Is ACTN2 p.Ser369= (c.1107G>A) pathogenic?

ACTN2 p.Ser369= (c.1107G>A) is classified Conflicting classifications of pathogenicity in ACTN2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.029%, eas); Associated with Cardiovascular phenotype.

What condition is associated with ACTN2 p.Ser369= (c.1107G>A)?

ACTN2 p.Ser369= (c.1107G>A) is associated with Cardiovascular phenotype, cardiomyopathy, dilated cardiomyopathy 1AA (ClinVar).

How common is ACTN2 p.Ser369= (c.1107G>A) in the general population?

ACTN2 p.Ser369= (c.1107G>A) is ultra-rare (popmax 0.029%, eas) (gnomAD).

ACTN2 p.Ser369=

c.1107G>A · rs369218950 · VCV463187

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Conditions

Cardiovascular phenotype

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 9.8	GERP 2.2, phastCons 1
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.029% East Asian · 13/44,868 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00688% 111/1,613,950 alleles · ultra-rare exomes 105/1,461,614 · genomes 6/152,336 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,451
European (non-Finnish)	0.00729%	13,720
Remaining individualsnot grpmax-eligible	0.0064%	15,621
South Asian	0.00439%	22,762
African / African-American	0.004%	25,017
Admixed American	0.00167%	59,998

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.Ser369=
Coding: c.1107G>A
MANE Select: NM_001103
dbSNP: rs369218950
Type: single nucleotide variant
Location: chr1:236739532 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 369: an α-helix

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

Disease context

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

Also linked: cardiomyopathy dilated cardiomyopathy 1AA familial hypertrophic cardiomyopathy

Similar variants

ACTN2 p.Ser369Leu 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-ser369 (accessed [today's date]).

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