Is ACTA1 p.Ala116Ser (c.346G>T) pathogenic?

ACTA1 p.Ala116Ser (c.346G>T) is classified Conflicting classifications of pathogenicity in ACTA1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2020-08-14). AlphaMissense: likely benign (0.2511); Absent from gnomAD v4.1; Associated with ACTA1-related myopathies.

What condition is associated with ACTA1 p.Ala116Ser (c.346G>T)?

ACTA1 p.Ala116Ser (c.346G>T) is associated with ACTA1-related myopathies, congenital myopathy 2a, typical, autosomal dominant (ClinVar).

How common is ACTA1 p.Ala116Ser (c.346G>T) in the general population?

ACTA1 p.Ala116Ser (c.346G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTA1 p.Ala116Ser (c.346G>T)?

AlphaMissense predicts likely benign (score 0.2511) — an in-silico prediction, not a clinical call.

ACTA1 p.Ala116Ser

c.346G>T · rs1659975786 · VCV1042202

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2511 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACTA1-related myopathies

Computational evidence

Protein change
AlphaMissense	0.2511	likely benign
REVEL	0.756	pathogenic-leaning
SaProt	LLR -9.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do 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	27.6	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.Ala116Ser
Coding: c.346G>T
MANE Select: NM_001100
dbSNP: rs1659975786
Type: single nucleotide variant
Location: chr1:229432664 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.21 · 5 PDB
Residue 116: an α-helix; the 'interaction with alpha-actinin' region; a UniProt-annotated variant site (in cmyo2a)

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

Disease context

ACTA1-related myopathies

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

Similar variants

ACTA1 p.Ala116Thr Likely pathogenic ★★ ⚠ same residue
ACTA1 p.Ala116Val Likely pathogenic ★★ ⚠ same residue
ACTA1 p.Ala116Pro Likely pathogenic ★ 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

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-ala116ser (accessed [today's date]).

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