
so cancer needs to be looked for.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: lung transplantation
term:
id: NCIT:C15274
label: Lung Transplantation
target_mechanisms:
- target: Respiratory insufficiency
evidence:
- reference: PMID:38020562
reference_title: Outcome of lung transplantation for adults with interstitial lung disease associated with genetic disorders of the surfactant system.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In our study, survival of lung transplant recipients with a SFTPA1
mutation was found significantly better compared to patients with other
genes involved, whereas the demographics were similar regarding age at
diagnosis and ILD histological pattern.
explanation: >-
Post-transplant survival of SFTPA1 recipients in the French series (five
SFTPA1 recipients, none of whom died during follow-up).
- reference: PMID:38020562
reference_title: Outcome of lung transplantation for adults with interstitial lung disease associated with genetic disorders of the surfactant system.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Lung transplantation in adults with interstitial lung disease associated
with genetic disorders of surfactant system may be a valid therapeutic
option.
explanation: Authors' conclusion for SFTPA1, SFTPA2 and SFTPC recipients together.
- reference: PMID:38020562
reference_title: Outcome of lung transplantation for adults with interstitial lung disease associated with genetic disorders of the surfactant system.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Two unrelated patients with a SFTPA1 mutation had a personal history of lung cancer before LTx.
explanation: Supports the cancer-screening caveat in the treatment description.
animal_models:
- name: Sftpa1 p.Tyr208His knock-in mouse (Sftpa1-KI)
species: Mouse
genotype: Sftpa1 Y208H knock-in, homozygous
publication: PMID:31601679
description: >-
Homozygous knock-in of the patient variant. Mice spontaneously develop
age-dependent pulmonary fibrosis, accelerated by influenza A infection,
with type II cell necroptosis.
modeled_mechanisms:
- target: Alveolar Type II Cell Necroptosis
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
limitations: >-
Models only the homozygous recessive allele; the necroptosis pathway has
not been tested for the heterozygous dominant alleles that account for
most ILD1 families, and human support is one patient's lung specimen.
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Sftpa1-KI mice showed increased necroptosis of alveolar epithelial type
II (AEII) cells with phosphorylation of IRE1α leading to JNK-mediated
up-regulation of Ripk3.
explanation: Type II cell necroptosis in the knock-in mouse.
- target: Progressive Fibrotic Remodeling of the Distal Lung
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
limitations: >-
Homozygous recessive allele only; whether heterozygous mice develop
fibrosis is not reported.
evidence:
- reference: PMID:31601679
reference_title: A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as
patients spontaneously developed pulmonary fibrosis that was
accelerated by influenza virus infection.
explanation: Spontaneous pulmonary fibrosis in the knock-in mouse.
notes: >-
Entry type: a standalone gene-defined disease (OMIM 619611, MONDO:0030608)
rather than a subtype of idiopathic pulmonary fibrosis. Its phenotype extends
beyond IPF to infant-onset respiratory insufficiency, nonspecific
interstitial pneumonia and lung adenocarcinoma, and ClinGen curates it as a
distinct gene-disease pair. Idiopathic_Pulmonary_Fibrosis records SFTPA1 as
a rare familial subset gene, which is consistent with this entry.
SFTPA2-related familial pulmonary fibrosis is a separate MONDO disease; it is
mentioned here only where a cited cohort pools SFTPA1 and SFTPA2 carriers,
and those items say so. The necroptosis chain (ER stress, JNK, RIPK3, MLKL)
comes from the homozygous p.Tyr208His mouse and has not been shown for
dominant alleles. No edge to lung adenocarcinoma is drawn because no cited
source establishes the mechanism linking the secretion defect to cancer.
Causal edges from the fibrotic remodeling node are drawn only where a cited
source states the link (NSIP pattern, fatal respiratory failure); the
imaging, physiological and symptom phenotypes are recorded without an
inbound edge because the SFTPA1 case reports describe them but do not
attribute them to a mechanism.
No GeneReviews chapter is titled for ILD1 or SFTPA1. The Pulmonary Fibrosis
Predisposition Overview (PMID:20301408) covers surfactant genes generally,
and its PubMed record holds only a statement of purpose, so it is not cited
as evidence.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Interstitial_Lung_Disease_1 · 2026-10-15T15:20:22Z · View source
Curated SFTPA1-defined interstitial lung disease 1 (MONDO:0030608, OMIM 619611) as a standalone gene-defined Disease, not an IPF subtype: the phenotype spans infant-onset respiratory insufficiency, NSIP/UIP and lung adenocarcinoma, and ClinGen curates the pair separately (Moderate, autosomal dominant only). Deep research: Perplexity sonar-deep-research run at reasoning_effort=low, because default-effort requests were repeatedly cut off. Its reference validation resolved 12/12 identifiers. The five CL/DOID terms its term validation lists as mislabelled are table-column artefacts (role text read as labels); it also cites the obsolete GO:0045045, which was not used. The body's bracketed citation numbers ([78], [83] and so on) do not match its 55-item citation list, so references were taken from the PMIDs named in the text and re-found in PubMed. just preflight-dr returned WARN only because SFTPA2 is mentioned at 32% of SFTPA1; those mentions come from cohorts that pool SFTPA1 and SFTPA2 carriers, so the report is about ILD1. GeneReviews: just check-genereviews returned NO_CHAPTER, offline and with --online. The Pulmonary Fibrosis Predisposition Overview (PMID:20301408) has no quotable text in its PubMed record and is not cited. Sources: Nathan 2016 (p.Trp211Arg family), Doubkova 2019 (p.Val178Met family, PMC full text), Takezaki 2019 (homozygous p.Tyr208His family and knock-in mouse; the ER stress, JNK, RIPK3 and MLKL necroptosis chain is graded MODEL_ORGANISM and noted as untested for dominant alleles), Legendre 2020 (pooled SFTPA1/SFTPA2 functional series), Brudon 2024 (OrphaLung lung cancer cohort), Bermudez 2023 (transplant series), Tirelli 2026 (systematic review), and the ClinGen CGGV assertion. relationship_type is left unset because ClinGen rates the pair Moderate. Lung adenocarcinoma has no inbound causal edge because no cited source establishes the mechanism. Not used: PMID:28869238 (Indian familial IPF case series; ClinGen counts it, but its abstract does not name the variant), common SP-A1 polymorphism association studies, SFTPA2-specific evidence, and antifibrotic drugs (no SFTPA1-specific evidence). The CGGV cache file was built by just fetch-reference from a ClinGen export newer than the MANIFEST pin. In a follow-up commit on the same branch, every downstream edge was given its own evidence that states the link, uncited edges from the fibrotic remodeling node to imaging, physiology and symptom phenotypes were removed (3 of 14 phenotypes now have an inbound causal edge), context-dependent snippets were replaced with self-contained sentences, and pulmonary function testing and a molecular-diagnosis item were added to diagnosis. Validation: just validate, just count-verified-snippets (68/68 verified), just validate-terms, the offline gates, and just validate-disorders.
Disease: Interstitial lung disease 1 (ILD1)
MONDO: MONDO:0030608
Defining gene: SFTPA1
OMIM phenotype: 619611
Inheritance: Usually autosomal dominant with incomplete, age-dependent penetrance; one autosomal-recessive family is established
Evidence base reviewed through: 15 October 2026
Scope note. ILD1 is the specific Mendelian surfactant-protein-A1 disorder caused by pathogenic germline variants in SFTPA1. It should not be conflated with the broad clinical category “interstitial lung disease,” with SFTPA2-associated ILD2, or with all familial pulmonary fibrosis.
Interstitial lung disease 1 is an exceptionally rare, predominantly lung-limited surfactant disorder whose clinical spectrum ranges from fatal infantile fibrosing interstitial pneumonia to adult-onset idiopathic interstitial pneumonia, usual interstitial pneumonia/idiopathic pulmonary fibrosis, respiratory failure, and lung adenocarcinoma. The phenotype can be absent in young carriers and is highly variable even within a family. OMIM maps ILD1 to SFTPA1 at 10q22.3 and recognizes both autosomal-dominant and autosomal-recessive inheritance. [1][31]
Disease-associated missense variants cluster in exon 6, which encodes the C-terminal carbohydrate-recognition domain of surfactant protein A1. The best-established variants are p.Val178Met, p.Tyr208His, p.Trp211Arg, and p.Val225Met. Functional studies consistently find preserved intracellular protein production but markedly reduced or absent extracellular secretion. In the recessive p.Tyr208His model, retained mutant protein activates an IRE1α–JNK–RIPK3–MLKL necroptosis pathway in alveolar type II cells, leading to epithelial loss, inflammation, collagen deposition, impaired gas exchange, and progressive fibrosis. Influenza A infection markedly accelerates this process in knock-in mice. [53][78][83]
No therapy is approved specifically for SFTPA1-associated ILD. Current practice extrapolates from IPF and progressive pulmonary fibrosis: avoidance of inhalational injury, vaccination, pulmonary rehabilitation, oxygen when indicated, antifibrotic therapy according to the radiologic/clinical phenotype, early lung-transplant referral, and unusually careful surveillance for lung cancer. In a 2023 transplant cohort, 20 adults with surfactant-gene ILD—including five with SFTPA1 variants—had a median post-transplant survival of 8.6 years, and none of the five SFTPA1 recipients died during reported follow-up. [91][92]
ILD1 is a monogenic disorder caused by germline pathogenic variants in SFTPA1, encoding surfactant protein A1, a collectin produced mainly by alveolar epithelial type II cells. Its defining pathology is progressive remodeling and fibrosis of the distal lung, variably expressed as idiopathic interstitial pneumonia, nonspecific interstitial pneumonia, usual interstitial pneumonia, or clinical IPF. Dyspnea, restrictive physiology, ground-glass or reticular abnormalities, reduced gas transfer, clubbing, respiratory failure, and lung adenocarcinoma may occur. [31]
The original molecular report described phenotypes “ranging from severe respiratory insufficiency occurring early in life to the association of lung fibrosis and cancer in adult patients.” The same study showed that p.Trp211Arg impairs SP-A1 secretion and alters SP-A distribution in alveolar epithelium (Nathan et al., 15 April 2016, PMID 26792177, DOI: 10.1093/hmg/ddw014). [46][47]
| Resource | Identifier/name | Qualification |
|---|---|---|
| MONDO | MONDO:0030608 — interstitial lung disease 1 | Preferred disease ontology identifier |
| OMIM phenotype | #619611 — Interstitial lung disease 1; ILD1 | Gene–phenotype relation to SFTPA1 |
| OMIM gene | *178630 — SFTPA1 | Surfactant protein A1 |
| DOID | DOID:0060941 | Interstitial lung disease 1 |
| MedGen | C5562021, UID 1794231 | ILD1; associated gene SFTPA1 |
| Orphanet cross-reference | ORPHA:2032 | Orphanet’s broader “idiopathic pulmonary fibrosis” entry, not a perfectly specific ILD1 concept |
| ICD-10 | J84.1 | Other interstitial pulmonary diseases with fibrosis; phenotype-level code, not gene-specific |
| ICD-11 | CB03.4 | Idiopathic pulmonary fibrosis; phenotype-level code |
| MeSH | D054990 — Idiopathic Pulmonary Fibrosis | Includes familial idiopathic pulmonary fibrosis as a narrower concept |
| MeSH broader term | D011658 — Pulmonary Fibrosis | Useful when phenotype is not formally IPF |
| UMLS/MedGen synonym | ILD1; Interstitial lung disease 1 | Specific disease synonyms |
OMIM explicitly records SFTPA1-associated ILD1 as autosomal dominant or autosomal recessive. Orphanet/ICD/MeSH cross-references generally point to the broader IPF phenotype and therefore have lower specificity than MONDO:0030608 or OMIM:619611. [166][168][173][176]
Common names: ILD1; SFTPA1-associated interstitial lung disease; SP-A1–related interstitial lung disease; SFTPA1-related pulmonary fibrosis; familial idiopathic interstitial pneumonia due to SFTPA1; familial IPF due to SFTPA1.
The evidence is chiefly aggregated disease-level evidence from:
It is not primarily an EHR-defined disease. The foundational literature comprises small, deeply phenotyped families rather than population-scale clinical records.
The primary cause is a germline pathogenic SFTPA1 variant. Most reported disease is associated with a heterozygous missense variant and dominant inheritance; homozygous p.Tyr208His produced severe recessive disease in one consanguineous Japanese family. [16][76]
SFTPA1 encodes a calcium-dependent C-type lectin/collectin involved in:
Expression is strongly enriched in alveolar type II cells. [153][154]
| Factor | Evidence and interpretation |
|---|---|
| Heterozygous pathogenic SFTPA1 variant | Principal cause of dominant ILD1; penetrance is incomplete and age dependent |
| Biallelic pathogenic SFTPA1 variant | Established for p.Tyr208His; associated with earlier, severe progressive IPF |
| Variant location in CRD | All variants in the major functional series occurred in exon 6 encoding the carbohydrate-recognition domain |
| Family history of ILD/IPF | Strong indication for testing; 11/14 probands in one SP-A cohort had a first-degree ILD history |
| Personal/family lung cancer | Particularly important for SFTPA1/SFTPA2 disorders |
| Age | Risk rises with age, although infantile disease is possible |
| Other familial pulmonary-fibrosis genes | TERT, TERC, RTEL1, PARN, SFTPA2, SFTPC, ABCA3 and others are differential causes, not proven ILD1 modifiers |
No reproducible ILD1-specific modifier gene has yet been established.
Evidence is suggestive rather than sufficient to calculate exposure-specific relative risks.
No ILD1-specific genetic or environmental protective factor is validated.
Reasonable risk-reduction measures include:
These measures reduce additional lung injury but have not been shown to prevent disease in genetically susceptible carriers.
The strongest experimental interaction is:
SFTPA1 p.Tyr208His → latent epithelial vulnerability → influenza A exposure → amplified IRE1α/JNK/RIPK3 signaling → accelerated alveolar type II-cell necroptosis and fibrosis.
In the human p.Trp211Arg family, marked variability among relatives exposed to tobacco or occupational environments led the authors to propose environmental contributions, but causality could not be separated from age-dependent penetrance and other genetic modifiers. [47]
Frequencies below are based on very small ascertainment-biased cohorts. The most detailed mixed SFTPA1/SFTPA2 cohort contained 28 carriers, so these figures are informative but not ILD1 population estimates.
| Phenotype | Type, onset and course | Frequency/evidence | Suggested HPO term |
|---|---|---|---|
| Interstitial lung disease | Clinical/radiologic disease; infancy through late adulthood; usually chronic progressive | Defining feature in symptomatic carriers | HP:0006530 Abnormal pulmonary interstitial morphology |
| Pulmonary fibrosis | Imaging/pathologic manifestation; progressive, variable severity | Core phenotype; listed for SFTPA1 | HP:0002206 Pulmonary fibrosis |
| Idiopathic pulmonary fibrosis/UIP | Clinical/pathologic subtype, predominantly adult | Seen in dominant and recessive families | HP:0002206; consider disease-level MONDO annotation |
| Dyspnea | Symptom; exertional initially, potentially at rest in advanced disease | Present in the recessive family and expected in progressive ILD | HP:0002094 Dyspnea |
| Chronic cough | Symptom; often dry | Typical fibrotic-ILD symptom, but not quantified specifically in ILD1 | HP:0012735 Cough |
| Restrictive ventilatory defect | Functional sign; progressive | Characteristic of fibrotic ILD; individual ILD1 values sparsely reported | HP:0002091 Restrictive ventilatory defect |
| Reduced diffusing capacity | Physiologic abnormality | Likely common in clinically manifest fibrosis; frequency unavailable | HP:0045051 Reduced pulmonary diffusing capacity |
| Hypoxemia | Laboratory/physiologic abnormality; advanced disease | Demonstrated in the mouse model and clinically expected with respiratory failure | HP:0012418 Hypoxemia |
| Ground-glass opacity | HRCT sign | 7/10 centrally reviewed SFTPA1/SFTPA2 probands, 70% | HP:0025179 Ground-glass opacification |
| Reticulation/interlobular septal thickening | HRCT sign | Reported across patients | HP:0030878 Interstitial pulmonary abnormality |
| Honeycombing | HRCT/pathology sign; advanced fibrosis | Reported but not universal | HP:0025180 Honeycomb lung |
| Bronchiectasis/traction bronchiectasis | Imaging manifestation | Reported in the SP-A cohort | HP:0002110 Bronchiectasis |
| Digital clubbing | Physical sign | Included in the ILD1 clinical definition; no reliable percentage | HP:0001217 Clubbing |
| Respiratory insufficiency/failure | Severe clinical manifestation | Fatal at nine months in one p.Trp211Arg infant; severe in advanced adults | HP:0002878 Respiratory failure |
| Recurrent bronchitis/infection | Symptom/complication | Seen in some carriers; SP-A has innate immune function | HP:0002837 Recurrent respiratory infections |
| Lung adenocarcinoma | Neoplastic complication | Strongly enriched in SFTPA1/SFTPA2 families | HP:0030358 Lung adenocarcinoma |
| Acute exacerbation | Complication | Documented cause of death in the broader SP-A cohort | HP:0033678 Acute exacerbation of interstitial lung disease |
| Asymptomatic carrier state | Clinical status | Seven of 28 SFTPA1/SFTPA2 carriers were asymptomatic; some had subclinical CT/PFT abnormalities | HP:0000001 All plus explicit “asymptomatic carrier” qualifier |
The 2020 SP-A cohort reported the following exact abstract statement:
“Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6–65 years) and 48% underwent lung transplantation.”
Seven carriers were asymptomatic. Ground-glass opacity and fibrosis were each present in 7/10 centrally reviewed CT scans; UIP, indeterminate-UIP, NSIP, hypersensitivity-pneumonitis-like, and pleuroparenchymal fibroelastosis patterns all occurred. [74][83]
No disease-specific EQ-5D, SF-36 or PROMIS study has been reported for ILD1. Expected burdens are those of progressive fibrotic ILD:
Pulmonary rehabilitation is used to improve exercise tolerance, symptoms and emotional well-being, although it does not reverse fibrosis. [129]
| Attribute | Value |
|---|---|
| Gene | SFTPA1 |
| Full name | Surfactant protein A1 |
| HGNC | HGNC:10798 |
| NCBI Gene | 653509 |
| Ensembl | ENSG00000122852 |
| OMIM gene | 178630 |
| UniProt | P07714 |
| Cytogenetic location | 10q22.3 |
| Major disease transcript used in initial reports | NM_005411.4 |
| Protein class | Secreted C-type lectin/collectin |
| Principal producing cell | Alveolar epithelial type II cell |
| Key domain | C-terminal carbohydrate-recognition domain |
| Variant | Origin/inheritance | Classification/evidence | Population frequency | Functional consequence |
|---|---|---|---|---|
| NM_005411.4:c.532G>A, p.(Val178Met), rs1215316727 | Germline, heterozygous AD | Reported as likely pathogenic; segregated in familial IIP | 1/250,994 alleles in the 2020 gnomAD analysis | Preserved cellular production, abolished secretion |
| c.622T>C, p.(Tyr208His) | Germline, homozygous AR; parents heterozygous | Pathogenic based on segregation, absence from reference databases and strong functional/model evidence | Absent from 1000 Genomes and ExAC in the discovery report | Secretion failure; IRE1α/JNK/RIPK3/MLKL necroptosis |
| NM_005411.4:c.631T>C, p.(Trp211Arg) | Germline, heterozygous AD | Pathogenic; cosegregation, conservation and functional secretion defect | Not reported in 1000 Genomes, EVS or ExAC at discovery | Absent extracellular secretion; abnormal lung SP-A staining |
| c.673G>A, p.(Val225Met) | Germline, heterozygous AD | Likely pathogenic in the 2020 functional series | Not described in gnomAD in that report | Preserved production, abolished secretion |
| c.655C>T, p.(Arg219Trp), rs4253527 | Germline polymorphism | Benign/common; was in cis with p.Trp211Arg but did not segregate independently with disease | Approximately 2–25% across older databases/populations | No detectable secretion defect; modifier role unproven |
Nathan et al. identified nine heterozygous p.Trp211Arg carriers in one extended pedigree. Disease onset ranged from 7 months to 69 years, and unaffected carriers demonstrated incomplete penetrance (PMID 26792177). [46][50]
Doubková et al. identified heterozygous c.532G>A, p.Val178Met by WES and Sanger confirmation in a three-generation Czech family (published 5 March 2019, PMID 30854216, DOI: 10.1038/s41439-019-0044-z). Its abstract states: “This variant encodes the substitution p.(Val178Met), localized within the carbohydrate recognition domain.” [61][64]
Takezaki et al. identified homozygous p.Tyr208His in three brothers from a consanguineous family (published 10 October 2019, PMID 31601679, DOI: 10.1084/jem.20182351). [78]
For dominant alleles, the precise mechanism may combine:
A universal dominant-negative mechanism has not been directly proven. In p.Tyr208His experiments, mutant SP-A1 associated intracellularly with wild-type SP-A1 or SP-A2, but these complexes were scarcely secreted, supporting a potential retention effect. [78]
| Category | Relevance to ILD1 |
|---|---|
| Tobacco smoke | Plausible accelerator and major independent lung-cancer risk; not necessary for disease |
| Silica, metal, cement, wood or mixed dust | Potential additive epithelial/fibrogenic injury; reported in individual carriers |
| Birds/avian antigen and mold | May complicate the radiologic differential with hypersensitivity pneumonitis |
| Air pollution | General fibrotic-lung-disease concern; no ILD1-specific effect size |
| Influenza A | Experimental accelerator of Sftpa1 p.Tyr208His fibrosis |
| Other viruses | No specific causal pathogen established |
| Diet/alcohol/exercise | No evidence that these cause ILD1; exercise training can preserve function but is not disease-preventive |
| Radiation/pneumotoxic drugs | Potential superimposed lung injury; no ILD1-specific susceptibility estimate |
ILD1 is not infectious and is not transmitted between people. Infection is a potential trigger or accelerator, not the Mendelian cause.
A germline SFTPA1 missense lesion in the carbohydrate-recognition domain leads to structurally or electrostatically abnormal SP-A1.
Abnormal SP-A1 leads to failure of secretion from alveolar epithelial type II cells, despite preserved intracellular protein synthesis.
Failed secretion leads to reduced/abnormally distributed SP-A at the alveolar surface and intracellular retention in type II pneumocytes.
Intracellular retention leads to ER stress and IRE1α phosphorylation; this step is demonstrated for p.Tyr208His in mice and inferred for several dominant variants.
Phosphorylated IRE1α leads to JNK activation, which leads to increased RIPK3 expression.
RIPK3 activation leads to MLKL phosphorylation and membrane-disruptive necroptosis of alveolar epithelial type II cells.
Type II-cell necroptosis leads to loss of epithelial integrity and regenerative capacity, release of inflammatory/damage signals, macrophage recruitment and fibroblast activation.
Fibroblast/myofibroblast activation leads to excessive extracellular-matrix and collagen deposition, alveolar-wall thickening, architectural distortion and honeycombing.
Fibrotic remodeling leads to restrictive physiology, reduced diffusion capacity, hypoxemia, dyspnea and respiratory failure.
Chronic epithelial injury and compensatory proliferation lead—by an incompletely demonstrated branch—to increased lung-adenocarcinoma risk.
A respiratory viral insult such as influenza A can branch at steps 4–7 and leads to accelerated ER stress, necroptosis and fibrosis in the p.Tyr208His mouse model.
SP-A is a multimeric collectin. Its carbohydrate-recognition domain binds microbial and lipid ligands in a calcium-dependent manner. SP-A participates in tubular-myelin/surfactant organization and innate immune defense. SFTPA1 is strongly enriched in alveolar type II cells, whereas secreted protein is present at the alveolar air–liquid interface and in alveolar macrophages. [153][154]
Normal pulmonary surfactant is predominantly lipid, with a smaller protein fraction. SP-A is not the principal surface-tension-lowering component—that function depends strongly on phospholipids and hydrophobic surfactant proteins—but it organizes surfactant and regulates host defense.
| Mechanism | Evidence level | Suggested ontology annotation |
|---|---|---|
| Defective protein secretion | Human cells, patient tissue | GO:0009306 protein secretion; GO:0046903 secretion |
| ER stress/unfolded-protein response | Mouse and cultured cells; inferred in dominant human disease | GO:0034976 response to endoplasmic reticulum stress; GO:0006986 response to unfolded protein |
| IRE1-mediated UPR | Mouse p.Tyr208His model | GO:0036498 IRE1-mediated unfolded protein response |
| JNK/MAPK signaling | Mouse intervention evidence | GO:0007254 JNK cascade; GO:0000165 MAPK cascade |
| RIPK3–MLKL necroptosis | Human tissue marker plus genetic mouse rescue | GO:0070266 necroptotic process |
| Type II pneumocyte death | Human and mouse | GO:0012501 programmed cell death |
| Inflammation and macrophage activation | Mouse/pathology evidence | GO:0006954 inflammatory response |
| Fibroblast activation/ECM deposition | Histology and mouse model | GO:0048144 fibroblast proliferation; GO:0030198 extracellular matrix organization |
| Collagen accumulation | Human fibrosis and mouse hydroxyproline/Col1a1 | GO:0032963 collagen metabolic process |
| Impaired gas exchange | Clinical downstream effect | GO:0007585 respiratory gaseous exchange |
| Cell type | Role | Suggested CL term |
|---|---|---|
| Alveolar epithelial type II cell | Primary SFTPA1-producing and injured cell | CL:0002063 |
| Alveolar epithelial type I cell | Secondary impairment through architectural destruction | CL:0002062 |
| Alveolar macrophage | Surfactant clearance, innate immunity and inflammation | CL:0000583 |
| Lung fibroblast | ECM synthesis and fibrosis | CL:0000057 fibroblast |
| Myofibroblast | Contractile collagen-producing effector | CL:0000186 |
| Pulmonary epithelial progenitor/transitional cell | Likely repair response; ILD1-specific single-cell evidence limited | Appropriate epithelial progenitor term |
The p.Tyr208His study supplied unusually strong causal evidence:
The authors’ abstract states that p.Tyr208His “promotes necroptosis of AEII cells through JNK-mediated up-regulation of Ripk3.” These are model-system findings, not an established human therapy. [78]
SP-A binds carbohydrates on microorganisms and modulates phagocytosis, cytokine production and reactive-oxygen responses. Loss or mislocalization may therefore alter innate immunity. Sftpa1-null mice show reduced resistance to respiratory infection and exaggerated inflammatory responses to lipopolysaccharide. [158]
No evidence supports a primary autoimmune etiology. Rheumatoid arthritis occurred in a minority of the combined SFTPA1/SFTPA2 cohort, but causality is uncertain.
| Scale | Affected structure | Suggested ontology |
|---|---|---|
| Organ | Lung, usually bilateral and diffuse | UBERON:0002048 lung |
| Functional unit | Pulmonary alveolus | UBERON:0002299 pulmonary alveolus |
| Tissue | Alveolar epithelium | UBERON:0003215 alveolar epithelium |
| Tissue | Pulmonary interstitium/alveolar septum | UBERON:0004893 lung interstitium where supported |
| Distal airway | Respiratory bronchiole; may show bronchiolar metaplasia | UBERON respiratory bronchiole term |
| Pleura/subpleural lung | In UIP/PPFE patterns | UBERON pleura/subpleural region |
| Cell | Alveolar epithelial type II cell | CL:0002063 |
| Subcellular | Endoplasmic reticulum | GO:0005783 |
| Subcellular | ER lumen/secretory pathway | GO:0005788, GO:0045045 |
| Subcellular | Extracellular/alveolar surfactant layer | GO:0005576 extracellular region |
| Subcellular | Plasma membrane during MLKL necroptosis | GO:0005886 plasma membrane |
Disease is normally bilateral, not unilateral. Secondary structures include pulmonary vasculature and the right ventricle if chronic hypoxemia causes pulmonary hypertension/cor pulmonale. Lung cancer represents a secondary but major organ-level complication.
Onset is exceptionally broad:
The combined SP-A cohort’s mean/median onset was approximately 45 years, range 0.6–65 years. [83]
| Stage | Typical manifestations |
|---|---|
| Genetically at risk/subclinical | No symptoms; normal or subtle HRCT/PFT findings |
| Early disease | Exertional dyspnea, cough, ground glass or fine reticulation; mild DLCO/FVC reduction |
| Established fibrotic ILD | Progressive reticulation, traction bronchiectasis, UIP/NSIP/indeterminate pattern |
| Advanced disease | Honeycombing, severe restriction, exertional/resting hypoxemia, oxygen dependence |
| End-stage | Respiratory failure, acute exacerbation, transplantation or death |
| Cancer branch | Lung adenocarcinoma may arise during fibrotic disease or occasionally dominate presentation |
The course is generally chronic and progressive but highly variable. Spontaneous durable remission is not documented. Treatment may slow progression but does not reverse established fibrosis.
The recessive family showed severe progression: two brothers diagnosed in their twenties died at 32 and 34, while the third developed dyspnea at 40. [76]
A 2025 penetrance analysis of combined SFTPA1/SFTPA2 pathogenic-variant carriers estimated 89.3% penetrance by age 80 for either ILD or lung cancer. This is not a pure ILD1 estimate and should not be applied uncritically to every SFTPA1 variant. [84]
No reliable prevalence, incidence or carrier-frequency estimate exists specifically for ILD1.
A diagnosis requires integration of:
| Test | Purpose/findings |
|---|---|
| HRCT chest | Ground glass, reticulation, septal thickening, traction bronchiectasis, honeycombing, UIP/NSIP/PPFE patterns and lung nodules/cancer |
| Spirometry | FVC decline and restrictive physiology |
| Lung volumes | Reduced total lung capacity |
| DLCO | Often reduced before severe restriction |
| Rest/exercise oximetry | Detect hypoxemia |
| Six-minute walk | Functional capacity and exertional desaturation |
| Arterial blood gas | Advanced respiratory failure |
| Echocardiography | Screen for pulmonary hypertension/right-heart strain |
| Autoimmune serology | ANA, ENA, RF/anti-CCP, myositis testing as clinically indicated |
| Exposure assessment | Smoking, occupational dust, birds, mold and drugs |
| Bronchoscopy/BAL | Selected cases; exclude infection or alternative diagnoses |
| Surgical/cryobiopsy | Only if imaging/genetics do not establish diagnosis and result would alter care |
| Histology | UIP, fibrosing NSIP or indeterminate fibrosis; hyperplastic pneumocytes with abnormal intracellular/discontinuous SP-A staining |
Routine serum SP-A, SP-D, KL-6 or MMP-7 may reflect epithelial injury in some jurisdictions but are not validated as specific ILD1 diagnostics.
The 2023 ERS familial pulmonary fibrosis statement recommends offering sequencing to patients with fibrotic ILD plus an affected first- or second-degree relative, a relative with a known pathogenic variant, suspected short-telomere syndrome, or idiopathic fibrosing ILD before age 50 (published 16 March 2023, PMID 36549714). Telomere- and surfactant-related genes should generally be included. [109][113]
Preferred workflow:
| Test | ILD1 utility |
|---|---|
| Single-gene SFTPA1 sequencing | Appropriate when a familial SFTPA1 variant is known or phenotype is highly specific |
| Multigene panel | Preferred first-line assay in most familial ILD |
| WES | Useful for panel-negative Mendelian disease; may miss deep intronic and some structural variants |
| WGS | Broadest SNV, indel, intronic and structural-variant coverage; interpretation remains limiting |
| CMA | Low yield unless syndromic developmental findings suggest a CNV |
| Karyotype/FISH | Not routinely indicated |
| mtDNA testing | Not routinely indicated |
| Repeat-expansion testing | Not relevant to known ILD1 |
| RNA sequencing | Research/variant-resolution role; potentially demonstrates altered splicing |
| Protein secretion assay | Research-level functional evidence for a missense VUS |
| Disorder | Distinguishing points |
|---|---|
| SFTPA2-associated ILD2 | Similar fibrosis/cancer phenotype; pathogenic variant in SFTPA2 |
| SFTPC-associated ILD | More frequent pediatric disease; pro-SP-C misfolding/processing abnormalities |
| ABCA3 deficiency | Usually recessive; neonatal respiratory distress or childhood ILD; lamellar-body defect |
| Telomere biology disorder | Premature greying, marrow failure, liver disease, short telomeres |
| Hermansky–Pudlak syndrome | Albinism and bleeding diathesis |
| Autoimmune ILD | Serologic/systemic rheumatologic features |
| Hypersensitivity pneumonitis | Relevant antigen exposure, air trapping/mosaic attenuation and BAL lymphocytosis |
| Occupational pneumoconiosis | Specific dust exposure and characteristic imaging/pathology |
| Sarcoidosis | Granulomas, nodal disease, extrapulmonary manifestations |
| Infection | Microbiologic evidence and acute/subacute course |
| Lymphangitic cancer | Nodular septal thickening and primary malignancy |
| Sporadic IPF | No pathogenic Mendelian variant or informative family history |
Prognosis ranges from lifelong asymptomatic carriage to fatal infantile disease or rapidly progressive adult IPF. Poor prognostic factors likely include:
No validated SFTPA1-specific prognostic calculator or biomarker exists.
In the combined 2020 SFTPA1/SFTPA2 cohort:
These results are affected by referral and severity ascertainment. [83]
The 2023 French transplant study included 20 surfactant-gene patients—SFTPA1 n=5, SFTPA2 n=7, SFTPC n=8:
The investigators concluded that transplantation “may be a valid therapeutic option” and emphasized cancer screening before and after transplant (PMID 38020562, published 20 November 2023). [91][92]
The latest major 2024 cohort of 99 carriers of surfactant-related variants found:
The authors called for specific ILD and lung-cancer surveillance in this relatively young population (published 2 May 2024). [97][100]
There is no genotype-specific approved treatment and no randomized trial confined to ILD1. Management should occur in a multidisciplinary ILD/genetics center.
| Intervention | Role and evidence | Suggested NCIT annotation |
|---|---|---|
| Pirfenidone | Standard antifibrotic for an IPF phenotype; ILD1-specific response unknown | NCIT: Pirfenidone; antifibrotic agent |
| Nintedanib | Antifibrotic for IPF and conditionally recommended for progressive pulmonary fibrosis after standard management | NCIT: Nintedanib; tyrosine kinase inhibitor |
| Supplemental oxygen | Resting or exertional hypoxemia | NCIT: Oxygen Therapy |
| Pulmonary rehabilitation | Exercise capacity, dyspnea coping and quality of life | NCIT: Pulmonary Rehabilitation |
| Vaccination | Reduce respiratory-infection burden | NCIT: Vaccination |
| Smoking cessation | Reduces additive epithelial and cancer injury | NCIT: Smoking Cessation |
| Lung transplantation | Definitive organ-replacement treatment for eligible end-stage disease | NCIT: Lung Transplantation |
| Palliative/supportive care | Dyspnea, anxiety, cough and advance-care planning | NCIT: Palliative Care |
| Cancer-directed treatment | Stage- and genotype-specific surgery/systemic/radiation therapy | Appropriate NCIT oncologic intervention terms |
The 2022 ATS/ERS/JRS/ALAT guideline conditionally recommends nintedanib for non-IPF progressive pulmonary fibrosis after failure of standard management and calls for further pirfenidone research in non-IPF PPF. Both pirfenidone and nintedanib remain appropriate for a patient meeting standard IPF indications, irrespective of SFTPA1 status, absent contraindication. [121][122]
In the 2020 SP-A cohort, some SFTPA1 patients received pirfenidone, nintedanib or unspecified antifibrotic therapy, but the sample was too small for a genotype-specific response rate. [83]
No approved gene, cell, RNA or CRISPR therapy exists for ILD1.
Potential research strategies include:
IRE1α/JNK/necroptosis interventions are supported only by the p.Tyr208His mouse model. They should not currently be used clinically outside a properly regulated trial. [78]
A 2023 review of personalized therapies for surfactant disorders emphasized gene-, RNA-, protein- and cell-based possibilities but did not identify an approved SFTPA1-directed therapy. [104]
No clinically actionable pharmacogenomic variant is established for antifibrotic choice in ILD1.
The inherited variant cannot currently be prevented after conception. Risk-reduction includes:
There is no proven population-wide screening program because ILD1 is ultra-rare.
After identification of a familial pathogenic variant:
For dominant disease, each child of a heterozygous carrier generally has a 50% transmission probability, but disease severity cannot be predicted reliably. For two heterozygous carriers of a recessive pathogenic allele, the classic per-pregnancy risks are 25% affected, 50% carrier and 25% non-carrier.
| Species | Taxon | Ortholog/model relevance |
|---|---|---|
| Human | NCBI Taxon 9606 | Natural ILD1; SFTPA1 NCBI Gene 653509 |
| House mouse | 10090 | Sftpa1 knockout and p.Tyr208His knock-in models; MGI:109518 |
| Norway rat | 10116 | Sftpa1 ortholog; surfactant and collectin biology |
| Dog | 9615 | Conserved SP-A biology; no established natural SFTPA1-ILD1 counterpart |
| Cat | 9685 | No established natural orthologous ILD1 |
| Other mammals | Various | SP-A structure and innate immune function are evolutionarily conserved |
MGI reports that homozygous Sftpa1-null mice have impaired responses to lung stress, reduced resistance to pulmonary infection and enhanced LPS-induced inflammation. [158]
Idiopathic pulmonary fibrosis occurs naturally in animals—most notably West Highland White Terriers—but a direct causal SFTPA1 ortholog variant equivalent to human ILD1 has not been established. Consequently:
| Model | Construction | Phenotype recapitulation | Main application | Limitation |
|---|---|---|---|---|
| Sftpa1 p.Tyr208His knock-in mouse | Targeted knock-in and independently CRISPR-generated line | Age-dependent spontaneous fibrosis, collagen accumulation, type II-cell loss, hypoxemia and mortality | Causal pathway and therapeutic-target studies | Models one recessive allele, not all dominant ILD1 |
| Influenza-challenged p.Tyr208His mouse | H3N2 exposure at 20 weeks | Rapid fibrosis and ∼70% mortality by day 28 despite similar viral titers | Gene–environment interaction | Acute experimental infection differs from human exposure history |
| Ripk3- or Mlkl-deficient knock-in mouse | Genetic epistasis | Rescue of fibrosis, oxygenation and survival | Establishes necroptosis causality | Whole-animal deletion; cell-specific effects incompletely resolved |
| JNK/IRE1α inhibitor mouse | SP600125 or KIRA6 | Reduced signaling and fibrosis | Preclinical pathway targeting | Compounds are not established ILD1 treatments |
| Sftpa1 knockout mouse | Targeted null | Infection susceptibility, exaggerated inflammation; enhanced fibrosis after injury | SP-A immune/homeostatic function | Does not reproduce secretion-defective missense toxicity |
| HEK293T expression system | Wild-type/mutant constructs | Preserved production, absent secretion | Variant functional classification | Non-pulmonary transformed cell line |
| A549 alveolar-like cells | Co-expression of SP-A1/SP-A2 constructs | Intracellular complex formation but failed mutant-complex secretion | Oligomerization/retention studies | Cancer line, not primary type II cells |
| Patient lung tissue | Biopsy/explant | Hyperplastic pneumocytes, intracellular/discontinuous SP-A, fibrosis; pMLKL in p.Tyr208His case | Human validation | Very limited number of samples |
| Future iPSC/organoid model | Patient-derived or engineered | Not yet standardized | Precision rescue and drug screening | Maturity and surfactant physiology limitations |
The central model paper’s abstract directly reports:
“Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as patients spontaneously developed pulmonary fibrosis that was accelerated by influenza virus infection.”
It further reports that JNK inhibition ameliorated fibrosis and that RIPK3 overexpression worsened it (Takezaki et al., PMID 31601679). [78]
Useful model resources are MGI, IMSR/MMRRC, IMPC, GEO/SRA for expression datasets, and patient-derived repositories maintained by ILD reference centers.
| Publication/date | Development | Relevance |
|---|---|---|
| Borie et al., ERS familial pulmonary fibrosis statement, 16 March 2023, PMID 36549714 | Formal expert guidance on who should receive genetic sequencing and family screening | Supports surfactant-gene testing in familial and early-onset ILD [113] |
| Bermudez et al., 20 November 2023, PMID 38020562 | First multicenter transplant-outcome study focused on adult surfactant-gene ILD | Median post-transplant survival 8.6 years; transplant is a valid option [91] |
| “Towards personalized therapies…,” 22 November 2023 | Review of gene/RNA/protein/cell strategies | Frames future disease-modifying approaches; none yet approved [104] |
| Luyapan et al., 2023 | Surfactant-pathway genetics and lung-cancer susceptibility research | Supports broader surfactant-pathway involvement; not a new monogenic ILD1 determinant [72] |
| Legendre/Nathan-group cohort, 2 May 2024 | Quantified cancer burden among surfactant-gene variant carriers | 15-year cancer-free survival 0.43 for SFTPA1/SFTPA2 vs 0.85 for other surfactant genes [97][100] |
| Rare genetic ILD pictorial review, 13 November 2024 | Updated radiologic synthesis | Reinforces adult-onset ILD and lung-cancer association for heterozygous SFTPA1/SFTPA2 variants [87] |
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 12 |
| Resolved | 12 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 12 |
| On topic | 5 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 52 |
| Resolved | 47 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 4 |
| Terms whose name was checked | 7 |
| Terms named correctly | 2 |
| Terms named as a different term | 5 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
DOID:0060941 (1 mention) - the report calls it "DOID"; DOID calls it interstitial lung disease 1CL:0002063 (2 mentions) - the report calls it "Primary SFTPA1-producing and injured cell", "Alveolar epithelial type II cell"; CL calls it pulmonary alveolar type 2 cellCL:0002062 (1 mention) - the report calls it "Secondary impairment through architectural destruction"; CL calls it pulmonary alveolar type 1 cellCL:0000583 (1 mention) - the report calls it "Surfactant clearance, innate immunity and inflammation"; CL calls it alveolar macrophageCL:0000186 (1 mention) - the report calls it "Contractile collagen-producing effector"; CL calls it myofibroblast cellThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0045045 (obsolete secretory pathway) (1 mention) - replaced by GO:0032940The report gives these identifiers more than one name of its own:
CL:0002063 - called "Primary SFTPA1-producing and injured cell", "Alveolar epithelial type II cell"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIM, MGI.