Is ACTA1 p.Ala274Val (c.821C>T) pathogenic?

ACTA1 p.Ala274Val (c.821C>T) is classified Pathogenic/Likely pathogenic in ACTA1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-01-05). AlphaMissense: likely benign (0.2915); Absent from gnomAD v4.1; Associated with progressive scapulohumeroperoneal distal myopathy.

What condition is associated with ACTA1 p.Ala274Val (c.821C>T)?

ACTA1 p.Ala274Val (c.821C>T) is associated with progressive scapulohumeroperoneal distal myopathy, congenital myopathy 2a, typical, autosomal dominant, nemaline myopathy 2 (ClinVar).

How common is ACTA1 p.Ala274Val (c.821C>T) in the general population?

ACTA1 p.Ala274Val (c.821C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTA1 p.Ala274Val (c.821C>T)?

AlphaMissense predicts likely benign (score 0.2915) — an in-silico prediction, not a clinical call.

ACTA1 p.Ala274Val

Q: How is Progressive scapulohumeroperoneal distal myopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.821C>T · rs1553255357 · VCV432685

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2915 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

progressive scapulohumeroperoneal distal myopathy

Computational evidence

Protein change
AlphaMissense	0.2915	likely benign ⚠ discordant with ClinVar
REVEL	0.603	indeterminate
SaProt	LLR -10.71	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 2.6, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 1,613 bp · p 1.6e-54 · regional, not allelic
Overall
CADD	28.9	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

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.Ala274Val
Coding: c.821C>T
MANE Select: NM_001100
dbSNP: rs1553255357
Type: single nucleotide variant
Location: chr1:229431890 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.21 · 5 PDB
Residue 274: a UniProt-annotated variant site (in cmyo2a)

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

Disease context

progressive scapulohumeroperoneal distal myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myopathy 2a, typical, autosomal dominant nemaline myopathy 2

For Progressive scapulohumeroperoneal distal myopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

ACTA1 p.Ala274Glu Pathogenic ★ same residue
ACTA1 p.Ala274Ser Uncertain significance ★ same residue
ACTA1 c.617-5C>A Likely pathogenic ★★★ same condition
ACTA1 c.990+1G>T Pathogenic ★★★ same condition
ACTA1 p.Asp13Asn Likely pathogenic ★★★ same condition
ACTA1 p.Asp290His Pathogenic ★★★ same condition
ACTA1 p.Asp58Asn Likely pathogenic ★★★ same condition
ACTA1 p.Cys376Phe Likely pathogenic ★★★ same condition

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-ala274val (accessed [today's date]).

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