# NM_144668.6(CFAP251):c.123del (p.Asp42fs)

https://sugi.bio/variant/cfap251-p-asp42fs

## Summary

**CFAP251 p.Asp42fs (c.123del)** is classified **Pathogenic** in CFAP251 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2024-03-04). Very rare (popmax 0.0033%, sas); Associated with spermatogenic failure 33.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs749163856 · 2 submitters · 2 linked conditions · very rare (popmax 0.0033%, sas)

## For patients & families {#patients}

This is a change in the CFAP251 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to spermatogenic failure 33.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018406/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CFAP251](https://sugi.bio/atlas/gene/CFAP251/) |
| Protein change (HGVS p.) | p.Asp42fs |
| Coding change (HGVS c.) | c.123del |
| MANE Select transcript | [NM_144668](https://www.ncbi.nlm.nih.gov/nuccore/NM_144668) |
| dbSNP | [rs749163856](https://www.ncbi.nlm.nih.gov/snp/rs749163856/) |
| Variant type | Deletion |
| Location | chr12:121921425-121921425 (GRCh38) |
| ClinVar | [VCV548450](https://www.ncbi.nlm.nih.gov/clinvar/variation/548450/) |

**All HGVS expressions:** `NC_000012.11:g.122359334del`, `NC_000012.12:g.121921428del`, `NG_021364.2:g.7872del`, `NM_001178003.2:c.123del`, `NM_144668.6:c.123del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -2.151, GERP -1.94 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.829, pLI 5.7652e-19. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 22**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0033%** (sas) · FAF95 0.000876% · FAF99 0.000443% · 3/91,014 in the highest group · 3/1,461,790 alleles overall — very rare (popmax 0.0033%, sas).

*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}

**CFAP251** population constraint: LOEUF 0.829, pLI 5.7652e-19, missense-Z 1.6369. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **42** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 76.84, 50% of residues very-high.

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

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-03-04.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2018–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2024-03-04 |
| Marseille Medical Genetics, U1251, Aix Marseille University, Inserm | Pathogenic | no assertion criteria provided | clinical testing | 2018-06-29 |

## Associated conditions {#conditions}

[spermatogenic failure 33](https://sugi.bio/atlas/disease/spermatogenic-failure-33/), [male infertility with teratozoospermia due to single gene mutation](https://sugi.bio/atlas/disease/male-infertility-with-teratozoospermia-due-to-single-gene-mutation/).

**Reported phenotype names (ClinVar):** Spermatogenic failure 33, Male infertility with teratozoospermia due to single gene mutation, Non-syndromic male infertility due to sperm motility disorder.

## Similar variants {#similar}

Related CFAP251 variant pages (same residue, condition, or type): [CFAP251 p.Arg644fs](/variant/cfap251-p-arg644fs), [CFAP251 p.Glu68fs](/variant/cfap251-p-glu68fs), [CFAP251 c.3007-4915_3338-930del](/variant/cfap251-c-3007-minus-4915-3338-minus-930del), [CFAP251 p.Leu530fs](/variant/cfap251-p-leu530fs), [CFAP251 p.Arg267Ter](/variant/cfap251-p-arg267ter), [CFAP251 p.Glu111Ter](/variant/cfap251-p-glu111ter), [CFAP251 c.-20-2A>C](/variant/cfap251-c-minus-20-minus-2a-c), [CFAP251 p.Gln129Ter](/variant/cfap251-p-gln129ter).

### 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 548450). 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.*