Is ACTN2 p.Ser80Ter (c.239C>G) pathogenic?

ACTN2 p.Ser80Ter (c.239C>G) is classified Likely pathogenic in ACTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-03). Absent from gnomAD v4.1; Associated with intrinsic cardiomyopathy.

What condition is associated with ACTN2 p.Ser80Ter (c.239C>G)?

ACTN2 p.Ser80Ter (c.239C>G) is associated with intrinsic cardiomyopathy (ClinVar).

How common is ACTN2 p.Ser80Ter (c.239C>G) in the general population?

ACTN2 p.Ser80Ter (c.239C>G) is absent from gnomAD v4.1 (gnomAD).

ACTN2 p.Ser80Ter

c.239C>G · rs2527534967 · VCV3068664

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

intrinsic cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 2 of 21
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Overall
CADD	42.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACTN2
Protein: p.Ser80Ter
Coding: c.239C>G
MANE Select: NM_001103
dbSNP: rs2527534967
Type: single nucleotide variant
Location: chr1:236717970 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 80: the calponin-homology (ch) 1 domain; an α-helix; the 'actin-binding' region

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

Disease context

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

Similar variants

ACTN2 p.Ala859Thr Uncertain significance ★★ ⚠ same condition
ACTN2 c.698-2A>G Likely pathogenic ★ same condition
ACTN2 p.Ala446Val Conflicting classifications of pathogenicity ★ ⚠ same condition
ACTN2 p.Arg852Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
ACTN2 p.Gln9Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
ACTN2 p.Thr668Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
ACTN2 c.448+1115_615+666del Likely pathogenic ★ same condition
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ same type

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-ser80ter (accessed [today's date]).

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