Is CWC25 p.Arg135Trp (c.403C>T) pathogenic?

CWC25 p.Arg135Trp (c.403C>T) is classified Uncertain significance in CWC25 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-25). AlphaMissense: likely pathogenic (0.929); Ultra-rare (popmax 0.0165%, mid).

How common is CWC25 p.Arg135Trp (c.403C>T) in the general population?

CWC25 p.Arg135Trp (c.403C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CWC25 p.Arg135Trp (c.403C>T)?

AlphaMissense predicts likely pathogenic (score 0.929) — an in-silico prediction, not a clinical call.

CWC25 p.Arg135Trp

c.403C>T · rs367659955 · VCV2388493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.929 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.929	likely pathogenic
REVEL	0.544	indeterminate
SaProt	LLR -13.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 19 kb · p 0.014 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00564% 91/1,613,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
African / African-American	0.00805%	12,424
European (non-Finnish)	0.00678%	14,747
East Asian	0.00223%	44,848
South Asian	0.0022%	45,526
Remaining individualsnot grpmax-eligible	0.0016%	62,450

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.Arg135Trp
Coding: c.403C>T
MANE Select: NM_017748
dbSNP: rs367659955
Type: single nucleotide variant
Location: chr17:38814886 (GRCh38)
Gene constraint: LOEUF 0.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.55 · 4 PDB

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

Similar variants

CWC25 p.Arg135Gln Uncertain significance ★ ⚠ 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.Arg151Gln Uncertain significance ★ ⚠ same type
CWC25 p.Arg198Cys Uncertain significance ★ ⚠ same type
CWC25 p.Arg232Gln 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-arg135trp (accessed [today's date]).

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