Is ACTA1 p.Ala28Ser (c.82G>T) pathogenic?

ACTA1 p.Ala28Ser (c.82G>T) is classified Uncertain significance in ACTA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.7099); Very rare (popmax 0.005%, amr); Associated with congenital myopathy 2a, typical, autosomal dominant.

What condition is associated with ACTA1 p.Ala28Ser (c.82G>T)?

ACTA1 p.Ala28Ser (c.82G>T) is associated with congenital myopathy 2a, typical, autosomal dominant (ClinVar).

How common is ACTA1 p.Ala28Ser (c.82G>T) in the general population?

ACTA1 p.Ala28Ser (c.82G>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ACTA1 p.Ala28Ser (c.82G>T)?

AlphaMissense predicts likely pathogenic (score 0.7099) — an in-silico prediction, not a clinical call.

ACTA1 p.Ala28Ser

Q: How is Congenital myopathy with excess of thin filaments inherited?

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

c.82G>T · rs546670743 · VCV1428668

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myopathy 2a, typical, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.7099	likely pathogenic
REVEL	0.685	pathogenic-leaning
SaProt	LLR -9.95	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	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	27.0	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 0.005% Admixed American · 3/60,028 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,613,862 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.Ala28Ser
Coding: c.82G>T
MANE Select: NM_001100
dbSNP: rs546670743
Type: single nucleotide variant
Location: chr1:229433034 (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

Disease context

congenital myopathy 2a, typical, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital myopathy with excess of thin filaments (Orphanet):

Inheritance: Autosomal dominant

Similar variants

ACTA1 p.Ala28Pro Uncertain significance ★ ⚠ same residue
ACTA1 p.Ala28Thr Uncertain significance ★ ⚠ same residue
ACTA1 p.Ala28Cys Uncertain significance ★ same residue
ACTA1 p.Ala28Gly 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

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-ala28ser (accessed [today's date]).

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