Is ACTA1 p.Met134fs (c.400del) pathogenic?

ACTA1 p.Met134fs (c.400del) is classified Pathogenic in ACTA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-19). Very rare (popmax 0.000508%, nfe); Associated with congenital myopathy 2a, typical, autosomal dominant.

What condition is associated with ACTA1 p.Met134fs (c.400del)?

ACTA1 p.Met134fs (c.400del) is associated with congenital myopathy 2a, typical, autosomal dominant (ClinVar).

How common is ACTA1 p.Met134fs (c.400del) in the general population?

ACTA1 p.Met134fs (c.400del) is very rare (popmax 0.000508%, nfe) (gnomAD).

ACTA1 p.Met134fs

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.400del · rs2102736194 · VCV1451534

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Conditions

congenital myopathy 2a, typical, autosomal dominant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,179,972 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,782 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.Met134fs
Coding: c.400del
MANE Select: NM_001100
dbSNP: rs2102736194
Type: Deletion
Location: chr1:229432610 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.21 · 5 PDB
Residue 134: a β-strand; a UniProt-annotated variant site (in cmyo2a)

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.Met134Ile Likely pathogenic ★★ same residue
ACTA1 p.Met134Val Pathogenic ★ ⚠ same residue
ACTA1 p.Asp181fs Pathogenic ★★★ same condition
ACTA1 p.Ala146fs Pathogenic/Likely pathogenic ★★ same condition
ACTA1 p.Phe92del Pathogenic/Likely pathogenic ★★ same condition
ACTA1 p.Asn117fs Likely pathogenic ★ same condition
ACTA1 p.Glu336fs Pathogenic ★ same condition
ACTA1 p.Leu238fs 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-met134fs (accessed [today's date]).

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