Is ACTC1 p.Cys2Tyr (c.5G>A) pathogenic?

ACTC1 p.Cys2Tyr (c.5G>A) is classified Uncertain significance in ACTC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-06). AlphaMissense: likely pathogenic (0.5737); Very rare (popmax 8.48e-05%, nfe); Associated with hypertrophic cardiomyopathy 11.

What condition is associated with ACTC1 p.Cys2Tyr (c.5G>A)?

ACTC1 p.Cys2Tyr (c.5G>A) is associated with hypertrophic cardiomyopathy 11, cardiomyopathy, atrial septal defect 5 (ClinVar).

How common is ACTC1 p.Cys2Tyr (c.5G>A) in the general population?

ACTC1 p.Cys2Tyr (c.5G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ACTC1 p.Cys2Tyr (c.5G>A)?

AlphaMissense predicts likely pathogenic (score 0.5737) — an in-silico prediction, not a clinical call.

ACTC1 p.Cys2Tyr

c.5G>A · rs1469206760 · VCV938099

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypertrophic cardiomyopathy 11

Computational evidence

Protein change
AlphaMissense	0.5737	likely pathogenic
REVEL	0.557	indeterminate
SaProt	LLR -9.84	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 36 bp · p 0.14 · regional, not allelic
Overall
CADD	26.2	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 8.48e-05% European (non-Finnish) · 1/1,179,054 alleles

Overall 0.000657% 1/152,180 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: ACTC1
Protein: p.Cys2Tyr
Coding: c.5G>A
dbSNP: rs1469206760
Type: single nucleotide variant
Location: chr15:34794804 (GRCh38)

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

Disease context

hypertrophic cardiomyopathy 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy atrial septal defect 5 dilated cardiomyopathy 1R

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-cys2tyr (accessed [today's date]).

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