Is ACTA2 p.Arg185Ter (c.553C>T) pathogenic?

ACTA2 p.Arg185Ter (c.553C>T) is classified Conflicting classifications of pathogenicity in ACTA2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-10-16). Very rare (popmax 0.00223%, eas); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with ACTA2 p.Arg185Ter (c.553C>T)?

ACTA2 p.Arg185Ter (c.553C>T) is associated with familial thoracic aortic aneurysm and aortic dissection, aortic aneurysm, familial thoracic 6, multisystemic smooth muscle dysfunction syndrome (ClinVar).

How common is ACTA2 p.Arg185Ter (c.553C>T) in the general population?

ACTA2 p.Arg185Ter (c.553C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

ACTA2 p.Arg185Ter

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.553C>T · rs772473154 · VCV389807

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 6 of 9
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 2, phastCons 1
Overall
CADD	42.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,784 alleles

Overall 0.000124% 2/1,612,438 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,784
European (non-Finnish)	8.48e-05%	1,179,536

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.Arg185Ter
Coding: c.553C>T
MANE Select: NM_001613
dbSNP: rs772473154
Type: single nucleotide variant
Location: chr10:88941292 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.43
Residue 185: 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 multisystemic smooth muscle dysfunction syndrome Moyamoya disease 5

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

ACTA2 p.Arg185Gly Uncertain significance ★★ ⚠ same residue
ACTA2 p.Arg185Gln Conflicting classifications of pathogenicity ★ ⚠ 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
ACTA2 p.Arg198Cys Pathogenic/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-arg185ter (accessed [today's date]).

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