Is ACTN2 p.Ala644= (c.1932C>A) pathogenic?

ACTN2 p.Ala644= (c.1932C>A) is classified Benign/Likely benign in ACTN2 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-03). Rare (popmax 0.915%, afr); Associated with cardiomyopathy.

What condition is associated with ACTN2 p.Ala644= (c.1932C>A)?

ACTN2 p.Ala644= (c.1932C>A) is associated with cardiomyopathy, dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Ala644= (c.1932C>A) in the general population?

ACTN2 p.Ala644= (c.1932C>A) is rare (popmax 0.915%, afr) (gnomAD).

ACTN2 p.Ala644=

c.1932C>A · rs144680712 · VCV43921

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

rare (popmax 0.915%, afr)

Conditions

cardiomyopathy

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 -3.5	GERP -4.8
Overall
CADD	0.339	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.915% African / African-American · 687/75,060 alleles

Filtering AF 0.859% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.836%

Overall 0.0515% 832/1,614,114 alleles · rare exomes 388/1,461,798 · genomes 444/152,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.915%	109
Admixed American	0.107%	938
Remaining individualsnot grpmax-eligible	0.0992%	1,008
Middle Eastern	0.0165%	6,062
South Asian	0.00769%	13,011
European (non-Finnish)	0.000932%	107,277

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.Ala644=
Coding: c.1932C>A
MANE Select: NM_001103
dbSNP: rs144680712
Type: single nucleotide variant
Location: chr1:236754039 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB

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

Disease context

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1AA familial hypertrophic cardiomyopathy

Similar variants

ACTN2 p.Ala644Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTN2 p.Ala119Thr 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
ACTN2 c.127-3C>A 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-ala644 (accessed [today's date]).

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