Is ACTA2 p.Arg39Cys (c.115C>T) pathogenic?

ACTA2 p.Arg39Cys (c.115C>T) is classified Pathogenic/Likely pathogenic in ACTA2 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2025-11-28). AlphaMissense: likely pathogenic (0.9651); Very rare (popmax 0.000657%); Associated with ACTA2-related disorder.

What condition is associated with ACTA2 p.Arg39Cys (c.115C>T)?

ACTA2 p.Arg39Cys (c.115C>T) is associated with ACTA2-related disorder, aortic aneurysm, familial thoracic 6, multisystemic smooth muscle dysfunction syndrome (ClinVar).

How common is ACTA2 p.Arg39Cys (c.115C>T) in the general population?

ACTA2 p.Arg39Cys (c.115C>T) is very rare (popmax 0.000657%) (gnomAD).

What do computational predictors say about ACTA2 p.Arg39Cys (c.115C>T)?

AlphaMissense predicts likely pathogenic (score 0.9651) — an in-silico prediction, not a clinical call.

ACTA2 p.Arg39Cys

c.115C>T · rs112901682 · VCV65449

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely pathogenic

0.9651 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000657%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACTA2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9651	likely pathogenic ✓ concordant with ClinVar
REVEL	0.853	moderately pathogenic-leaning
SaProt	LLR -14.88	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 14 kb · p 5.8e-32 · regional, not allelic
Overall
CADD	33.0	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 0.000657%

Overall 0.000657% 1/152,112 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: ACTA2
Protein: p.Arg39Cys
Coding: c.115C>T
MANE Select: NM_001613
dbSNP: rs112901682
Type: single nucleotide variant
Location: chr10:88948816 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.43
Residue 39: a UniProt-annotated variant site (in aat6)

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

Disease context

ACTA2-related disorder

Also linked: aortic aneurysm, familial thoracic 6 multisystemic smooth muscle dysfunction syndrome Moyamoya disease 5 familial thoracic aortic aneurysm and aortic dissection

Similar variants

ACTA2 p.Arg39Gly Pathogenic/Likely pathogenic ★★ same residue
ACTA2 p.Arg39His Pathogenic/Likely pathogenic ★★ same residue
ACTA2 p.Arg39Leu Likely pathogenic ★ same residue
ACTA2 p.Arg39Ser 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

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-arg39cys (accessed [today's date]).

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