# NM_033364.4(CFAP91):c.124G>C (p.Asp42His)

https://sugi.bio/variant/cfap91-p-asp42his

## Summary

**CFAP91 p.Asp42His (c.124G>C)** is classified **Uncertain significance** in CFAP91 (ClinVar, Single submitter, 3 submitters; last evaluated 2022-10-03). AlphaMissense: likely pathogenic (0.8155); Ultra-rare (popmax 0.0333%, mid); Associated with CFAP91-related condition.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs149348782 · 3 submitters · 3 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0333%, mid)

## For patients & families {#patients}

This is a change in the CFAP91 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to CFAP91-related condition.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CFAP91](https://sugi.bio/atlas/gene/CFAP91/) |
| Protein change (HGVS p.) | p.Asp42His |
| Coding change (HGVS c.) | c.124G>C |
| MANE Select transcript | [NM_033364](https://www.ncbi.nlm.nih.gov/nuccore/NM_033364) |
| dbSNP | [rs149348782](https://www.ncbi.nlm.nih.gov/snp/rs149348782/) |
| Variant type | single nucleotide variant |
| Location | chr3:119703222-119703222 (GRCh38) |
| ClinVar | [VCV812096](https://www.ncbi.nlm.nih.gov/clinvar/variation/812096/) |

**All HGVS expressions:** `NC_000003.11:g.119422069G>C`, `NC_000003.12:g.119703222G>C`, `NM_001320316.2:c.15G>C`, `NM_001320317.2:c.15G>C`, `NM_001320318.2:c.-20G>C`, `NM_033364.4:c.124G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.8155)
- REVEL 0.588 (indeterminate)
- SaProt LLR -10.193 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **donor gain** (Δ 0.48) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 10.77, GERP 1.3, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in CFAP91 (of 4,498 modeled).
- CADD: **PHRED 34.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.02** across the covering region of the MANE Select transcript (119,703,099–119,751,094), spanning 47,995 bp. Chi-square p 0.55. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.35**, acceptor gain **0.00**, donor gain **0.48**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.35**, acceptor gain **0.00**, donor gain **0.48**.
- Pangolin: Δ**0.67** (loss), gain 0.48 / loss 0.67. SpliceAI calls gain. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0333%** (mid) · FAF95 0.0103% · FAF99 0.00948% · 2/6,008 in the highest group · 161/1,611,692 alleles overall — ultra-rare (popmax 0.0333%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0333% | 3,004 |
| Admixed American | 0.0184% | 5,427 |
| European (non-Finnish) | 0.0117% | 8,544 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,911 |
| African / African-American | 0.004% | 25,001 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CFAP91** population constraint: LOEUF 1.129, pLI 9.8021e-20, missense-Z 0.12954. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.20, 23% of residues very-high.

**1 experimental structure(s)** (PDB): [8J07](https://www.rcsb.org/structure/8J07).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-03.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Uncertain significance).

**Submission history:** 3 submissions (2019–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2021-02-08 |
| Genetics of Infertility and Preimplantation Genetic Diagnosis, Centre Hospitalier Universitaire Grenoble Alpes | Pathogenic | no assertion criteria provided | case-control | 2019-08-21 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | research | 2022-10-03 |

## Associated conditions {#conditions}

[CFAP91-related condition](https://sugi.bio/atlas/disease/cfap91-related-condition/), [male infertility with teratozoospermia due to single gene mutation](https://sugi.bio/atlas/disease/male-infertility-with-teratozoospermia-due-to-single-gene-mutation/), [spermatogenic failure 51](https://sugi.bio/atlas/disease/spermatogenic-failure-51/).

**Reported phenotype names (ClinVar):** CFAP91-related condition, Male infertility with teratozoospermia due to single gene mutation, Spermatogenic failure 51.

## Similar variants {#similar}

Related CFAP91 variant pages (same residue, condition, or type): [CFAP91 c.359+1G>A](/variant/cfap91-c-359-plus-1g-a), [CFAP91 p.Gln545Ter](/variant/cfap91-p-gln545ter), [CFAP91 p.Gln415Ter](/variant/cfap91-p-gln415ter), [CFAP91 c.682+1G>A](/variant/cfap91-c-682-plus-1g-a), [CFAP91 p.Ile285fs](/variant/cfap91-p-ile285fs), [CFAP91 c.501-3T>C](/variant/cfap91-c-501-minus-3t-c), [CFAP91 p.Ala249Asp](/variant/cfap91-p-ala249asp), [CFAP91 p.Ala256Thr](/variant/cfap91-p-ala256thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 812096). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*