Is ACTA2 p.Pro335Ala (c.1003C>G) pathogenic?

ACTA2 p.Pro335Ala (c.1003C>G) is classified Uncertain significance in ACTA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-24). AlphaMissense: ambiguous (0.5632); Very rare (popmax 8.48e-05%, nfe); Associated with aortic aneurysm, familial thoracic 6.

What condition is associated with ACTA2 p.Pro335Ala (c.1003C>G)?

ACTA2 p.Pro335Ala (c.1003C>G) is associated with aortic aneurysm, familial thoracic 6 (ClinVar).

How common is ACTA2 p.Pro335Ala (c.1003C>G) in the general population?

ACTA2 p.Pro335Ala (c.1003C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ACTA2 p.Pro335Ala (c.1003C>G)?

AlphaMissense predicts ambiguous (score 0.5632) — an in-silico prediction, not a clinical call.

ACTA2 p.Pro335Ala

Q: How is Multisystemic smooth muscle dysfunction syndrome inherited?

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

c.1003C>G · rs1057518929 · VCV374148

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5632 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

aortic aneurysm, familial thoracic 6

Computational evidence

Protein change
AlphaMissense	0.5632	ambiguous
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -11.74	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
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	29.0	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 8.48e-05% European (non-Finnish) · 1/1,179,796 alleles

Overall 6.84e-05% 1/1,461,546 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.Pro335Ala
Coding: c.1003C>G
dbSNP: rs1057518929
Type: single nucleotide variant
Location: chr10:88935354 (GRCh38)

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

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-pro335ala (accessed [today's date]).

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