Is ACTA2 p.Glu216= (c.648G>A) pathogenic?

ACTA2 p.Glu216= (c.648G>A) is classified Likely benign in ACTA2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-01-11). Very rare (popmax 0.004%, afr); Associated with aortic aneurysm, familial thoracic 6.

What condition is associated with ACTA2 p.Glu216= (c.648G>A)?

ACTA2 p.Glu216= (c.648G>A) is associated with aortic aneurysm, familial thoracic 6, multisystemic smooth muscle dysfunction syndrome, Moyamoya disease 5 (ClinVar).

How common is ACTA2 p.Glu216= (c.648G>A) in the general population?

ACTA2 p.Glu216= (c.648G>A) is very rare (popmax 0.004%, afr) (gnomAD).

ACTA2 p.Glu216=

Q: How is Multisystemic smooth muscle dysfunction syndrome inherited?

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

c.648G>A · rs775575485 · VCV1090017

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

aortic aneurysm, familial thoracic 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.2	GERP 2, phastCons 1
Overall
CADD	17.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,926 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000929% 15/1,613,946 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,975
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.000932%	107,272

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.Glu216=
Coding: c.648G>A
dbSNP: rs775575485
Type: single nucleotide variant
Location: chr10:88939667 (GRCh38)

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: multisystemic smooth muscle dysfunction syndrome Moyamoya disease 5 familial thoracic aortic aneurysm and aortic dissection

For Multisystemic smooth muscle dysfunction syndrome (Orphanet):

Inheritance: Unknown
Onset: Infancy

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-glu216 (accessed [today's date]).

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