Is ACTA2 p.Cys19Ser (c.56G>C) pathogenic?

ACTA2 p.Cys19Ser (c.56G>C) is classified Uncertain significance in ACTA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-19). AlphaMissense: likely pathogenic (0.8323); Absent from gnomAD v4.1; Associated with aortic aneurysm, familial thoracic 6.

What condition is associated with ACTA2 p.Cys19Ser (c.56G>C)?

ACTA2 p.Cys19Ser (c.56G>C) is associated with aortic aneurysm, familial thoracic 6 (ClinVar).

How common is ACTA2 p.Cys19Ser (c.56G>C) in the general population?

ACTA2 p.Cys19Ser (c.56G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTA2 p.Cys19Ser (c.56G>C)?

AlphaMissense predicts likely pathogenic (score 0.8323) — an in-silico prediction, not a clinical call.

ACTA2 p.Cys19Ser

Q: How is Multisystemic smooth muscle dysfunction syndrome inherited?

Typically Unknown (Orphanet). A genetic counselor can assess individual risk for a family.

c.56G>C · rs2494578654 · VCV2717812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8323 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

aortic aneurysm, familial thoracic 6

Computational evidence

Protein change
AlphaMissense	0.8323	likely pathogenic
REVEL	0.641	indeterminate
SaProt	LLR -10.82	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 14 kb · p 5.8e-32 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: ACTA2
Protein: p.Cys19Ser
Coding: c.56G>C
MANE Select: NM_001613
dbSNP: rs2494578654
Type: single nucleotide variant
Location: chr10:88948875 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.43

Full ACTA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

aortic aneurysm, familial thoracic 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multisystemic smooth muscle dysfunction syndrome (Orphanet):

Inheritance: Unknown
Onset: Infancy

Similar variants

ACTA2 p.Cys19Arg Likely pathogenic ★★ same residue
ACTA2 p.Arg118Gln Pathogenic/Likely pathogenic ★★ same condition
ACTA2 p.Arg149Cys Pathogenic ★★ same condition
ACTA2 p.Arg149Leu Pathogenic/Likely pathogenic ★★ same condition
ACTA2 p.Arg179Cys Pathogenic ★★ same condition
ACTA2 p.Arg179His Pathogenic ★★ same condition
ACTA2 p.Arg198Cys Pathogenic/Likely pathogenic ★★ same condition
ACTA2 p.Arg198His Pathogenic/Likely pathogenic ★★ 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/acta2-p-cys19ser (accessed [today's date]).

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