Is CWC25 p.Val231Phe (c.691G>T) pathogenic?

CWC25 p.Val231Phe (c.691G>T) is classified Uncertain significance in CWC25 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-03). AlphaMissense: likely benign (0.0929); Ultra-rare (popmax 0.0181%, nfe).

How common is CWC25 p.Val231Phe (c.691G>T) in the general population?

CWC25 p.Val231Phe (c.691G>T) is ultra-rare (popmax 0.0181%, nfe) (gnomAD).

What do computational predictors say about CWC25 p.Val231Phe (c.691G>T)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

CWC25 p.Val231Phe

c.691G>T · rs187341764 · VCV3079104

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0181%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -6.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.12	GERP -4.5, phastCons 0.62
Regional constraint	o/e 0.89	unconstrained · MANE · 19 kb · p 0.014 · regional, not allelic
Overall
CADD	15.32	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0181% European (non-Finnish) · 213/1,176,370 alleles

Filtering AF 0.0161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0153%

Overall 0.0135% 216/1,604,614 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0181%	5,523
African / African-American	0.0027%	37,074
South Asian	0.00111%	90,224

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CWC25
Protein: p.Val231Phe
Coding: c.691G>T
MANE Select: NM_017748
dbSNP: rs187341764
Type: single nucleotide variant
Location: chr17:38806976 (GRCh38)
Gene constraint: LOEUF 0.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.55 · 4 PDB
Residue 231: the 'disordered' region

Full CWC25 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CWC25 p.Val231Ile Likely benign ★ same residue
CWC25 p.Ala124Gly Uncertain significance ★ ⚠ same type
CWC25 p.Ala329Val Uncertain significance ★ ⚠ same type
CWC25 p.Ala367Ser Uncertain significance ★ ⚠ same type
CWC25 p.Ala367Thr Uncertain significance ★ ⚠ same type
CWC25 p.Arg135Gln Uncertain significance ★ ⚠ same type
CWC25 p.Arg135Trp Uncertain significance ★ ⚠ same type
CWC25 p.Arg151Gln Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cwc25-p-val231phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown