Is CAP1 p.Gly446Ser (c.1336G>A) pathogenic?

CAP1 p.Gly446Ser (c.1336G>A) is classified Uncertain significance in CAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-22). AlphaMissense: likely benign (0.11); Very rare (popmax 0.00568%, nfe).

How common is CAP1 p.Gly446Ser (c.1336G>A) in the general population?

CAP1 p.Gly446Ser (c.1336G>A) is very rare (popmax 0.00568%, nfe) (gnomAD).

What do computational predictors say about CAP1 p.Gly446Ser (c.1336G>A)?

AlphaMissense predicts likely benign (score 0.11) — an in-silico prediction, not a clinical call.

CAP1 p.Gly446Ser

c.1336G>A · VCV3995095

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.11 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.11	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -13.51	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 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 12 kb · p 1.1e-11 · regional, not allelic
Overall
CADD	25.0	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 0.00568% European (non-Finnish) · 67/1,178,620 alleles

Filtering AF 0.00454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00429% 69/1,610,060 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00568%	17,591
East Asian	0.00446%	22,435

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.Gly446Ser
Coding: c.1336G>A
MANE Select: NM_006367
Type: single nucleotide variant
Location: chr1:40070971 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.85 · 5 PDB
Residue 446: the c-cap/cofactor c-like domain; a turn

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

Similar variants

CAP1 p.Gly446Asp 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-gly446ser (accessed [today's date]).

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