Is ACTA2 p.Pro335Leu (c.1004C>T) pathogenic?

ACTA2 p.Pro335Leu (c.1004C>T) is classified Uncertain significance in ACTA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-17). AlphaMissense: likely pathogenic (0.9061); Very rare (popmax 8.48e-05%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with ACTA2 p.Pro335Leu (c.1004C>T)?

ACTA2 p.Pro335Leu (c.1004C>T) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is ACTA2 p.Pro335Leu (c.1004C>T) in the general population?

ACTA2 p.Pro335Leu (c.1004C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ACTA2 p.Pro335Leu (c.1004C>T)?

AlphaMissense predicts likely pathogenic (score 0.9061) — an in-silico prediction, not a clinical call.

ACTA2 p.Pro335Leu

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

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

c.1004C>T · rs2494502597 · VCV3073497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9061 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.9061	likely pathogenic
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -13.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	33.0	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,786 alleles

Overall 6.2e-05% 1/1,613,834 alleles · very rare exomes 1/1,461,536 · genomes 0/152,298 · joint denominator

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.Pro335Leu
Coding: c.1004C>T
MANE Select: NM_001613
dbSNP: rs2494502597
Type: single nucleotide variant
Location: chr10:88935353 (GRCh38)

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

Disease context

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

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

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-pro335leu (accessed [today's date]).

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