Is ACTA1 p.Leu238fs (c.712del) pathogenic?

ACTA1 p.Leu238fs (c.712del) is classified Pathogenic in ACTA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-09). Very rare (popmax 8.48e-05%, nfe); Associated with congenital myopathy 2a, typical, autosomal dominant.

What condition is associated with ACTA1 p.Leu238fs (c.712del)?

ACTA1 p.Leu238fs (c.712del) is associated with congenital myopathy 2a, typical, autosomal dominant (ClinVar).

How common is ACTA1 p.Leu238fs (c.712del) in the general population?

ACTA1 p.Leu238fs (c.712del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

ACTA1 p.Leu238fs

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.712del · rs1211561143 · VCV662552

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, 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 5 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.1	GERP 2.6, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,870 alleles

Overall 0.000657% 1/152,112 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.Leu238fs
Coding: c.712del
MANE Select: NM_001100
dbSNP: rs1211561143
Type: Deletion
Location: chr1:229432090 (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.Leu238Pro Uncertain significance ★★ ⚠ 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.Leu238Arg Likely pathogenic ★ same residue
ACTA1 p.Lys328del 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-leu238fs (accessed [today's date]).

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