Is CAP1 p.Ala259Ser (c.775G>T) pathogenic?

CAP1 p.Ala259Ser (c.775G>T) is classified Uncertain significance in CAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely benign (0.0727); Very rare (popmax 0.00264%, nfe).

How common is CAP1 p.Ala259Ser (c.775G>T) in the general population?

CAP1 p.Ala259Ser (c.775G>T) is very rare (popmax 0.00264%, nfe) (gnomAD).

What do computational predictors say about CAP1 p.Ala259Ser (c.775G>T)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

CAP1 p.Ala259Ser

c.775G>T · VCV3484680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00264%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -7.29	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 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	27.7	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 0.00264% European (non-Finnish) · 31/1,172,386 alleles

Filtering AF 0.00189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00165%

Overall 0.00232% 37/1,597,876 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0138%	7,257
European (non-Finnish)grpmax	0.00264%	37,819
Admixed American	0.00175%	57,296
Remaining individualsnot grpmax-eligible	0.00162%	61,760

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala259Ser
Coding: c.775G>T
MANE Select: NM_006367
Type: single nucleotide variant
Location: chr1:40067684 (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.Ala259Thr 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.Ala270Gly Uncertain significance ★ ⚠ same type
CAP1 p.Ala302Val Uncertain significance ★ ⚠ same type
CAP1 p.Ala52Val 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-ala259ser (accessed [today's date]).

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