Is ACTA1 p.Glu197Asp (c.591G>C) pathogenic?

ACTA1 p.Glu197Asp (c.591G>C) is classified Uncertain significance in ACTA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-25). AlphaMissense: likely pathogenic (0.9245); Absent from gnomAD v4.1.

How common is ACTA1 p.Glu197Asp (c.591G>C) in the general population?

ACTA1 p.Glu197Asp (c.591G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTA1 p.Glu197Asp (c.591G>C)?

AlphaMissense predicts likely pathogenic (score 0.9245) — an in-silico prediction, not a clinical call.

ACTA1 p.Glu197Asp

c.591G>C · rs869312739 · VCV1690664

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9245 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9245	likely pathogenic
REVEL	0.604	indeterminate
SaProt	LLR -11.86	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 3.3	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	24.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACTA1
Protein: p.Glu197Asp
Coding: c.591G>C
MANE Select: NM_001100
dbSNP: rs869312739
Type: single nucleotide variant
Location: chr1:229432295 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.21 · 5 PDB
Residue 197: an α-helix; a UniProt-annotated variant site (in shpm; no effect on cytoskeleton structure)

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

Similar variants

ACTA1 p.Glu197Lys Likely pathogenic ★ 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-glu197asp (accessed [today's date]).

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