Is ACTN2 p.Thr435= (c.1305A>G) pathogenic?

ACTN2 p.Thr435= (c.1305A>G) is classified Likely benign in ACTN2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-08-19). Very rare (popmax 0.00446%, eas); Associated with myopathy, distal, 6, adult-onset, autosomal dominant.

What condition is associated with ACTN2 p.Thr435= (c.1305A>G)?

ACTN2 p.Thr435= (c.1305A>G) is associated with myopathy, distal, 6, adult-onset, autosomal dominant, dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Thr435= (c.1305A>G) in the general population?

ACTN2 p.Thr435= (c.1305A>G) is very rare (popmax 0.00446%, eas) (gnomAD).

ACTN2 p.Thr435=

c.1305A>G · rs12043223 · VCV43900

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

myopathy, distal, 6, adult-onset, autosomal dominant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -4.8
Overall
CADD	0.062	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,868 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000929% 15/1,614,220 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,434
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.00102%	98,336

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: ACTN2
Protein: p.Thr435=
Coding: c.1305A>G
MANE Select: NM_001103
dbSNP: rs12043223
Type: single nucleotide variant
Location: chr1:236744675 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 435: an α-helix

Full ACTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myopathy, distal, 6, adult-onset, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1AA familial hypertrophic cardiomyopathy myopathy, congenital, with structured cores and z-line abnormalities

Similar variants

ACTN2 p.Thr435Ile Uncertain significance ★ ⚠ same residue
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ same condition
ACTN2 p.Leu727Arg Pathogenic/Likely pathogenic ★★ same condition
ACTN2 p.Thr247Met Likely pathogenic ★★ same condition
ACTN2 c.1107+3G>A Uncertain significance ★★ same condition
ACTN2 c.1108-10A>G Uncertain significance ★★ same condition
ACTN2 c.1255+1G>C Uncertain significance ★★ same condition
ACTN2 c.126+2T>G Uncertain significance ★★ 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/actn2-p-thr435 (accessed [today's date]).

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