Is ACTC1 p.Thr280Ser (c.839C>G) pathogenic?

ACTC1 p.Thr280Ser (c.839C>G) is classified Uncertain significance in ACTC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-05). AlphaMissense: likely benign (0.1867); Absent from gnomAD v4.1; Associated with cardiomyopathy.

What condition is associated with ACTC1 p.Thr280Ser (c.839C>G)?

ACTC1 p.Thr280Ser (c.839C>G) is associated with cardiomyopathy (ClinVar).

How common is ACTC1 p.Thr280Ser (c.839C>G) in the general population?

ACTC1 p.Thr280Ser (c.839C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTC1 p.Thr280Ser (c.839C>G)?

AlphaMissense predicts likely benign (score 0.1867) — an in-silico prediction, not a clinical call.

ACTC1 p.Thr280Ser

c.839C>G · rs1566967118 · VCV630098

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1867 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.1867	likely benign
REVEL	0.791	moderately pathogenic-leaning
SaProt	LLR -10.61	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.32	acceptor loss, 10 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 850 bp · p 1.5e-13 · regional, not allelic
Overall
CADD	26.9	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

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: ACTC1
Protein: p.Thr280Ser
Coding: c.839C>G
MANE Select: NM_005159
dbSNP: rs1566967118
Type: single nucleotide variant
Location: chr15:34791265 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.47 · 16 PDB
Residue 280: an α-helix

Full ACTC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

ACTC1 p.Thr280= Likely benign ★ same residue
ACTC1 p.Glu101Lys Pathogenic ★★★ same condition
ACTC1 p.Val56Ile Uncertain significance ★★★ ⚠ same condition
ACTC1 p.Gly247Asp Pathogenic/Likely pathogenic ★★ same condition
ACTC1 c.455-6G>A Uncertain significance ★★ same condition
ACTC1 c.808+4A>G Uncertain significance ★★ same condition
ACTC1 c.-12A>G Uncertain significance ★★ same condition
ACTC1 c.-1G>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/actc1-p-thr280ser (accessed [today's date]).

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