Is ACTA2 p.Tyr135= (c.405T>C) pathogenic?

ACTA2 p.Tyr135= (c.405T>C) is classified Likely benign in ACTA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-24). Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is ACTA2 p.Tyr135= (c.405T>C) in the general population?

ACTA2 p.Tyr135= (c.405T>C) is absent from gnomAD v4.1 (gnomAD).

ACTA2 p.Tyr135=

Q: What condition is associated with ACTA2 p.Tyr135= (c.405T>C)?

ACTA2 p.Tyr135= (c.405T>C) is associated with familial thoracic aortic aneurysm and aortic dissection, aortic aneurysm, familial thoracic 6 (ClinVar).

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.405T>C · rs1476056716 · VCV3015057

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.6	GERP -4
Overall
CADD	0.196	PHRED · no single calibrated threshold — expert panels disagree

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.Tyr135=
Coding: c.405T>C
MANE Select: NM_001613
dbSNP: rs1476056716
Type: single nucleotide variant
Location: chr10:88941834 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.43
Residue 135: a UniProt-annotated variant site (in aat6)

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

Also linked: aortic aneurysm, familial thoracic 6

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

ACTA2 p.Tyr135His Uncertain significance ★★ ⚠ same residue
ACTA2 p.Tyr135Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTA2 p.Tyr135Ter Uncertain significance ★ 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

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-tyr135 (accessed [today's date]).

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