Is ACTN2 p.Asp182= (c.546T>C) pathogenic?

ACTN2 p.Asp182= (c.546T>C) is classified Conflicting classifications of pathogenicity in ACTN2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.037%, nfe); Associated with familial hypertrophic cardiomyopathy.

What condition is associated with ACTN2 p.Asp182= (c.546T>C)?

ACTN2 p.Asp182= (c.546T>C) is associated with familial hypertrophic cardiomyopathy, cardiomyopathy, dilated cardiomyopathy 1AA (ClinVar).

How common is ACTN2 p.Asp182= (c.546T>C) in the general population?

ACTN2 p.Asp182= (c.546T>C) is ultra-rare (popmax 0.037%, nfe) (gnomAD).

ACTN2 p.Asp182=

c.546T>C · rs34263845 · VCV219427

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.037%, nfe)

Conditions

familial hypertrophic 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 -7.7	GERP -4.5
Overall
CADD	1.381	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.037% European (non-Finnish) · 437/1,179,976 alleles

Filtering AF 0.0342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.0538% 869/1,614,128 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.568%	176
Remaining individualsnot grpmax-eligible	0.101%	992
European (non-Finnish)grpmax	0.037%	2,700
African / African-American	0.00666%	15,012

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp182=
Coding: c.546T>C
MANE Select: NM_001103
dbSNP: rs34263845
Type: single nucleotide variant
Location: chr1:236727687 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 182: the calponin-homology (ch) 2 domain; the 'actin-binding' region

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

Similar variants

ACTN2 p.Asp182Tyr Uncertain significance ★ ⚠ 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-asp182 (accessed [today's date]).

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