G6PC3 deficiency is an autosomal recessive metabolite-repair/proofreading disorder caused by biallelic G6PC3 variants. G6PC3 encodes the ubiquitously expressed endoplasmic-reticulum glucose-6-phosphatase catalytic subunit 3. The modern metabolite-repair model explains the neutrophil phenotype as failure to hydrolyze the nonclassical glucose analog 1,5-anhydroglucitol-6-phosphate (1,5-AG6P), which accumulates in granulocytes, inhibits hexokinase, impairs early glycolysis, and causes neutrophil dysfunction and neutropenia. A second documented branch is abnormal neutrophil glycosylation affecting gp91phox/NADPH oxidase. Clinically, the spectrum ranges from nonsyndromic severe congenital neutropenia to syndromic disease with recurrent bacterial infections, prominent superficial veins, congenital cardiac defects, and urogenital anomalies.
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name: G6PC3 Deficiency
category: Mendelian
creation_date: '2026-07-06T02:20:39Z'
synonyms:
- Ubiquitous glucose-6-phosphatase deficiency
- Glucose-6-phosphatase catalytic subunit 3 deficiency
- Severe congenital neutropenia type 4
- Severe congenital neutropenia due to G6PC3 deficiency
- Dursun syndrome
description: >-
G6PC3 deficiency is an autosomal recessive metabolite-repair/proofreading
disorder caused by biallelic G6PC3 variants. G6PC3 encodes the ubiquitously
expressed endoplasmic-reticulum glucose-6-phosphatase catalytic subunit 3.
The modern metabolite-repair model explains the neutrophil phenotype as
failure to hydrolyze the nonclassical glucose analog
1,5-anhydroglucitol-6-phosphate (1,5-AG6P), which accumulates in granulocytes,
inhibits hexokinase, impairs early glycolysis, and causes neutrophil
dysfunction and neutropenia.
A second documented branch is abnormal neutrophil glycosylation affecting
gp91phox/NADPH oxidase. Clinically, the spectrum ranges from nonsyndromic
severe congenital neutropenia to syndromic disease with recurrent bacterial
infections, prominent superficial veins, congenital cardiac defects, and
urogenital anomalies.
classifications:
icimd_category:
- classification_value: metabolite_proofreading
notes: >-
ICIMD package WP-031 classifies G6PC3-related ubiquitous
glucose-6-phosphatase deficiency under Intermediary Metabolism: Others ->
Disorders of metabolite repair/proofreading, based on failure to eliminate
the nonclassical metabolite 1,5-AG6P.
disease_term:
preferred_term: G6PC3 deficiency
term:
id: MONDO:0023124
label: Dursun syndrome
parents:
- Severe Congenital Neutropenia
- Inborn Error of Metabolism
- Congenital Disorder of Glycosylation
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
G6PC3 deficiency is caused by biallelic pathogenic variants in G6PC3.
evidence:
- reference: PMID:23758768
reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Bi-allelic G6PC3 mutations cause a multi-system autosomal recessive disorder of G6PC3 deficiency
explanation: Review evidence supports autosomal recessive inheritance of G6PC3 deficiency.
pathophysiology:
- name: G6PC3 endoplasmic-reticulum phosphatase deficiency
description: >-
Biallelic G6PC3 variants reduce ubiquitous endoplasmic-reticulum
glucose-6-phosphatase activity. In neutrophils, the critical repair defect
is failure to dephosphorylate the glucose analog 1,5-AG6P.
genes:
- preferred_term: G6PC3
term:
id: hgnc:24861
label: G6PC3
molecular_functions:
- preferred_term: glucose-6-phosphatase activity
term:
id: GO:0004346
label: glucose-6-phosphatase activity
modifier: DECREASED
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
locations:
- preferred_term: endoplasmic reticulum
term:
id: GO:0005783
label: endoplasmic reticulum
evidence:
- reference: PMID:19118303
reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Sequencing of G6PC3, the candidate gene encoding glucose-6-phosphatase, catalytic subunit 3, revealed a homozygous missense mutation in exon 6 that abolished the enzymatic activity of glucose-6-phosphatase in all affected children in the two families.
explanation: The original syndrome paper links G6PC3 variants to loss of glucose-6-phosphatase activity.
downstream:
- target: 1,5-AG6P accumulation and hexokinase inhibition
description: >-
G6PC3 normally collaborates with G6PT to destroy 1,5-AG6P; deficiency
allows this glucose analog phosphate to accumulate and inhibit low-KM
hexokinases.
causal_link_type: DIRECT
evidence:
- reference: PMID:30626647
reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
we demonstrate that G6PT and G6PC3 collaborate to destroy 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a close structural analog of glucose-6-phosphate and an inhibitor of low-KM hexokinases
explanation: Mechanistic experiments define the metabolite-repair substrate of G6PC3/G6PT.
- name: 1,5-AG6P accumulation and hexokinase inhibition
description: >-
Granulocytes deficient in G6PC3 accumulate millimolar 1,5-AG6P, inhibiting
hexokinase and reducing glucose utilization. This is especially damaging
for neutrophils, which depend heavily on glycolysis for effector function.
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
biological_processes:
- preferred_term: glycolytic process
term:
id: GO:0006096
label: glycolytic process
modifier: DECREASED
molecular_functions:
- preferred_term: hexokinase activity
term:
id: GO:0004396
label: hexokinase activity
modifier: DECREASED
chemical_entities:
- preferred_term: 1,5-anhydroglucitol-6-phosphate
description: >-
Nonclassical phosphorylated glucose analog; no CHEBI identifier was
identified in the local adapter during WP-031 curation.
modifier: INCREASED
evidence:
- reference: PMID:30626647
reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (~3 mM) that strongly inhibit hexokinase activity.
explanation: Patient granulocyte data directly support 1,5-AG6P accumulation and hexokinase inhibition.
downstream:
- target: Neutrophil functional defects
description: >-
1,5-AG6P accumulation decreases neutrophil glucose utilization and can
cause neutrophil cell death.
causal_link_type: DIRECT
evidence:
- reference: PMID:30626647
reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In a model of G6PC3-deficient mouse neutrophils, physiological concentrations of 1,5-anhydroglucitol caused massive accumulation of 1,5AG6P, a decrease in glucose utilization, and cell death.
explanation: Mouse neutrophil experiments connect 1,5-anhydroglucitol exposure to 1,5-AG6P buildup, reduced glucose use, and cell death.
- name: Neutrophil glycosylation and oxidase dysfunction
description: >-
G6PC3 deficiency is also associated with truncated neutrophil N- and
O-glycans and hypoglycosylation of gp91phox, the electron-transporting
NADPH oxidase component, providing a CDG-like branch of neutrophil
dysfunction.
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
biological_processes:
- preferred_term: respiratory burst
term:
id: GO:0045730
label: respiratory burst
modifier: DECREASED
evidence:
- reference: PMID:21385794
reference_title: "G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypo-glycosylation of gp91(phox), the electron-transporting component of the NADPH oxidase, in all of these patients.
explanation: Patient neutrophil data support gp91phox hypoglycosylation as a branch of G6PC3-related neutrophil dysfunction.
downstream:
- target: Neutrophil functional defects
description: >-
Glycolytic impairment and glycosylation defects converge on impaired
neutrophil migration, ingestion, bactericidal activity, and superoxide
production.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Early glycolysis and hexose monophosphate shunt impairment.
- gp91phox/NADPH oxidase hypoglycosylation.
evidence:
- reference: PMID:33259599
reference_title: "Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In human deficiency of G6PC3, metabolic defects resulting from the enzyme deficiency account for diverse neutrophil functional defects and present a major risk of infection.
explanation: Human neutrophil functional testing links G6PC3 metabolic defects to impaired neutrophil function and infection risk.
- name: Neutrophil functional defects
description: >-
G6PC3-deficient neutrophils have impaired migration, actin assembly,
bactericidal activity, superoxide generation, and survival, leading to
severe congenital neutropenia and recurrent bacterial infections.
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
biological_processes:
- preferred_term: neutrophil chemotaxis
term:
id: GO:0030593
label: neutrophil chemotaxis
modifier: DECREASED
- preferred_term: respiratory burst
term:
id: GO:0045730
label: respiratory burst
modifier: DECREASED
- preferred_term: neutrophil mediated immunity
term:
id: GO:0002446
label: neutrophil mediated immunity
modifier: DECREASED
- preferred_term: apoptotic process
term:
id: GO:0006915
label: apoptotic process
modifier: INCREASED
evidence:
- reference: PMID:33259599
reference_title: "Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Random and directed migration by the patient's neutrophils was severely diminished.
explanation: Patient neutrophil assays support impaired chemotaxis/migration.
- reference: PMID:33259599
reference_title: "Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Superoxide anion generation was <25% of control values
explanation: Patient neutrophil assays support defective respiratory burst.
downstream:
- target: Severe congenital neutropenia
description: Neutrophil death and functional impairment produce the hematologic phenotype of severe congenital neutropenia.
causal_link_type: DIRECT
evidence:
- reference: PMID:30626647
reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
In conclusion, we show that the neutropenia in patients with G6PC3 or G6PT mutations is a metabolite-repair deficiency, caused by a failure to eliminate the nonclassical metabolite 1,5AG6P.
explanation: The metabolite-repair paper directly states the mechanism for neutropenia in G6PC3 deficiency.
- target: Recurrent bacterial infections
description: Reduced mature neutrophils and impaired neutrophil effector function increase susceptibility to recurrent bacterial infection.
causal_link_type: DIRECT
evidence:
- reference: PMID:19118303
reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All index patients were susceptible to bacterial infections and had very few mature neutrophils in the bone marrow
explanation: The original syndrome paper links neutrophil scarcity to bacterial infection susceptibility.
phenotypes:
- category: Hematologic
name: Severe congenital neutropenia
description: >-
Persistent severe neutropenia is the core hematologic phenotype and may
occur with or without additional congenital anomalies.
phenotype_term:
preferred_term: Severe congenital neutropenia
term:
id: HP:0001875
label: Decreased total neutrophil count
evidence:
- reference: PMID:23758768
reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies.
explanation: Review of reported cases identifies severe congenital neutropenia as the cardinal phenotype.
- category: Immune
name: Recurrent bacterial infections
phenotype_term:
preferred_term: Recurrent bacterial infections
term:
id: HP:0002718
label: Recurrent bacterial infections
evidence:
- reference: PMID:23758768
reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies.
explanation: Review of reported cases supports recurrent bacterial infections as a characteristic feature.
- category: Hematologic
name: Intermittent thrombocytopenia
phenotype_term:
preferred_term: Thrombocytopenia
term:
id: HP:0001873
label: Thrombocytopenia
temporality: TRANSIENT
evidence:
- reference: PMID:23758768
reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies.
explanation: Review of reported cases supports intermittent thrombocytopenia in many patients.
- category: Vascular
name: Prominent superficial veins
phenotype_term:
preferred_term: Prominent superficial veins
term:
id: HP:0001015
label: Prominent superficial veins
evidence:
- reference: PMID:23758768
reference_title: "A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies.
explanation: Review of reported cases supports prominent superficial veins as a characteristic feature.
- category: Cardiovascular
name: Congenital cardiac defects
phenotype_term:
preferred_term: Congenital cardiac defects
term:
id: HP:0030680
label: Abnormal cardiovascular system morphology
evidence:
- reference: PMID:19118303
reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features.
explanation: The original syndrome paper reports structural heart defects in syndromic G6PC3 deficiency.
- category: Genitourinary
name: Urogenital anomalies
phenotype_term:
preferred_term: Urogenital anomalies
term:
id: HP:0000119
label: Abnormality of the genitourinary system
evidence:
- reference: PMID:19118303
reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features.
explanation: The original syndrome paper reports urogenital abnormalities in syndromic G6PC3 deficiency.
biochemical:
- name: 1,5-anhydroglucitol-6-phosphate
presence: INCREASED
context: >-
1,5-AG6P is the nonclassical phosphorylated glucose analog that accumulates
in G6PC3- or G6PT-deficient granulocytes and inhibits low-KM hexokinases.
biomarker_term:
preferred_term: 1,5-anhydroglucitol-6-phosphate
readouts:
- target: 1,5-AG6P accumulation and hexokinase inhibition
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: Increased 1,5-AG6P reports the failed G6PC3/G6PT metabolite-repair reaction.
evidence:
- reference: PMID:30626647
reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (~3 mM) that strongly inhibit hexokinase activity.
explanation: Patient granulocyte data support 1,5-AG6P as the proximal biochemical readout.
evidence:
- reference: PMID:30626647
reference_title: "Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (~3 mM) that strongly inhibit hexokinase activity.
explanation: Patient granulocyte data support increased 1,5-AG6P in G6PC3 deficiency.
- name: Neutrophil gp91phox hypoglycosylation
presence: PRESENT
context: >-
Hypoglycosylation of gp91phox/NADPH oxidase is a CDG-like biochemical and
cellular readout of G6PC3-related neutrophil dysfunction.
readouts:
- target: Neutrophil glycosylation and oxidase dysfunction
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: gp91phox hypoglycosylation reports the glycosylation branch of neutrophil dysfunction.
evidence:
- reference: PMID:21385794
reference_title: "G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypo-glycosylation of gp91(phox), the electron-transporting component of the NADPH oxidase, in all of these patients.
explanation: Patient neutrophil glycomics support gp91phox hypoglycosylation as a mechanistic readout.
evidence:
- reference: PMID:21385794
reference_title: "G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This aberrant neutrophil glycosylation is predicted to have profound effects on the neutrophil function and merit designation of both syndromes as a new class of congenital disorders of glycosylation.
explanation: The glycosylation paper supports classifying the glycan abnormality as a CDG-like mechanism.
genetic:
- name: G6PC3
gene_term:
preferred_term: G6PC3
term:
id: hgnc:24861
label: G6PC3
relationship_type: CAUSATIVE
variants:
- name: Biallelic G6PC3 pathogenic variants
description: >-
Missense, truncating, frameshift, splice-site, and other pathogenic
variants have been reported across the G6PC3 deficiency spectrum.
features: >-
G6PC3 encodes the ubiquitously expressed glucose-6-phosphatase catalytic
subunit 3 / G-6-Pase 3.
evidence:
- reference: PMID:19118303
reference_title: "A syndrome with congenital neutropenia and mutations in G6PC3."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified seven additional, unrelated patients who had severe congenital neutropenia with syndromic features and distinct biallelic mutations in G6PC3.
explanation: The original syndrome paper supports G6PC3 as the causative gene for syndromic severe congenital neutropenia.
- reference: PMID:23298686
reference_title: "G6PC3 mutations cause non-syndromic severe congenital neutropenia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we describe four patients from three families with non-syndromic severe congenital neutropenia and identify four G6PC3 mutations as causative in these cases.
explanation: This report extends the G6PC3 causal spectrum to nonsyndromic severe congenital neutropenia.
notes: >-
WP-031 placement decision: curate a G6PC3 Deficiency entry rather than only a
Dursun syndrome entry because independent sources describe a broader G6PC3
deficiency continuum, including nonsyndromic severe congenital neutropenia and
syndromic disease with cardiac/urogenital/venous findings. The disease_term is
anchored to the available gene-specific MONDO term (Dursun syndrome); the
package ORPHA:331176 label is broader than the MONDO term exposed in the local
ontology snapshot. The package code is 12.2.07.01; the current ICIMD enum
exposes the broader metabolite_proofreading value.