Is ACTA2 p.Ile73Thr (c.218T>C) pathogenic?

ACTA2 p.Ile73Thr (c.218T>C) is classified Conflicting classifications of pathogenicity in ACTA2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-04-29). AlphaMissense: likely pathogenic (0.9604); Very rare (popmax 0.00133%, afr); Associated with aortic aneurysm, familial thoracic 6.

What condition is associated with ACTA2 p.Ile73Thr (c.218T>C)?

ACTA2 p.Ile73Thr (c.218T>C) is associated with aortic aneurysm, familial thoracic 6, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is ACTA2 p.Ile73Thr (c.218T>C) in the general population?

ACTA2 p.Ile73Thr (c.218T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACTA2 p.Ile73Thr (c.218T>C)?

AlphaMissense predicts likely pathogenic (score 0.9604) — an in-silico prediction, not a clinical call.

ACTA2 p.Ile73Thr

Q: How is Multisystemic smooth muscle dysfunction syndrome inherited?

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

c.218T>C · rs2494570485 · VCV2575105

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9604 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aortic aneurysm, familial thoracic 6

Computational evidence

Protein change
AlphaMissense	0.9604	likely pathogenic
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -11.34	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 11	GERP 2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 14 kb · p 5.8e-32 · regional, not allelic
Overall
CADD	25.8	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 0.00133% African / African-American · 1/75,016 alleles

Overall 0.000137% 2/1,461,722 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,016
European (non-Finnish)	8.48e-05%	1,179,898

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.Ile73Thr
Coding: c.218T>C
MANE Select: NM_001613
dbSNP: rs2494570485
Type: single nucleotide variant
Location: chr10:88947298 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.43

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

Also linked: familial thoracic aortic aneurysm and aortic dissection

For Multisystemic smooth muscle dysfunction syndrome (Orphanet):

Inheritance: Unknown
Onset: Infancy

Similar variants

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
ACTA2 p.Arg198Cys Pathogenic/Likely pathogenic ★★ same condition
ACTA2 p.Arg198His Pathogenic/Likely pathogenic ★★ same condition
ACTA2 p.Arg256Cys Likely 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-ile73thr (accessed [today's date]).

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