Is ACTA1 p.Val131Ala (c.392T>C) pathogenic?

ACTA1 p.Val131Ala (c.392T>C) is classified Uncertain significance in ACTA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). AlphaMissense: likely pathogenic (0.5786); Very rare (popmax 8.47e-05%, nfe).

How common is ACTA1 p.Val131Ala (c.392T>C) in the general population?

ACTA1 p.Val131Ala (c.392T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACTA1 p.Val131Ala (c.392T>C)?

AlphaMissense predicts likely pathogenic (score 0.5786) — an in-silico prediction, not a clinical call.

ACTA1 p.Val131Ala

c.392T>C · VCV3390001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5786	likely pathogenic
REVEL	0.587	indeterminate
SaProt	LLR -6.37	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 1,613 bp · p 1.6e-54 · regional, not allelic
Overall
CADD	26.4	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 8.47e-05% European (non-Finnish) · 1/1,179,980 alleles

Overall 6.84e-05% 1/1,461,814 alleles · very rare

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: ACTA1
Protein: p.Val131Ala
Coding: c.392T>C
MANE Select: NM_001100
Type: single nucleotide variant
Location: chr1:229432618 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.21 · 5 PDB

Full ACTA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTA1 p.Val131Met Uncertain significance ★ ⚠ same residue
ACTA1 c.617-5C>A Likely pathogenic ★★★ same type
ACTA1 c.990+1G>T Pathogenic ★★★ same type
ACTA1 p.Asp13Asn Likely pathogenic ★★★ same type
ACTA1 p.Asp290His Pathogenic ★★★ same type
ACTA1 p.Asp58Asn Likely pathogenic ★★★ same type
ACTA1 p.Cys376Phe Likely pathogenic ★★★ same type
ACTA1 p.Cys376Ser Pathogenic ★★★ 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/acta1-p-val131ala (accessed [today's date]).

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