# NM_177965.4(CFAP418):c.253T>C (p.Ser85Pro)

https://sugi.bio/variant/cfap418-p-ser85pro

## Summary

**CFAP418 p.Ser85Pro (c.253T>C)** is classified **Uncertain significance** in CFAP418 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.0757); Very rare (popmax 0.00119%, sas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2537146537 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00119%, sas)

## For patients & families {#patients}

This is a change in the CFAP418 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [CFAP418](https://sugi.bio/atlas/gene/CFAP418/) |
| Protein change (HGVS p.) | p.Ser85Pro |
| Coding change (HGVS c.) | c.253T>C |
| MANE Select transcript | [NM_177965](https://www.ncbi.nlm.nih.gov/nuccore/NM_177965) |
| dbSNP | [rs2537146537](https://www.ncbi.nlm.nih.gov/snp/rs2537146537/) |
| Variant type | single nucleotide variant |
| Location | chr8:95260523-95260523 (GRCh38) |
| ClinVar | [VCV3143453](https://www.ncbi.nlm.nih.gov/clinvar/variation/3143453/) |

**All HGVS expressions:** `NC_000008.10:g.96272751A>G`, `NC_000008.11:g.95260523A>G`, `NG_032804.1:g.13712T>C`, `NM_001363260.1:c.253T>C`, `NM_177965.4:c.253T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0757)
- REVEL 0.126 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.225 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.472, GERP -2.12, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 16.86**. 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 1.01** across the covering region of the MANE Select transcript (95,247,620–95,269,189), spanning 21,569 bp. Chi-square p 0.91. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.26**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**. Largest is acceptor loss, 13 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00119%** (sas) · 1/84,376 in the highest group · 1/1,580,996 alleles overall — very rare (popmax 0.00119%, 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}

**CFAP418** population constraint: LOEUF 1.642, pLI 1.7648e-05, missense-Z 0.13822; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **ciliopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.73, 42% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-12.

**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 | 2021-08-12 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CFAP418 variant pages (same residue, condition, or type): [CFAP418 p.Ser85Phe](/variant/cfap418-p-ser85phe), [CFAP418 p.Ile171Arg](/variant/cfap418-p-ile171arg), [CFAP418 p.Arg177Trp](/variant/cfap418-p-arg177trp), [CFAP418 p.Trp147Ter](/variant/cfap418-p-trp147ter), [CFAP418 p.Trp185Ter](/variant/cfap418-p-trp185ter), [CFAP418 c.*408G>A](/variant/cfap418-c-star-408g-a), [CFAP418 c.*965C>G](/variant/cfap418-c-star-965c-g), [CFAP418 p.Ala178Val](/variant/cfap418-p-ala178val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 3143453). 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.*