Is CAP1 p.Arg254His (c.761G>A) pathogenic?

CAP1 p.Arg254His (c.761G>A) is classified Uncertain significance in CAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.1308); Ultra-rare (popmax 0.0223%, sas).

How common is CAP1 p.Arg254His (c.761G>A) in the general population?

CAP1 p.Arg254His (c.761G>A) is ultra-rare (popmax 0.0223%, sas) (gnomAD).

What do computational predictors say about CAP1 p.Arg254His (c.761G>A)?

AlphaMissense predicts likely benign (score 0.1308) — an in-silico prediction, not a clinical call.

CAP1 p.Arg254His

c.761G>A · rs575446557 · VCV3136996

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1308 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1308	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -12.13	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 12 kb · p 1.1e-11 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0223% South Asian · 20/89,788 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0123%

Overall 0.00244% 39/1,595,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0223%	4,489
East Asian	0.0115%	8,680
Remaining individualsnot grpmax-eligible	0.0081%	12,346
Ashkenazi Jewishnot grpmax-eligible	0.00345%	28,960
Admixed American	0.00176%	56,884
European (non-Finnish)	0.000598%	167,358

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: CAP1
Protein: p.Arg254His
Coding: c.761G>A
MANE Select: NM_006367
dbSNP: rs575446557
Type: single nucleotide variant
Location: chr1:40067670 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.85 · 5 PDB

Full CAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAP1 p.Arg254Cys Uncertain significance ★ ⚠ same residue
CAP1 p.Ala73= Benign ★★ same type
CAP1 p.Tyr31= Benign ★★ same type
CAP1 p.Ala145Ser Uncertain significance ★ ⚠ same type
CAP1 p.Ala161Ser Uncertain significance ★ ⚠ same type
CAP1 p.Ala259Ser Uncertain significance ★ ⚠ same type
CAP1 p.Ala259Thr Uncertain significance ★ ⚠ same type
CAP1 p.Ala270Gly 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/cap1-p-arg254his (accessed [today's date]).

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