Is ACTN2 p.Ala35Thr (c.103G>A) pathogenic?

ACTN2 p.Ala35Thr (c.103G>A) is classified Uncertain significance in ACTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-04). AlphaMissense: likely pathogenic (0.6931); Very rare (popmax 7.26e-05%); Associated with familial hypertrophic cardiomyopathy.

What condition is associated with ACTN2 p.Ala35Thr (c.103G>A)?

ACTN2 p.Ala35Thr (c.103G>A) is associated with familial hypertrophic cardiomyopathy, dilated cardiomyopathy 1AA (ClinVar).

How common is ACTN2 p.Ala35Thr (c.103G>A) in the general population?

ACTN2 p.Ala35Thr (c.103G>A) is very rare (popmax 7.26e-05%) (gnomAD).

What do computational predictors say about ACTN2 p.Ala35Thr (c.103G>A)?

AlphaMissense predicts likely pathogenic (score 0.6931) — an in-silico prediction, not a clinical call.

ACTN2 p.Ala35Thr

c.103G>A · rs2527438420 · VCV2946553

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 7.26e-05%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.6931	likely pathogenic
REVEL	0.2	benign-leaning
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP -0.13, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 50 kb · p 1.6e-10 · regional, not allelic
Overall
CADD	29.0	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 7.26e-05%

Overall 7.26e-05% 1/1,378,232 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: ACTN2
Protein: p.Ala35Thr
Coding: c.103G>A
MANE Select: NM_001103
dbSNP: rs2527438420
Type: single nucleotide variant
Location: chr1:236686776 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 35: an α-helix; 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: dilated cardiomyopathy 1AA

Similar variants

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
ACTN2 c.1974+4A>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-ala35thr (accessed [today's date]).

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