Is ACTN2 p.Arg328Trp (c.982C>T) pathogenic?

ACTN2 p.Arg328Trp (c.982C>T) is classified Conflicting classifications of pathogenicity in ACTN2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-27). AlphaMissense: ambiguous (0.38); Ultra-rare (popmax 0.01%, amr); Associated with familial hypertrophic cardiomyopathy.

What condition is associated with ACTN2 p.Arg328Trp (c.982C>T)?

ACTN2 p.Arg328Trp (c.982C>T) is associated with familial hypertrophic cardiomyopathy, cardiomyopathy, dilated cardiomyopathy 1AA (ClinVar).

How common is ACTN2 p.Arg328Trp (c.982C>T) in the general population?

ACTN2 p.Arg328Trp (c.982C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ACTN2 p.Arg328Trp (c.982C>T)?

AlphaMissense predicts ambiguous (score 0.38) — an in-silico prediction, not a clinical call.

ACTN2 p.Arg328Trp

c.982C>T · rs770855273 · VCV626370

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.38 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

familial hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.38	ambiguous
REVEL	0.34	indeterminate
SaProt	LLR -14.94	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	29.5	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

Grpmax group 0.01% Admixed American · 6/59,988 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00118% 19/1,613,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,998
Finnishnot grpmax-eligible	0.00312%	32,016
East Asian	0.00223%	44,870
South Asian	0.0011%	91,048
European (non-Finnish)	0.000763%	131,113

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.Arg328Trp
Coding: c.982C>T
MANE Select: NM_001103
dbSNP: rs770855273
Type: single nucleotide variant
Location: chr1:236739407 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 328: an α-helix

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

Disease context

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

Also linked: cardiomyopathy dilated cardiomyopathy 1AA myopathy, congenital, with structured cores and z-line abnormalities myopathy, distal, 6, adult-onset, autosomal dominant

Similar variants

ACTN2 p.Arg328Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTN2 p.Arg328= Likely benign ★ 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

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-arg328trp (accessed [today's date]).

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