👪

Inheritance

1

X-linked recessive HP:0001419

Affected men are hemizygous for missense variants, truncating variants or a deletion of CFAP47 on Xp21.1; none of the reported families is consanguineous. Daughters of affected men conceived by ICSI are obligate heterozygous carriers, and their sons have a 50% risk.

X-linked recessive inheritance

Show evidence (2 references)

PMID:33472045 SUPPORT Human clinical

"Altogether, our experimental observations in humans and mice demonstrate that hemizygous mutations in CFAP47 can induce X-linked MMAF and asthenoteratozoospermia, for which good ICSI prognosis is suggested."

Hemizygous X-linked inheritance in four unrelated men.

CGGV:assertion_5d2e51e3-fec5-4aa8-a093-d316c4feec02-2023-02-09T170000.000Z SUPPORT Other

"Nevertheless, the molecular mechanism appears to be hemizygous loss-of-function with an X-linked mode of inheritance, characterized in at least some cases by variants predicted to trigger the absence of a gene product."

ClinGen's summary of the mode of inheritance.

◈

Mechanistic Hypotheses

2

CFAP47 deficiency spans MMAF and asthenozoospermia with normal sperm morphology

cfap47_phenotypic_spectrum EMERGING

Evidence balance 3 support

Six men with missense variants or a whole-gene deletion had MMAF, while two men with an exon 28-62 deletion or a nonsense variant had asthenozoospermia with normal morphology and an apparently normal 9+2 axoneme, as do two independent Cfap47 knockout mouse lines. The determinants are unknown: allele class does not explain it, since the Australian whole-gene deletion gave MMAF, but that deletion also removed neighbouring Xp21.1 genes, and the cohorts were ascertained differently (MMAF cohorts versus an asthenozoospermia cohort).

Pathograph links

Loss of the C1-C2 Bridge of the Central Apparatus -> Reduced sperm motility DIRECT Shown directly for truncating alleles and knockout mice, in which motility falls without flagellar malformation.

Loss of the C1-C2 Bridge of the Central Apparatus -> Multiple Morphological Abnormalities of the Sperm Flagella INDIRECT UNKNOWN INTERMEDIATES Most reported men have MMAF with missing central or peripheral microtubules, but why central-apparatus bridge loss produces flagellar malformation in them and not in the truncating-allele men or knockout mice is unknown.

Show evidence (3 references)

PMID:33472045 SUPPORT Human clinical

"All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes."

The MMAF end of the spectrum.

PMID:40473901 SUPPORT Human clinical

"Consequently, the significant truncation of the CFAP47 gene in Patient 1 and Patient 2 resulted in the ANM phenotype of sperm, mirroring the phenotypes observed in Cfap47-KO mice."

The normal-morphology end of the spectrum.

PMID:33472045 SUPPORT Model organism

"Overall, the sperm phenotype of Cfap47-mutated male mice appears milder than the phenotype of men harboring hemizygous CFAP47 variants."

A first knockout line also lacked full MMAF.

CFAP47 deficiency is restricted to sperm rather than causing primary ciliary dyskinesia

cfap47_respiratory_involvement EMERGING

Evidence balance 4 support 2 refute

Men in the infertility cohorts had no PCD features, and Cfap47 knockout mice are otherwise healthy. Against this, three men with hemizygous missense variants and PCD-like disease (bronchiectasis, sinusitis, otitis media, low nasal nitric oxide and reduced or abnormal airway cilia) have been reported from one centre. That evidence is weak: the variants are missense, pathogenicity predictions were divergent for one, functional data are limited to reduced mRNA and staining, and one of the men fathered two children naturally.

Show evidence (6 references)

CGGV:assertion_5d2e51e3-fec5-4aa8-a093-d316c4feec02-2023-02-09T170000.000Z SUPPORT REVIEW SYNTHESIS Other

"While the number of patients published so far is quite small, all of them have been noted for the lack of phenotypes typically associated with primary ciliary dyskinesia, including absence of sinusitis, bronchitis, otitis media, and pneumonia (PMID: 33472045)."

ClinGen summary of the absence of PCD features in the infertility probands.

PMID:40473901 SUPPORT Model organism

"While Cfap47-KO mice were otherwise healthy, males display drastically reduced fertility"

Knockout mice have no extra-reproductive disease.

PMID:37723893 REFUTE Human clinical

"Altogether, our results indicate that CFAP47 hemizygous variants can result in PCD phenotypes both in lung and in sperm and that this gene is a novel PCD pathogenic gene."

Two men with hemizygous missense variants and PCD-like disease.

+ 3 more references

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Pathophysiology

4

Hemizygous Loss of CFAP47 Function

Missense variants reduce CFAP47 mRNA and protein in sperm; a whole-gene deletion, an exon 28-62 deletion and a nonsense variant remove or truncate the protein. In wild-type mouse sperm CFAP47 forms the bridge between the C1 and C2 central-pair microtubules, binding both.

CFAP47 hgnc:26708

microtubule binding (C1 and C2 central-pair microtubules) GO:0008017 ↓ DECREASED structural constituent of the central apparatus bridge GO:0005200 ↓ DECREASED

Axonemal central apparatus GO:1990716

Downstream

Loss of the C1-C2 Bridge of the Central Apparatus

Mislocalization of CFAP65 in Sperm

Show evidence (3 references)

PMID:33472045 SUPPORT Human clinical

"Immunoblotting and immunofluorescence assays revealed obviously reduced levels of CFAP47 in spermatozoa from all three men harboring deleterious missense variants of CFAP47."

Missense alleles reduce CFAP47 in patient sperm.

PMID:33472045 SUPPORT Human clinical

"Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene."

A whole-gene deletion in a further proband.

PMID:40473901 SUPPORT In vitro / ex vivo

"CFAP47, the core structural component of the bridge, binds C1 through its N-terminal domains, interacts with HYDIN via its central CFAP47-ring, and anchors to C2 through its C-terminal region."

Cryo-electron tomography of mouse sperm shows CFAP47 binds both central microtubules as a structural bridge, grounding the molecular functions.

Loss of the C1-C2 Bridge of the Central Apparatus

Without CFAP47 the bridge between the two central microtubules is hollow, weakening the C1-C2 connection and the force transmission of the central apparatus. In knockout mice and in two men with truncating alleles this gives asthenozoospermia with normal sperm morphology and an apparently normal 9+2 axoneme, with flagella beating at reduced curvature and amplitude.

CFAP47 deficiency spans MMAF and asthenozoospermia with normal sperm morphology

Axonemal central apparatus assembly GO:1904158 ↓ DECREASED

Axonemal central apparatus GO:1990716

Animal models

Cfap47 knockout mouse (exons 2-50 deletion) Mouse recapitulates Shows the structural lesion directly and reproduces the asthenozoospermia with normal morphology seen in men with truncating alleles.

Downstream

Reduced sperm motility Shown directly for truncating alleles and knockout mice, in which motility falls without flagellar malformation.

Multiple Morphological Abnormalities of the Sperm Flagella Most reported men have MMAF with missing central or peripheral microtubules, but why central-apparatus bridge loss produces flagellar malformation in them and not in the truncating-allele men or knockout mice is unknown.

Show evidence (2 references)

PMID:40473901 SUPPORT Model organism

"In the sperm of Cfap47-knockout (KO) mice, a hollow bridge region within the CA structure was observed, correlating with abnormal sperm motility and confirming the essential role of CFAP47 in CA function."

Bridge loss in knockout sperm.

PMID:40473901 SUPPORT Human clinical

"Despite normal morphology under Papanicolaou staining (Fig. 6e), the sperm flagella waveform pattern showed abnormal curvature and amplitude (Fig. 6f)."

Abnormal waveform in a man with an exon 28-62 deletion.

Mislocalization of CFAP65 in Sperm

CFAP47 co-immunoprecipitates with CFAP65, the C2a projection protein mutated in spermatogenic failure 40. In men with CFAP47 variants CFAP65 leaves the flagellar base and clusters in the acrosome, and conversely CFAP47 is reduced in sperm of men with CFAP65 variants.

Sperm CL:0000019

Downstream

Multiple Morphological Abnormalities of the Sperm Flagella The authors propose that disturbed CFAP47-CFAP65 interaction contributes to the flagellar and head defects.

Show evidence (1 reference)

PMID:33472045 SUPPORT Human clinical

"In addition, sperm cells from men harboring bi-allelic CFAP65 variants displayed a significantly reduced CFAP47 staining when compared with the obvious CFAP47 signal in the mid-piece of flagella in normal spermatozoa (Figure S7)."

Reciprocal dependence of CFAP47 and CFAP65 in human sperm.

Multiple Morphological Abnormalities of the Sperm Flagella

Absent, short, coiled and irregular-caliber flagella with severely reduced progressive motility, in men carrying missense variants or the whole-gene deletion. Electron microscopy shows disorganized outer dense fibers and missing peripheral or central microtubules.

Sperm CL:0000019

Sperm flagellum assembly GO:0120316 ↓ DECREASED

Animal models

Cfap47 frameshift mouse Mouse partially recapitulates Reproduces sterility and asthenozoospermia but only part of the MMAF phenotype.

Cfap47 knockout mouse (exons 2-50 deletion) Mouse fails to recapitulate Knockout sperm have normal morphology, so MMAF is not reproduced.

Downstream

Reduced sperm motility

Male infertility Malformed, poorly motile sperm cannot reach or fertilize the oocyte in vivo.

Absent sperm flagella

Short sperm flagella

Coiled sperm flagella

Irregularly shaped sperm tail

Abnormal sperm axoneme morphology

Show evidence (2 references)

PMID:33472045 SUPPORT Human clinical

"All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes."

MMAF in four hemizygous men.

PMID:37424856 SUPPORT Human clinical

"Intriguingly, in addition to the MMAF phenotype very analogous to the previous report, the two patients notably presented abnormal morphology of sperm heads, the sperm mitochondrial sheath was obviously disorganized, and the sperm annulus were almost defective."

MMAF in two further men with a recurrent missense variant.

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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Male infertility Reproductive HP:0003251

Show evidence (2 references)

CGGV:assertion_5d2e51e3-fec5-4aa8-a093-d316c4feec02-2023-02-09T170000.000Z SUPPORT REVIEW SYNTHESIS Other

"Consistent features among the reported male patients are infertility, reduced sperm motility, and multiple morphological abnormalities of the sperm flagellum."

ClinGen summary of the consistent phenotype.

PMID:33472045 SUPPORT Human clinical

"Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF."

Infertile probands with MMAF.

Reduced sperm motility Reproductive HP:0012207

Show evidence (2 references)

PMID:33472045 SUPPORT Human clinical

"A semen analysis indicated the severely reduced sperm motility in all of four men harboring hemizygous CFAP47 variants (Table 2)."

Reduced motility in four men with MMAF.

PMID:40473901 SUPPORT Human clinical

"However, the progressive motility rate of the spermatozoa decreased dramatically to 7.6% ± 5.1%, with rapid progressive motility at 2.4% ± 3.3% and slow progressive motility at 5.3% ± 1.8% (Supplementary information, Video S3)."

Reduced motility in a man with normal sperm morphology.

Absent sperm flagella Reproductive HP:0032558

Show evidence (1 reference)

PMID:33472045 SUPPORT Human clinical

"the spermatozoa from men harboring hemizygous CFAP47 variants displayed frequently abnormal flagella, including absent, short, coiled flagella, and irregular caliber"

Absent flagella in patient sperm.

Short sperm flagella Reproductive HP:0032559

Show evidence (1 reference)

PMID:33472045 SUPPORT Human clinical

"the spermatozoa from men harboring hemizygous CFAP47 variants displayed frequently abnormal flagella, including absent, short, coiled flagella, and irregular caliber"

Short flagella in patient sperm.

Coiled sperm flagella Reproductive HP:0032560

Show evidence (1 reference)

PMID:33472045 SUPPORT Human clinical

"the spermatozoa from men harboring hemizygous CFAP47 variants displayed frequently abnormal flagella, including absent, short, coiled flagella, and irregular caliber"

Coiled flagella in patient sperm.

Irregularly shaped sperm tail Reproductive HP:0033393

Show evidence (1 reference)

PMID:33472045 SUPPORT Human clinical

"the spermatozoa from men harboring hemizygous CFAP47 variants displayed frequently abnormal flagella, including absent, short, coiled flagella, and irregular caliber"

Irregular-caliber flagella in patient sperm.

Abnormal sperm axoneme morphology Reproductive HP:0033524

Show evidence (2 references)

PMID:33472045 SUPPORT Human clinical

"the sperm flagella of men harboring hemizygous CFAP47 variants displayed a variety of ultrastructural defects, including disorganization of outer dense fibers, and absence of peripheral or central microtubules at the midpiece and principal piece of sperm flagella"

Axonemal defects in men with MMAF.

PMID:40473901 REFUTE Human clinical

"Transmission electron microscopy (TEM) revealed an apparently normal “9 + 2” axoneme structure (Fig. 6g)."

Not present in a man with an exon 28-62 deletion.

Abnormal sperm head morphology Reproductive HP:0012865

Show evidence (1 reference)

PMID:37424856 SUPPORT Human clinical

"All evidence indicates that CFAP47 mutation contributes not only to the MMAF phenotype but also to abnormalities in the sperm head and annulus."

Head and annulus defects in two men.

🧬

Genetic Associations

1

CFAP47 (Causal)

Gene: CFAP47 hgnc:26708

Show evidence (3 references)

PMID:33472045 SUPPORT Human clinical

"Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF."

Primary gene-disease report.

PMID:37424856 SUPPORT Human clinical

"Sanger sequencing confirmed a hemizygous CFAP47 missense variant in the two families."

Two further unrelated men.

PMID:40473901 SUPPORT Human clinical

"Notably, an exon deletion in Patient 1 and a nonsense mutation in Patient 2 were strongly linked to asthenozoospermia (Supplementary information, Table S4)."

Truncating alleles from a 320-man asthenozoospermia cohort.

💊

Medical Actions

2

Intracytoplasmic Sperm Injection

Action: Intracytoplasmic Sperm Injection NCIT:C185482

Platform: Other

ICSI bypasses the motility defect. Three of four couples in the first series achieved pregnancy (the fourth wife had poor oocyte quality), one man with an exon deletion obtained nine transferable embryos, and one couple with a recurrent missense variant did not conceive after one cycle. A man with c.8006C>T had cleavage failure after ICSI that improved with assisted oocyte activation (AOA), with ongoing pregnancy, and altered PLCZ1 localization in sperm.

Mechanism Target:

Multiple Morphological Abnormalities of the Sperm Flagella — Direct injection makes flagellar propulsion irrelevant to fertilization.

Show evidence (1 reference)

PMID:33472045 SUPPORT Human clinical

"Therefore, our studies strongly indicated that the damaged male fertility caused by hemizygous CFAP47 variants can be rescued by ICSI treatment."

ICSI circumvents the flagellar defect.

Show evidence (4 references)

PMID:33472045 SUPPORT Human clinical

"Similarly, three out of the four men harboring hemizygous CFAP47 variants in this study achieved good clinical outcomes after assisted reproductive therapy by ICSI (Table 3)."

Good ICSI outcomes in three of four couples.

PMID:40473901 SUPPORT Human clinical

"Assisted reproductive technology, specifically intracytoplasmic sperm injection (ICSI) for Patient 1 and his wife, resulted in successful fertilization of 11 metaphase II (MII) oocytes, yielding 9 transferable embryos"

Successful fertilization for a man with a truncating deletion.

PMID:37424856 REFUTE Human clinical

"Regrettably, his wife has not succeeded in pregnancy."

An unsuccessful ICSI cycle; the authors could not exclude female factors.

+ 1 more reference

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

X-linked recessive counselling. Daughters of an affected man are obligate carriers and his sons are unaffected; a carrier woman's sons each have a 50% risk of infertility.

Show evidence (1 reference)

PMID:33472045 SUPPORT Human clinical

"In contrast, for ICSI performed in case of X-linked CFAP47-associated MMAF, 100% of female (but no male) offspring will inherit heterozygous deleterious variants of CFAP47."

The transmission risks that counselling must convey.

🔬

Diagnosis

4

Molecular Genetic Testing

Establishes the diagnosis. Exome sequencing finds the hemizygous SNVs; copy-number analysis of exome or genome data is needed to find Xp21.1 deletions.

Genetic Testing NCIT:C15709

Show evidence (2 references)

PMID:33472045 SUPPORT Human clinical

"Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene."

Copy-number analysis of exome data detected a whole-gene deletion.

PMID:33472045 SUPPORT Human clinical

"Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF."

Exome sequencing detected the missense variants.

Semen Analysis

Shows severely reduced progressive motility, usually with MMAF; sperm morphology can be normal with truncating alleles.

Show evidence (1 reference)

PMID:33472045 SUPPORT Human clinical

"A semen analysis indicated the severely reduced sperm motility in all of four men harboring hemizygous CFAP47 variants (Table 2)."

Semen analysis findings.

Transmission Electron Microscopy of Sperm Flagella

Shows missing central or peripheral microtubules and disorganized outer dense fibers in men with MMAF; can be normal with truncating alleles.

Transmission Electron Microscopy NCIT:C18216

Show evidence (1 reference)

PMID:33472045 SUPPORT Human clinical

"the sperm flagella of men harboring hemizygous CFAP47 variants displayed a variety of ultrastructural defects, including disorganization of outer dense fibers, and absence of peripheral or central microtubules at the midpiece and principal piece of sperm flagella"

TEM findings.

Immunofluorescence of CFAP47 in Sperm

Reduced or absent CFAP47 staining at the flagellar base, with displaced CFAP65, supports pathogenicity of missense variants.

Show evidence (1 reference)

PMID:33472045 SUPPORT Human clinical

"CFAP47 staining is concentrated at the base of sperm flagella from the control individual, but the signal was almost absent in the sperm flagella from men harboring hemizygous CFAP47 variants."

Immunofluorescence demonstrates protein loss.

🐁

Animal Models

2

Cfap47 frameshift mouse

Hemizygous males are sterile with reduced motility and bent flagella arising in the epididymis, normal sperm concentration and no gross axonemal defect; ICSI rescues fertilization.

Species

Mouse

Genotype

Cfap47 c.2559insT (p.Gly855Profs*8), hemizygous (Cfap47-/Y)

Publication

PMID:33472045

Pathograph links

Multiple Morphological Abnormalities of the Sperm Flagella partially recapitulates fidelity: low Reproduces sterility and asthenozoospermia but only part of the MMAF phenotype.

Limitations: Mutant sperm show mainly bent flagella and no obvious axonemal ultrastructural defect, a milder phenotype than the full MMAF of most patients.

Divergences from the human mechanism

species mismatch qualifying

Mouse sperm lacking CFAP47 keep their flagellar form and axoneme, whereas most hemizygous men have short, absent and coiled flagella with missing microtubules; the mouse models the motility defect better than the malformation.

Show evidence (1 reference)

PMID:33472045 SUPPORT Model organism

"Overall, the sperm phenotype of Cfap47-mutated male mice appears milder than the phenotype of men harboring hemizygous CFAP47 variants."

Authors' statement of the milder mouse phenotype.

Cfap47 knockout mouse (exons 2-50 deletion)

Knockout males are otherwise healthy, with normal sperm counts and morphology but reduced motility and fertility; the central apparatus lacks the CFAP47 bridge density.

Species

Mouse

Genotype

Cfap47 171.6-kb deletion of exons 2-50, hemizygous

Publication

PMID:40473901

Pathograph links

Loss of the C1-C2 Bridge of the Central Apparatus recapitulates fidelity: high Shows the structural lesion directly and reproduces the asthenozoospermia with normal morphology seen in men with truncating alleles.

Show evidence (1 reference)

PMID:40473901 SUPPORT Model organism

"Cfap47-KO mice lack density associated with the CFAP47 and SPAG6 proteins in the bridge region of the CA structure."

Bridge density is lost in knockout sperm.

Multiple Morphological Abnormalities of the Sperm Flagella fails to recapitulate fidelity: low Knockout sperm have normal morphology, so MMAF is not reproduced.

Limitations: Normal sperm counts and morphology in knockout mice match the truncating-allele men but not the majority of reported men, who have MMAF.

Divergences from the human mechanism

species mismatch qualifying

Mouse sperm without CFAP47 are motility-impaired but morphologically normal; whether human MMAF in CFAP47 men reflects a species difference, variant-specific effects or contributions from co-deleted genes is unknown.

Show evidence (1 reference)

PMID:40473901 SUPPORT Model organism

"This phenotype, characterized by asthenozoospermia with normal morphology, is hereafter referred to as ANM."

Knockout sperm morphology is normal.

{ }

Source YAML

click to show

name: Spermatogenic Failure X-linked 3
creation_date: "2026-10-16T00:00:00Z"
category: Mendelian
synonyms:
- SPGFX3
- spermatogenic failure, X-linked, 3
- CFAP47-related multiple morphological abnormalities of the sperm flagella
- CFAP47-related asthenozoospermia
description: >-
  Spermatogenic failure X-linked 3 (SPGFX3) is X-linked recessive male
  infertility caused by hemizygous variants in CFAP47, a large X-chromosomal
  cilia- and flagella-associated protein. In the sperm axoneme CFAP47 is the
  core structural component of the bridge that links the C1 and C2
  microtubules of the central apparatus: it binds C1 through its N-terminal
  domains, HYDIN through a central ring, and C2 through its C-terminus. It
  also interacts with CFAP65, whose localization in sperm depends on it.

  Hemizygous men present with primary infertility and asthenozoospermia.
  Most reported men, carrying missense variants or a whole-gene deletion,
  have asthenoteratozoospermia with multiple morphological abnormalities of
  the sperm flagella (MMAF): absent, short, coiled and irregular-caliber
  flagella with missing central or peripheral microtubules, and in some men
  abnormal heads and sperm annulus. Two men with truncating variants had
  asthenozoospermia with normal sperm morphology and an apparently normal
  axoneme, as do Cfap47 knockout mice. Fertility has been achieved by
  intracytoplasmic sperm injection (ICSI), with assisted oocyte activation
  in one man with cleavage failure. Daughters of affected men are obligate
  carriers. Hemizygous CFAP47 missense variants have also been reported in
  three men with primary ciliary dyskinesia-like respiratory disease.
disease_term:
  preferred_term: spermatogenic failure, X-linked, 3
  term:
    id: MONDO:0025354
    label: spermatogenic failure, X-linked, 3
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 301059. ClinGen classifies
  CFAP47 in SPGFX3 as Limited (X-linked, 2023), scoring three hemizygous
  missense probands from PMID:33472045; it did not score the Australian
  proband's Xp21.1 deletion, whose breakpoints were undefined, and the second
  study it mentions was then unpublished (a recurrent missense variant,
  apparently PMID:37424856 in its published form, which is cited here). The
  Australian proband's deletion spans about 3.2 Mb of Xp21.1 and so removes
  other genes besides CFAP47. Separately, ClinGen classifies CFAP47 in
  X-linked polycystic kidney disease as Disputed (2025); kidney cysts are not
  part of SPGFX3. Hemizygous CFAP47 missense variants reported in men with
  primary ciliary dyskinesia-like disease (PMID:37723893, PMID:40636384) are
  recorded under the respiratory hypothesis rather than as phenotypes,
  because the variants are missense with limited functional data and one of
  those men fathered children naturally.
  No GeneReviews or StatPearls chapter covers this disorder.
inheritance:
- name: X-linked recessive
  description: >-
    Affected men are hemizygous for missense variants, truncating variants or
    a deletion of CFAP47 on Xp21.1; none of the reported families is
    consanguineous. Daughters of affected men conceived by ICSI are obligate
    heterozygous carriers, and their sons have a 50% risk.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Altogether, our experimental observations in humans and mice demonstrate that hemizygous mutations in CFAP47 can induce X-linked MMAF and asthenoteratozoospermia, for which good ICSI prognosis is suggested."
    explanation: Hemizygous X-linked inheritance in four unrelated men.
  - reference: CGGV:assertion_5d2e51e3-fec5-4aa8-a093-d316c4feec02-2023-02-09T170000.000Z
    reference_title: "CFAP47 / spermatogenic failure, X-linked, 3 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nevertheless, the molecular mechanism appears to be hemizygous loss-of-function with an X-linked mode of inheritance, characterized in at least some cases by variants predicted to trigger the absence of a gene product."
    explanation: ClinGen's summary of the mode of inheritance.
pathophysiology:
- name: Hemizygous Loss of CFAP47 Function
  description: >-
    Missense variants reduce CFAP47 mRNA and protein in sperm; a whole-gene
    deletion, an exon 28-62 deletion and a nonsense variant remove or
    truncate the protein. In wild-type mouse sperm CFAP47 forms the bridge
    between the C1 and C2 central-pair microtubules, binding both.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CFAP47
    term:
      id: hgnc:26708
      label: CFAP47
  molecular_functions:
  - preferred_term: microtubule binding (C1 and C2 central-pair microtubules)
    modifier: DECREASED
    term:
      id: GO:0008017
      label: microtubule binding
  - preferred_term: structural constituent of the central apparatus bridge
    modifier: DECREASED
    term:
      id: GO:0005200
      label: structural constituent of cytoskeleton
  cellular_components:
  - preferred_term: Axonemal central apparatus
    term:
      id: GO:1990716
      label: axonemal central apparatus
  downstream:
  - target: Loss of the C1-C2 Bridge of the Central Apparatus
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40473901
      reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the sperm of Cfap47-knockout (KO) mice, a hollow bridge region within the CA structure was observed, correlating with abnormal sperm motility and confirming the essential role of CFAP47 in CA function."
      explanation: Knockout sperm lack the bridge density.
  - target: Mislocalization of CFAP65 in Sperm
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33472045
      reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "CFAP65 staining was observed mainly at the equatorial segment of sperm head and the base of flagella in control spermatozoa, but the signal was only diffusely clustered in the acrosome of spermatozoa from men harboring hemizygous CFAP47 variants."
      explanation: CFAP65 is mislocalized in patient sperm.
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunoblotting and immunofluorescence assays revealed obviously reduced levels of CFAP47 in spermatozoa from all three men harboring deleterious missense variants of CFAP47."
    explanation: Missense alleles reduce CFAP47 in patient sperm.
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene."
    explanation: A whole-gene deletion in a further proband.
  - reference: PMID:40473901
    reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CFAP47, the core structural component of the bridge, binds C1 through its N-terminal domains, interacts with HYDIN via its central CFAP47-ring, and anchors to C2 through its C-terminal region."
    explanation: >-
      Cryo-electron tomography of mouse sperm shows CFAP47 binds both central
      microtubules as a structural bridge, grounding the molecular functions.
- name: Loss of the C1-C2 Bridge of the Central Apparatus
  description: >-
    Without CFAP47 the bridge between the two central microtubules is hollow,
    weakening the C1-C2 connection and the force transmission of the
    central apparatus. In knockout mice and in two men with truncating
    alleles this gives asthenozoospermia with normal sperm morphology and an
    apparently normal 9+2 axoneme, with flagella beating at reduced curvature
    and amplitude.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: Axonemal central apparatus
    term:
      id: GO:1990716
      label: axonemal central apparatus
  biological_processes:
  - preferred_term: Axonemal central apparatus assembly
    modifier: DECREASED
    term:
      id: GO:1904158
      label: axonemal central apparatus assembly
  downstream:
  - target: Reduced sperm motility
    causal_link_type: DIRECT
    hypothesis_groups:
    - cfap47_phenotypic_spectrum
    description: >-
      Shown directly for truncating alleles and knockout mice, in which
      motility falls without flagellar malformation.
    evidence:
    - reference: PMID:40473901
      reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Consequently, the significant truncation of the CFAP47 gene in Patient 1 and Patient 2 resulted in the ANM phenotype of sperm, mirroring the phenotypes observed in Cfap47-KO mice."
      explanation: Truncating alleles give asthenozoospermia with normal morphology.
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - cfap47_phenotypic_spectrum
    description: >-
      Most reported men have MMAF with missing central or peripheral
      microtubules, but why central-apparatus bridge loss produces flagellar
      malformation in them and not in the truncating-allele men or knockout
      mice is unknown.
  evidence:
  - reference: PMID:40473901
    reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the sperm of Cfap47-knockout (KO) mice, a hollow bridge region within the CA structure was observed, correlating with abnormal sperm motility and confirming the essential role of CFAP47 in CA function."
    explanation: Bridge loss in knockout sperm.
  - reference: PMID:40473901
    reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite normal morphology under Papanicolaou staining (Fig. 6e), the sperm flagella waveform pattern showed abnormal curvature and amplitude (Fig. 6f)."
    explanation: Abnormal waveform in a man with an exon 28-62 deletion.
- name: Mislocalization of CFAP65 in Sperm
  description: >-
    CFAP47 co-immunoprecipitates with CFAP65, the C2a projection protein
    mutated in spermatogenic failure 40. In men with CFAP47 variants CFAP65
    leaves the flagellar base and clusters in the acrosome, and conversely
    CFAP47 is reduced in sperm of men with CFAP65 variants.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The authors propose that disturbed CFAP47-CFAP65 interaction contributes to the flagellar and head defects.
    evidence:
    - reference: PMID:33472045
      reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Thus, the reduced sperm motility and higher rates of abnormal sperm morphologies in men harboring hemizygous CFAP47 variants may partially result from the abnormal interaction or regulation between CFAP47 and CFAP65."
      explanation: The proposed link is the authors' inference, not a demonstrated step.
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, sperm cells from men harboring bi-allelic CFAP65 variants displayed a significantly reduced CFAP47 staining when compared with the obvious CFAP47 signal in the mid-piece of flagella in normal spermatozoa (Figure S7)."
    explanation: Reciprocal dependence of CFAP47 and CFAP65 in human sperm.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    Absent, short, coiled and irregular-caliber flagella with severely reduced
    progressive motility, in men carrying missense variants or the whole-gene
    deletion. Electron microscopy shows disorganized outer dense fibers and
    missing peripheral or central microtubules.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  biological_processes:
  - preferred_term: Sperm flagellum assembly
    modifier: DECREASED
    term:
      id: GO:0120316
      label: sperm flagellum assembly
  downstream:
  - target: Reduced sperm motility
    causal_link_type: DIRECT
  - target: Male infertility
    causal_link_type: DIRECT
    description: Malformed, poorly motile sperm cannot reach or fertilize the oocyte in vivo.
  - target: Absent sperm flagella
    causal_link_type: DIRECT
  - target: Short sperm flagella
    causal_link_type: DIRECT
  - target: Coiled sperm flagella
    causal_link_type: DIRECT
  - target: Irregularly shaped sperm tail
    causal_link_type: DIRECT
  - target: Abnormal sperm axoneme morphology
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes."
    explanation: MMAF in four hemizygous men.
  - reference: PMID:37424856
    reference_title: "A novel mutation in CFAP47 causes male infertility due to multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intriguingly, in addition to the MMAF phenotype very analogous to the previous report, the two patients notably presented abnormal morphology of sperm heads, the sperm mitochondrial sheath was obviously disorganized, and the sperm annulus were almost defective."
    explanation: MMAF in two further men with a recurrent missense variant.
mechanistic_hypotheses:
- hypothesis_group_id: cfap47_phenotypic_spectrum
  hypothesis_label: CFAP47 deficiency spans MMAF and asthenozoospermia with normal sperm morphology
  status: EMERGING
  description: >-
    Six men with missense variants or a whole-gene deletion had MMAF, while
    two men with an exon 28-62 deletion or a nonsense variant had
    asthenozoospermia with normal morphology and an apparently normal 9+2
    axoneme, as do two independent Cfap47 knockout mouse lines. The
    determinants are unknown: allele class does not explain it, since the
    Australian whole-gene deletion gave MMAF, but that deletion also removed
    neighbouring Xp21.1 genes, and the cohorts were ascertained differently
    (MMAF cohorts versus an asthenozoospermia cohort).
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes."
    explanation: The MMAF end of the spectrum.
  - reference: PMID:40473901
    reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consequently, the significant truncation of the CFAP47 gene in Patient 1 and Patient 2 resulted in the ANM phenotype of sperm, mirroring the phenotypes observed in Cfap47-KO mice."
    explanation: The normal-morphology end of the spectrum.
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overall, the sperm phenotype of Cfap47-mutated male mice appears milder than the phenotype of men harboring hemizygous CFAP47 variants."
    explanation: A first knockout line also lacked full MMAF.
- hypothesis_group_id: cfap47_respiratory_involvement
  hypothesis_label: CFAP47 deficiency is restricted to sperm rather than causing primary ciliary dyskinesia
  status: EMERGING
  description: >-
    Men in the infertility cohorts had no PCD features, and Cfap47 knockout
    mice are otherwise healthy. Against this, three men with hemizygous
    missense variants and PCD-like disease (bronchiectasis, sinusitis, otitis
    media, low nasal nitric oxide and reduced or abnormal airway cilia) have
    been reported from one centre. That evidence is weak: the variants are
    missense, pathogenicity predictions were divergent for one, functional
    data are limited to reduced mRNA and staining, and one of the men
    fathered two children naturally.
  evidence:
  - reference: CGGV:assertion_5d2e51e3-fec5-4aa8-a093-d316c4feec02-2023-02-09T170000.000Z
    reference_title: "CFAP47 / spermatogenic failure, X-linked, 3 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "While the number of patients published so far is quite small, all of them have been noted for the lack of phenotypes typically associated with primary ciliary dyskinesia, including absence of sinusitis, bronchitis, otitis media, and pneumonia (PMID: 33472045)."
    explanation: ClinGen summary of the absence of PCD features in the infertility probands.
  - reference: PMID:40473901
    reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "While Cfap47-KO mice were otherwise healthy, males display drastically reduced fertility"
    explanation: Knockout mice have no extra-reproductive disease.
  - reference: PMID:37723893
    reference_title: "Mutations in CFAP47, a previously reported MMAF causative gene, also contribute to the respiratory defects in patients with PCD."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Altogether, our results indicate that CFAP47 hemizygous variants can result in PCD phenotypes both in lung and in sperm and that this gene is a novel PCD pathogenic gene."
    explanation: Two men with hemizygous missense variants and PCD-like disease.
  - reference: PMID:37723893
    reference_title: "Mutations in CFAP47, a previously reported MMAF causative gene, also contribute to the respiratory defects in patients with PCD."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had two naturally conceived healthy children."
    explanation: >-
      One of the two PCD probands was naturally fertile, which weakens the
      link between his variant and the sperm disease. Indirect: it bears on
      the claim only by weakening the opposing PCD evidence.
  - reference: PMID:40636384
    reference_title: "Case Report: Identification of a novel hemizygous CFAP47 variant in a primary ciliary dyskinesia patient with dual ciliary and flagellar defects."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated a male patient with suspected PCD who exhibited \"9 + 2\" ultrastructural abnormalities in both bronchial cilia and sperm flagella."
    explanation: A third man with airway and sperm axonemal defects.
  - reference: PMID:40636384
    reference_title: "Case Report: Identification of a novel hemizygous CFAP47 variant in a primary ciliary dyskinesia patient with dual ciliary and flagellar defects."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pathogenicity of this variant was assessed through multiple in silico tools, with divergent predictions."
    explanation: >-
      The PCD-associated variant in this case has uncertain pathogenicity.
      Indirect: it bears on the claim only by weakening the opposing PCD
      evidence.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Primary infertility, the presenting complaint.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: CGGV:assertion_5d2e51e3-fec5-4aa8-a093-d316c4feec02-2023-02-09T170000.000Z
    reference_title: "CFAP47 / spermatogenic failure, X-linked, 3 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Consistent features among the reported male patients are infertility, reduced sperm motility, and multiple morphological abnormalities of the sperm flagellum."
    explanation: ClinGen summary of the consistent phenotype.
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF."
    explanation: Infertile probands with MMAF.
- category: Reproductive
  name: Reduced sperm motility
  description: Present in every reported man, including those with normal sperm morphology.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A semen analysis indicated the severely reduced sperm motility in all of four men harboring hemizygous CFAP47 variants (Table 2)."
    explanation: Reduced motility in four men with MMAF.
  - reference: PMID:40473901
    reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the progressive motility rate of the spermatozoa decreased dramatically to 7.6% ± 5.1%, with rapid progressive motility at 2.4% ± 3.3% and slow progressive motility at 5.3% ± 1.8% (Supplementary information, Video S3)."
    explanation: Reduced motility in a man with normal sperm morphology.
- category: Reproductive
  name: Absent sperm flagella
  description: Part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Absent sperm flagella
    term:
      id: HP:0032558
      label: Absent sperm flagella
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the spermatozoa from men harboring hemizygous CFAP47 variants displayed frequently abnormal flagella, including absent, short, coiled flagella, and irregular caliber"
    explanation: Absent flagella in patient sperm.
- category: Reproductive
  name: Short sperm flagella
  description: Part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Short sperm flagella
    term:
      id: HP:0032559
      label: Short sperm flagella
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the spermatozoa from men harboring hemizygous CFAP47 variants displayed frequently abnormal flagella, including absent, short, coiled flagella, and irregular caliber"
    explanation: Short flagella in patient sperm.
- category: Reproductive
  name: Coiled sperm flagella
  description: Part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Coiled sperm flagella
    term:
      id: HP:0032560
      label: Coiled sperm flagella
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the spermatozoa from men harboring hemizygous CFAP47 variants displayed frequently abnormal flagella, including absent, short, coiled flagella, and irregular caliber"
    explanation: Coiled flagella in patient sperm.
- category: Reproductive
  name: Irregularly shaped sperm tail
  description: Irregular-caliber flagella are part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Irregular-caliber sperm flagella
    term:
      id: HP:0033393
      label: Irregularly shaped sperm tail
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the spermatozoa from men harboring hemizygous CFAP47 variants displayed frequently abnormal flagella, including absent, short, coiled flagella, and irregular caliber"
    explanation: Irregular-caliber flagella in patient sperm.
- category: Reproductive
  name: Abnormal sperm axoneme morphology
  description: >-
    In men with MMAF, electron microscopy shows disorganized outer dense
    fibers and missing peripheral or central microtubules. Men with
    truncating alleles and normal sperm morphology had an apparently normal
    axoneme.
  phenotype_term:
    preferred_term: Abnormal sperm axoneme morphology
    term:
      id: HP:0033524
      label: Abnormal sperm axoneme morphology
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the sperm flagella of men harboring hemizygous CFAP47 variants displayed a variety of ultrastructural defects, including disorganization of outer dense fibers, and absence of peripheral or central microtubules at the midpiece and principal piece of sperm flagella"
    explanation: Axonemal defects in men with MMAF.
  - reference: PMID:40473901
    reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Transmission electron microscopy (TEM) revealed an apparently normal “9 + 2” axoneme structure (Fig. 6g)."
    explanation: Not present in a man with an exon 28-62 deletion.
- category: Reproductive
  name: Abnormal sperm head morphology
  description: >-
    Two men with a recurrent missense variant had abnormal sperm heads,
    disorganized mitochondrial sheaths and defective annuli. No mechanism is
    established, so this phenotype is not linked to the causal chain.
  phenotype_term:
    preferred_term: Abnormal sperm head morphology
    term:
      id: HP:0012865
      label: Abnormal sperm head morphology
  evidence:
  - reference: PMID:37424856
    reference_title: "A novel mutation in CFAP47 causes male infertility due to multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All evidence indicates that CFAP47 mutation contributes not only to the MMAF phenotype but also to abnormalities in the sperm head and annulus."
    explanation: Head and annulus defects in two men.
genetic:
- name: CFAP47
  association: Causal
  gene_term:
    preferred_term: CFAP47
    term:
      id: hgnc:26708
      label: CFAP47
  gene_disease_validity:
  - validity_classification: LIMITED
    classified_by: CLINGEN
    external_id: CGGV:assertion_5d2e51e3-fec5-4aa8-a093-d316c4feec02-2023-02-09T170000.000Z
    evidence:
    - reference: CGGV:assertion_5d2e51e3-fec5-4aa8-a093-d316c4feec02-2023-02-09T170000.000Z
      reference_title: "CFAP47 / spermatogenic failure, X-linked, 3 (Limited)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CFAP47 | HGNC:26708 | spermatogenic failure, X-linked, 3 | MONDO:0025354 | XL | Limited"
      explanation: ClinGen gene-disease validity record classifying this gene-disease pair as Limited.
  notes: >-
    Reported alleles: hemizygous missense p.Ile2385Asn, p.Ser1742Gly and
    p.Pro2890Thr, a 3.2-Mb Xp21.1 deletion removing the whole gene
    (PMID:33472045), the recurrent missense p.V472M (PMID:37424856), an exon
    28-62 deletion and nonsense p.W3023* (PMID:40473901), and c.8006C>T in a
    man with cleavage failure after ICSI (PMID:42522280). ClinGen's 2023
    Limited classification scored only the three missense probands of
    PMID:33472045; all of those papers are cited here, and the later ones
    postdate the curation.
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF."
    explanation: Primary gene-disease report.
  - reference: PMID:37424856
    reference_title: "A novel mutation in CFAP47 causes male infertility due to multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing confirmed a hemizygous CFAP47 missense variant in the two families."
    explanation: Two further unrelated men.
  - reference: PMID:40473901
    reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, an exon deletion in Patient 1 and a nonsense mutation in Patient 2 were strongly linked to asthenozoospermia (Supplementary information, Table S4)."
    explanation: Truncating alleles from a 320-man asthenozoospermia cohort.
animal_models:
- name: Cfap47 frameshift mouse
  species: Mouse
  genotype: Cfap47 c.2559insT (p.Gly855Profs*8), hemizygous (Cfap47-/Y)
  publication: PMID:33472045
  description: >-
    Hemizygous males are sterile with reduced motility and bent flagella
    arising in the epididymis, normal sperm concentration and no gross
    axonemal defect; ICSI rescues fertilization.
  modeled_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Reproduces sterility and asthenozoospermia but only part of the MMAF phenotype.
    limitations: >-
      Mutant sperm show mainly bent flagella and no obvious axonemal
      ultrastructural defect, a milder phenotype than the full MMAF of most
      patients.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse sperm lacking CFAP47 keep their flagellar form and axoneme,
        whereas most hemizygous men have short, absent and coiled flagella
        with missing microtubules; the mouse models the motility defect
        better than the malformation.
    evidence:
    - reference: PMID:33472045
      reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Overall, the sperm phenotype of Cfap47-mutated male mice appears milder than the phenotype of men harboring hemizygous CFAP47 variants."
      explanation: Authors' statement of the milder mouse phenotype.
- name: Cfap47 knockout mouse (exons 2-50 deletion)
  species: Mouse
  genotype: Cfap47 171.6-kb deletion of exons 2-50, hemizygous
  publication: PMID:40473901
  description: >-
    Knockout males are otherwise healthy, with normal sperm counts and
    morphology but reduced motility and fertility; the central apparatus
    lacks the CFAP47 bridge density.
  modeled_mechanisms:
  - target: Loss of the C1-C2 Bridge of the Central Apparatus
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Shows the structural lesion directly and reproduces the asthenozoospermia
      with normal morphology seen in men with truncating alleles.
    evidence:
    - reference: PMID:40473901
      reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Cfap47-KO mice lack density associated with the CFAP47 and SPAG6 proteins in the bridge region of the CA structure."
      explanation: Bridge density is lost in knockout sperm.
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: Knockout sperm have normal morphology, so MMAF is not reproduced.
    limitations: >-
      Normal sperm counts and morphology in knockout mice match the
      truncating-allele men but not the majority of reported men, who have
      MMAF.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse sperm without CFAP47 are motility-impaired but morphologically
        normal; whether human MMAF in CFAP47 men reflects a species difference,
        variant-specific effects or contributions from co-deleted genes is
        unknown.
    evidence:
    - reference: PMID:40473901
      reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This phenotype, characterized by asthenozoospermia with normal morphology, is hereafter referred to as ANM."
      explanation: Knockout sperm morphology is normal.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI bypasses the motility defect. Three of four couples in the first
    series achieved pregnancy (the fourth wife had poor oocyte quality), one
    man with an exon deletion obtained nine transferable embryos, and one
    couple with a recurrent missense variant did not conceive after one
    cycle. A man with c.8006C>T had cleavage failure after ICSI that improved
    with assisted oocyte activation (AOA), with ongoing pregnancy, and
    altered PLCZ1 localization in sperm.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Intracytoplasmic Sperm Injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    description: Direct injection makes flagellar propulsion irrelevant to fertilization.
    evidence:
    - reference: PMID:33472045
      reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Therefore, our studies strongly indicated that the damaged male fertility caused by hemizygous CFAP47 variants can be rescued by ICSI treatment."
      explanation: ICSI circumvents the flagellar defect.
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, three out of the four men harboring hemizygous CFAP47 variants in this study achieved good clinical outcomes after assisted reproductive therapy by ICSI (Table 3)."
    explanation: Good ICSI outcomes in three of four couples.
  - reference: PMID:40473901
    reference_title: "In situ structure of the mouse sperm central apparatus reveals mechanistic insights into asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Assisted reproductive technology, specifically intracytoplasmic sperm injection (ICSI) for Patient 1 and his wife, resulted in successful fertilization of 11 metaphase II (MII) oocytes, yielding 9 transferable embryos"
    explanation: Successful fertilization for a man with a truncating deletion.
  - reference: PMID:37424856
    reference_title: "A novel mutation in CFAP47 causes male infertility due to multiple morphological abnormalities of the sperm flagella."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Regrettably, his wife has not succeeded in pregnancy."
    explanation: An unsuccessful ICSI cycle; the authors could not exclude female factors.
  - reference: PMID:42522280
    reference_title: "Genotype-based management of fertilization and cleavage failure: case-series evidence from DNAH10, DNAH12, CFAP47 , and PLCZ1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Management-matched genotype: ICSI restored fertilization in DNAH10/DNAH12 deficiency, whereas ICSI plus assisted oocyte activation (AOA) improved cleavage and yielded ongoing pregnancies in CFAP47/PLCZ1 deficiency."
    explanation: ICSI with AOA in a man with CFAP47-associated cleavage failure.
- name: Genetic Counseling
  description: >-
    X-linked recessive counselling. Daughters of an affected man are obligate
    carriers and his sons are unaffected; a carrier woman's sons each have a
    50% risk of infertility.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, for ICSI performed in case of X-linked CFAP47-associated MMAF, 100% of female (but no male) offspring will inherit heterozygous deleterious variants of CFAP47."
    explanation: The transmission risks that counselling must convey.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis. Exome sequencing finds the hemizygous SNVs;
    copy-number analysis of exome or genome data is needed to find Xp21.1
    deletions.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene."
    explanation: Copy-number analysis of exome data detected a whole-gene deletion.
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF."
    explanation: Exome sequencing detected the missense variants.
- name: Semen Analysis
  description: >-
    Shows severely reduced progressive motility, usually with MMAF; sperm
    morphology can be normal with truncating alleles.
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A semen analysis indicated the severely reduced sperm motility in all of four men harboring hemizygous CFAP47 variants (Table 2)."
    explanation: Semen analysis findings.
- name: Transmission Electron Microscopy of Sperm Flagella
  description: >-
    Shows missing central or peripheral microtubules and disorganized outer
    dense fibers in men with MMAF; can be normal with truncating alleles.
  diagnosis_term:
    preferred_term: Transmission Electron Microscopy
    term:
      id: NCIT:C18216
      label: Transmission Electron Microscopy
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the sperm flagella of men harboring hemizygous CFAP47 variants displayed a variety of ultrastructural defects, including disorganization of outer dense fibers, and absence of peripheral or central microtubules at the midpiece and principal piece of sperm flagella"
    explanation: TEM findings.
- name: Immunofluorescence of CFAP47 in Sperm
  description: >-
    Reduced or absent CFAP47 staining at the flagellar base, with displaced
    CFAP65, supports pathogenicity of missense variants.
  evidence:
  - reference: PMID:33472045
    reference_title: "Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP47 staining is concentrated at the base of sperm flagella from the control individual, but the signal was almost absent in the sperm flagella from men harboring hemizygous CFAP47 variants."
    explanation: Immunofluorescence demonstrates protein loss.

📚

References & Deep Research

Deep Research

1

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.

Evaluations and curation notes (1)

Create: Spermatogenic Failure X-linked 3 (CFAP47) · 2026-10-16T13:41:55Z · View source

New entry for SPGFX3 (MONDO:0025354), X-linked recessive asthenozoospermia/MMAF caused by hemizygous CFAP47 variants. Deep research with the claude_code provider (research/Spermatogenic_Failure_X-linked_3-deep-research-claude_code.md; preflight-dr matched CFAP47) was used as leads only; PubMed search added the central-apparatus cryo-ET study with two truncating-allele men (PMID:40473901), a recurrent missense family (PMID:37424856), PCD-like reports (PMID:37723893, PMID:40636384) and an AOA case series (PMID:42522280). Inheritance bound to HP:0001419. ClinGen Limited (XL, 2023) copied from the CGGV record; ClinGen's Disputed PKD curation is noted only. Pathograph: CFAP47 loss (GO:0008017 microtubule binding and GO:0005200, DECREASED) -> C1-C2 bridge loss -> reduced motility (and, mechanism unknown, MMAF) plus CFAP65 mislocalization -> MMAF. Two hypotheses: phenotypic spectrum (MMAF vs asthenozoospermia with normal morphology) and sperm restriction vs PCD, with REFUTE items and stated weakness of the PCD evidence. Two mouse models, one FAILS_TO_RECAPITULATE MMAF, with SPECIES_MISMATCH divergences. ICSI outcomes including AOA, X-linked counselling, exome/CNV testing, semen analysis, TEM, immunofluorescence. No GeneReviews/StatPearls chapter. Stub stubs/Spermatogenic_Failure_X-linked_3.yaml deleted. Validated with the same gates.

Claude Code ▸

Spermatogenic Failure, X-linked, 3 (SPGFX3; CFAP47-related MMAF): Research Report

claude-haiku-5-5, claude-sonnet-5-5 8 citations 2026-10-16T13:13:47.243370

Spermatogenic Failure, X-linked, 3 (SPGFX3; CFAP47-related MMAF): Research Report

Scope and verification. I verified the core facts below by search or fetch in this session. These are the OMIM, MONDO and DOID identifiers, the gene assignment, and the contents of two primary papers (Liu C 2021, PMID 33472045; Liu M 2023, DOI 10.3389/fendo.2023.1155639).

Only those two primary papers were read. Other CFAP47 reports exist in the literature, and I did not retrieve them.
Ontology IDs marked (unverified) are from memory. Look them up before binding them; do not copy them into a KB entry as written.
I did not obtain a PMID for the 2023 Frontiers paper.
OMIM, Orphanet, ClinVar, gnomAD and GeneReviews pages were not read directly. Claims attributed to them come from search snippets or from the primary papers' own text.
The fetch-reference cache and just validate-* were not run, so none of the snippets below has been checked against references_cache/.

1. Disease Information

Overview. SPGFX3 is an X-linked recessive cause of male infertility. It is characterized by asthenoteratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF): flagella that are absent, short, coiled, bent or of irregular caliber. It is caused by hemizygous loss-of-function or missense variants in CFAP47 at Xp21.1. Affected men are otherwise described as having isolated infertility. Neither paper reports a syndromic extra-reproductive phenotype.

Identifiers.

System	ID	Source
OMIM	301059	LOVD disease #06940, MalaCards
MONDO	MONDO:0025354	SAIL concept library
DOID	DOID:0112274	Disease Ontology
UMLS / MedGen	C5542347 / 1784059	MedGen
Gene	CFAP47 (formerly CXorf59), Xp21.1, Entrez 286464	GlyCosmos and LOVD

Synonyms: SPGFX3; X-linked spermatogenic failure 3.
Parent concept (Mondo): spermatogenic failure, within male infertility.
OMIM cross-reference: SPGF1 (258150) for genetic heterogeneity of spermatogenic failure.
Naming discrepancy: the LOVD entry uses the obsolete symbol CXorf59, which is the old name of CFAP47.
Source level: the evidence is from individual patients (exome sequencing, semen analysis, sperm electron microscopy). OMIM and MONDO are aggregated disease-level resources built on those reports.
Near-namesake caution: an unofficial dismech-hosted report on SPGFX1/TEX11 exists. Search-result commentary flagged its SPGFX gene mappings as internally inconsistent. Do not take SPGFX2 or SPGFX4 assignments from it. Confirm each against OMIM.

2. Etiology

Causal factor: genetic. Hemizygous CFAP47 variants in males. Reported alleles are missense changes and one whole-gene deletion.
Genetic risk factors: no modifier genes or susceptibility loci have been described in the papers I read.
Environmental risk factors, protective factors, gene-environment interactions: none reported. I would not infer any.
Allele caution: p.V472M (c.1414G>A) is reported at about 0.009 allele frequency in East Asian reference populations, per Liu M 2023. That is high for a fully penetrant X-linked recessive allele, so its pathogenicity rests on functional data, not rarity.

3. Phenotypes

All phenotypes are laboratory or sperm-morphology findings in adult males (human clinical evidence). Frequencies are the cohort counts in the primary papers. Four men were reported in 2021 and two in 2023, so no population-level frequency exists.

Phenotype	Detail	Suggested HPO (unverified)
Male infertility (primary)	All reported men	Male infertility, HP:0003251
Asthenozoospermia	Motility 10–23% (WHO limit 40%) in the 2021 men; 11–21% in the 2023 men	Asthenozoospermia, HP:0012206
Teratozoospermia / MMAF	Absent, short, coiled flagella	Teratozoospermia, HP:0012864
Oligozoospermia (variable)	0.5–29.5 ×10⁶/mL (2021); 0.9 and 6.0 (2023)	Oligozoospermia, HP:0000798
Abnormal sperm head morphology	Pyriform, round, small heads; small or absent acrosomes (2023 patients)	Look up
Abnormal axoneme ultrastructure	Disorganized outer dense fibers; missing peripheral doublets or central pair	Look up

2021 morphology by subject (Liu C 2021, Table 2, as summarized by the fetch):

T115: absent 37.5%, short 34%, coiled 18.5%.
T176: absent 11%, short 17%, coiled 42%.
H025: absent 22%, short 14%, coiled 50.5%.

Onset, progression, quality of life. Not reported. Presentation is in adulthood, as couple infertility. Nothing is known about progression or quality of life. Semen findings are presumably stable, but that is an inference.

Hormones and testis. The 2021 paper reports no FSH, LH, testosterone or testicular histology data. I would leave endocrine phenotypes uncurated.

4. Genetic/Molecular Information

Gene: CFAP47 (cilia- and flagella-associated protein 47). A very large X-linked gene highly expressed in testis.
Variants reported:

Variant	Type	Reference
c.7154T>A, p.Ile2385Asn	missense	Liu C 2021
c.5224A>G, p.Ser1742Gly	missense	Liu C 2021
c.8668C>A, p.Pro2890Thr	missense	Liu C 2021
~3.2 Mb Xp21.1 deletion removing all of CFAP47	deletion	Liu C 2021 (Australian man MA2603)
c.1414G>A, p.Val472Met	missense	Liu M 2023, two unrelated patients

Screening yield (2021): 243 men with MMAF (CITIC-Xiangya, Changsha) and 88 (Anhui Medical University), plus 24 Australian men with asthenoteratozoospermia. These yielded three missense carriers and the one deletion. The fetch did not give the exact per-cohort breakdown.
Origin: germline, hemizygous in males.
Functional consequence: CFAP47 protein is strongly reduced in patient sperm. Loss of function, or reduced function from missense variants, is the working model. I would not claim dominant negative or gain of function.
Modifier genes, epigenetics, chromosomal abnormalities: none described, apart from the Xp21.1 deletion.
ClinGen / validity: a search snippet showed a disease database linking CFAP47 to this MONDO term at only "limited" evidence. I did not find a ClinGen CGGV: record. If you record gene-disease validity, copy it from a source record. Do not assign it.

5. Environmental Information

None reported. No toxins, lifestyle factors or infectious agents are implicated.

6. Mechanism / Pathophysiology

Causal chain.

A hemizygous CFAP47 variant (missense or deletion) arises in a male. Males have no second X allele to compensate (demonstrated genetically).
This leads to markedly reduced CFAP47 protein in sperm. Immunofluorescence shows the signal almost absent at the flagellar base (demonstrated for the 2021 men; Western blot reduction in the 2023 patients).
This is associated with reduced or mislocalized partner proteins. CFAP65 is mislocalized in mutant sperm and co-immunoprecipitates with CFAP47. CFAP69, SEPTIN4 and CFAP65 are reduced in the 2023 patients. These expression and localization changes are correlative. Whether CFAP47 regulates them, or is only co-lost with them, is inferred, not demonstrated.
This leads to defective axonemal and peri-axonemal assembly. TEM shows disorganized outer dense fibers and missing peripheral doublets or central pair. SPAG16 is reduced. The 2023 patients also show a defective annulus and a disorganized mitochondrial sheath.
This results in absent, short, coiled or bent flagella and impaired motility (MMAF, asthenoteratozoospermia).
This results in male infertility. Branch (2023 patients): abnormal head morphology and small or absent acrosomes. How a flagellar protein loss produces head defects is not explained and is not established.

Mouse timing. In the Cfap47 mutant mouse, flagellar bending was first seen in the corpus epididymis, not the testis. That suggests a late structural defect, but this is one study.

Cell types and processes.

Cell types: spermatid and spermatozoon, with Sertoli-cell context.
Suggested terms (unverified): spermatozoon (CL), spermatid (CL); GO terms for sperm flagellum assembly and axoneme assembly.

Omics, single-cell, CRISPR screens, immune or metabolic involvement. Not reported.

7. Anatomical Structures Affected

Organs: testis and the male reproductive tract (UBERON testis, epididymis (unverified)).
Cells: developing and mature sperm.
Subcellular: sperm flagellum, axoneme, outer dense fibers, fibrous sheath, annulus, mitochondrial sheath, flagellar base (GO cellular component terms to be looked up).
Lateralization: not applicable.

8. Temporal Development

Onset: presumably congenital. It is clinically ascertained in adulthood by infertility.
Course: lifelong. Spontaneous remission is not reported.
Critical period: none identified.

9. Inheritance and Population

Inheritance: X-linked recessive (HPO "X-linked recessive inheritance" (verify ID)). Males are affected, with hemizygous variants.
Carrier females: no phenotype is reported in the sources I read.
Penetrance and expressivity: semen parameters vary (concentration 0.5–29.5 ×10⁶/mL), but all reported men are infertile. I would not state a formal penetrance.
Prevalence: not documented. This is a very rare, recently described condition. Do not assign a prevalence class beyond "not yet documented" without a source.
Populations: reported cases are mostly Chinese, plus one Australian man. Founder effects, anticipation and mosaicism are not described.
Sex ratio: affects males only.

10. Diagnostics

Semen analysis shows asthenozoospermia or oligoasthenoteratozoospermia, with a high proportion of absent, short, coiled or irregular-caliber flagella.
Sperm TEM: disorganized axoneme and outer dense fibers.
Immunofluorescence of sperm for CFAP47 (and CFAP65, SPAG16) is a research tool, not a clinical test.
Genetic testing: exome sequencing or an MMAF gene panel including CFAP47. Use chromosomal microarray or CNV analysis for deletions, because the whole-gene deletion was found that way.
Differential diagnosis: other MMAF genes (for example DNAH1, CFAP43, CFAP44, CFAP69) and primary ciliary dyskinesia. I did not retrieve sources for these; confirm in the literature before curating.
Screening: none established.

11. Outcome/Prognosis

No mortality or morbidity beyond infertility is reported. Reproductive prognosis with assisted reproduction (ICSI) appears favorable in the 2021 cohort and was mixed in the 2023 patients (see Treatment).

12. Treatment

No curative therapy exists. Sperm from these men is usable for ICSI.

NCIT terms to use, from your CLAUDE.md list:

Assisted reproduction: bind the closest action term, or leave term: empty. NCIT:C15329 (Surgical Procedure) is not right for ICSI. Search NCIT for ICSI directly.
Genetic counseling: NCIT:C15240.

ICSI outcomes, Liu C 2021 (Table 3):

Subject	Oocytes injected	Fertilized	Blastocysts	Outcome
T115	1	0	–	No pregnancy; partner aged 41
T176	9	8 (89%)	5 (63%)	Clinical pregnancy
H025	11	9 (82%)	7 (78%)	Clinical pregnancy
MA2603	12	10 (83%)	3 (30%)	Clinical pregnancy; one miscarriage

Three of four couples achieved clinical pregnancy.

ICSI outcomes, Liu M 2023: no pregnancies in the cycles reported.

Patient A: 3/5 fertilized, one 8-cell embryo transferred, no pregnancy.
Patient B: first cycle 1/4 fertilized, second cycle 2/3 fertilized, embryos failed to develop.
The authors attribute the failures possibly to female factors.

Reconciliation. Pooling both papers, ICSI achieved fertilization in most cycles but pregnancy in three of six couples. The small numbers and female-factor confounders mean this is not a success rate.

Experimental treatments: no NCT trials identified. I did not search ClinicalTrials.gov.

13. Prevention

Genetic counseling: a carrier mother passes the variant to half of her sons. Daughters of an affected man are obligate carriers. This is standard X-linked reasoning, not drawn from the papers.
Prenatal and preimplantation testing: possible once the family variant is known. Not discussed in the sources I read.
Primary prevention: none.

14. Other Species / Natural Disease

I did not search OMIA, so I cannot confirm a naturally occurring animal disease. Treat this section as not assessed.

15. Model Organisms

Mouse (Liu C 2021). A Cfap47 frameshift allele, c.2559insT (p.Gly855Profs*8), made hemizygous in males.

Fertility: males were sterile over 3 months of breeding.
Sperm: reduced total and progressive motility, abnormal "folding" movement, lower VCL, VSL and VAP. Sperm concentration was not significantly different.
Morphology: bent flagella, first seen in the corpus epididymis, and unevenly distributed fibrous sheaths on TEM.
IVF: lower two-cell and blastocyst rates. ICSI: rates comparable to wild type.
Localization: Cfap47 signal is mainly in the midpiece in mouse sperm. In human control sperm it is at the flagellar base, which is a species difference.
Fidelity: the mouse recapitulates infertility, asthenozoospermia and flagellar abnormalities. It differs from humans in having normal sperm concentration and, apparently, a milder morphology (bent flagella versus the human absent, short and coiled mix).
Suggested links: modeled_mechanisms with PARTIALLY_RECAPITULATES against a flagellar-assembly node; evidence_source: MODEL_ORGANISM.
Resources: IMPC and MGI entries exist (the search surfaced an MGI:3605549 phenotype page). I did not check them.

Evidence and snippet candidates

Quotes below come from the fetch's paraphrase and summaries, not from verified abstract text. Re-copy exact snippets from references_cache after just fetch-reference PMID:33472045.

Claim	Reference	Evidence source
Hemizygous CFAP47 variants cause X-linked MMAF and asthenoteratozoospermia	PMID:33472045	HUMAN_CLINICAL
ICSI restores fertility in the mouse and in 3 of 4 men	PMID:33472045	MODEL_ORGANISM (mouse); HUMAN_CLINICAL (men). Split these into separate items
p.V472M in two patients; CFAP47 binds CFAP69 and SEPTIN4	DOI:10.3389/fendo.2023.1155639 (PMID not found)	HUMAN_CLINICAL (variant); IN_VITRO or ex vivo (co-IP in human testis)

Gaps and recommendations

Look up the PMID for Liu M 2023 and read any other CFAP47 papers (cohort studies, follow-ups) before finalizing prevalence, yield and variant spectrum.
Check OMIM 301059, GeneReviews and Orphanet directly.
Search NCIT for an ICSI term. Do not guess a CURIE.
Verify every HPO, GO, CL and UBERON term listed above with runoak or the term caches.
Check ClinGen for a CFAP47 validity record before filling gene_disease_validity.

Sources: - LOVD SPGFX3 disease #06940 - MalaCards SPGFX3 - Disease Ontology DOID:0112274 - MedGen C5542347 - MONDO:0025354 record - Liu C et al., Am J Hum Genet 2021 (PMC7895902) - Liu M et al., Front Endocrinol 2023 - The X chromosome and male infertility (PMC7864851)

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	4
Resolved	4
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	4
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	9
Resolved	8
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	3
Terms named correctly	1
Terms named as a different term	2

Terms the report names something else

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:

MONDO:0025354 (5 mentions) - the report calls it "MONDO"; MONDO calls it spermatogenic failure, X-linked, 3
DOID:0112274 (5 mentions) - the report calls it "DOID"; DOID calls it X-linked spermatogenic failure 3

Prefixes with no resolver

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: MGI.

Spermatogenic Failure X-linked 3

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References & Deep Research

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Spermatogenic Failure, X-linked, 3 (SPGFX3; CFAP47-related MMAF): Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence and snippet candidates

Gaps and recommendations

Reference Validation

Term Validation

Terms the report names something else

Prefixes with no resolver