# NM_173528.4(CFAP161):c.757G>C (p.Asp253His)

https://sugi.bio/variant/cfap161-p-asp253his

## Summary

**CFAP161 p.Asp253His (c.757G>C)** is classified **Uncertain significance** in CFAP161 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.7928); Very rare (popmax 0.00297%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs780944441 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00297%, nfe)

## For patients & families {#patients}

This is a change in the CFAP161 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CFAP161](https://sugi.bio/atlas/gene/CFAP161/) |
| Protein change (HGVS p.) | p.Asp253His |
| Coding change (HGVS c.) | c.757G>C |
| MANE Select transcript | [NM_173528](https://www.ncbi.nlm.nih.gov/nuccore/NM_173528) |
| dbSNP | [rs780944441](https://www.ncbi.nlm.nih.gov/snp/rs780944441/) |
| Variant type | single nucleotide variant |
| Location | chr15:81148384-81148384 (GRCh38) |
| ClinVar | [VCV3143345](https://www.ncbi.nlm.nih.gov/clinvar/variation/3143345/) |

**All HGVS expressions:** `NC_000015.10:g.81148384G>C`, `NC_000015.9:g.81440725G>C`, `NM_173528.4:c.757G>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** (0.7928)
- REVEL 0.343 (indeterminate)
- SaProt LLR -14.807 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.313, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 9%** most-pathogenic-predicted substitutions in CFAP161 (of 1,769 modeled).
- CADD: **PHRED 23.5**. 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 0.99** across the covering region of the MANE Select transcript (81,134,330–81,148,530), spanning 14,200 bp. Chi-square p 0.8. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.23**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 46 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.26** (loss), gain 0.01 / loss 0.26. Agrees with SpliceAI. 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 **0.00297%** (nfe) · FAF95 0.00215% · FAF99 0.00191% · 35/1,180,032 in the highest group · 40/1,614,058 alleles overall — very rare (popmax 0.00297%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,498 |
| European (non-Finnish) (grpmax) | 0.00297% | 33,715 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CFAP161** population constraint: LOEUF 1.029, pLI 0.00034972, missense-Z 0.21932. *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 87.29, 63% of residues very-high.

**2 experimental structure(s)** (PDB): [7UNG](https://www.rcsb.org/structure/7UNG), [8J07](https://www.rcsb.org/structure/8J07).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-30.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-30 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CFAP161 variant pages (same residue, condition, or type): [CFAP161 p.Ala115Thr](/variant/cfap161-p-ala115thr), [CFAP161 p.Ala295Ser](/variant/cfap161-p-ala295ser), [CFAP161 p.Ala2Ser](/variant/cfap161-p-ala2ser), [CFAP161 p.Arg203Cys](/variant/cfap161-p-arg203cys), [CFAP161 p.Arg203His](/variant/cfap161-p-arg203his), [CFAP161 p.Arg226Gln](/variant/cfap161-p-arg226gln), [CFAP161 p.Arg226Trp](/variant/cfap161-p-arg226trp), [CFAP161 p.Arg87His](/variant/cfap161-p-arg87his).

### 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 3143345). 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.*