Is ACTA2 p.Thr320Met (c.959C>T) pathogenic?

ACTA2 p.Thr320Met (c.959C>T) is classified Uncertain significance in ACTA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-26). AlphaMissense: likely benign (0.2167); Ultra-rare (popmax 0.0209%, sas); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is ACTA2 p.Thr320Met (c.959C>T) in the general population?

ACTA2 p.Thr320Met (c.959C>T) is ultra-rare (popmax 0.0209%, sas) (gnomAD).

What do computational predictors say about ACTA2 p.Thr320Met (c.959C>T)?

AlphaMissense predicts likely benign (score 0.2167) — an in-silico prediction, not a clinical call.

ACTA2 p.Thr320Met

Q: What condition is associated with ACTA2 p.Thr320Met (c.959C>T)?

ACTA2 p.Thr320Met (c.959C>T) 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.959C>T · rs757656209 · VCV627744

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2167 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.2167	likely benign
REVEL	0.722	pathogenic-leaning
SaProt	LLR -11.82	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.8	GERP 2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 14 kb · p 5.8e-32 · regional, not allelic
Overall
CADD	28.7	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 0.0209% South Asian · 19/91,090 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00235% 38/1,613,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0209%	4,794
African / African-American	0.00401%	24,967
Remaining individualsnot grpmax-eligible	0.0032%	31,238
European (non-Finnish)	0.00119%	84,280

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.Thr320Met
Coding: c.959C>T
dbSNP: rs757656209
Type: single nucleotide variant
Location: chr10:88938092 (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

Also linked: aortic aneurysm, familial thoracic 6

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-thr320met (accessed [today's date]).

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