Is CAP2 p.Arg125Trp (c.373C>T) pathogenic?

CAP2 p.Arg125Trp (c.373C>T) is classified Uncertain significance in CAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely pathogenic (0.9437); Ultra-rare (popmax 0.0367%, amr).

How common is CAP2 p.Arg125Trp (c.373C>T) in the general population?

CAP2 p.Arg125Trp (c.373C>T) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

What do computational predictors say about CAP2 p.Arg125Trp (c.373C>T)?

AlphaMissense predicts likely pathogenic (score 0.9437) — an in-silico prediction, not a clinical call.

CAP2 p.Arg125Trp

c.373C>T · rs143260592 · VCV2566730

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9437 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9437	likely pathogenic · top 1% in CAP2
REVEL	0.557	indeterminate
SaProt	LLR -15.85	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 4	GERP 0.95, phastCons 1
Overall
CADD	27.6	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 0.0367% Admixed American · 22/60,014 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.0031% 50/1,614,024 alleles · ultra-rare exomes 44/1,461,786 · genomes 6/152,238 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,728
Middle Eastern	0.0165%	6,062
South Asian	0.00439%	22,769
Remaining individualsnot grpmax-eligible	0.0032%	31,253
European (non-Finnish)	0.00178%	56,188

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: CAP2
Protein: p.Arg125Trp
Coding: c.373C>T
MANE Select: NM_006366
dbSNP: rs143260592
Type: single nucleotide variant
Location: chr6:17507241 (GRCh38)
Structure: AlphaFold pLDDT 88.01
Residue 125: the srcr domain

Full CAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMPRSS4 p.Ser125Tyr Uncertain significance ★ ⚠ same residue
CAP2 p.Arg17His Uncertain significance ★★ ⚠ same type
CAP2 p.His203Arg Uncertain significance ★★ ⚠ same type
TMPRSS4 p.Ala44Val Likely benign ★★ same type
CAP2 c.1003-5T>G Uncertain significance ★ same type
CAP2 p.Ala162Thr Uncertain significance ★ ⚠ same type
CAP2 p.Ala262Pro Uncertain significance ★ ⚠ same type
CAP2 p.Ala272Thr 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/cap2-p-arg125trp (accessed [today's date]).

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