Is ACTA2 p.Glu272Asp (c.816G>C) pathogenic?

ACTA2 p.Glu272Asp (c.816G>C) is classified Uncertain significance in ACTA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-08). AlphaMissense: likely pathogenic (0.8647); Absent from gnomAD v4.1; Associated with aortic aneurysm, familial thoracic 6.

What condition is associated with ACTA2 p.Glu272Asp (c.816G>C)?

ACTA2 p.Glu272Asp (c.816G>C) is associated with aortic aneurysm, familial thoracic 6 (ClinVar).

How common is ACTA2 p.Glu272Asp (c.816G>C) in the general population?

ACTA2 p.Glu272Asp (c.816G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTA2 p.Glu272Asp (c.816G>C)?

AlphaMissense predicts likely pathogenic (score 0.8647) — an in-silico prediction, not a clinical call.

ACTA2 p.Glu272Asp

Q: How is Multisystemic smooth muscle dysfunction syndrome inherited?

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

c.816G>C · rs2133246658 · VCV1305287

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8647 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

aortic aneurysm, familial thoracic 6

Computational evidence

Protein change
AlphaMissense	0.8647	likely pathogenic
REVEL	0.616	indeterminate
SaProt	LLR -13.09	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.22	GERP -2.5, phastCons 0.27
Regional constraint	o/e 0.47	unconstrained · MANE · 14 kb · p 5.8e-32 · regional, not allelic
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Glu272Asp
Coding: c.816G>C
MANE Select: NM_001613
dbSNP: rs2133246658
Type: single nucleotide variant
Location: chr10:88938235 (GRCh38)
Gene constraint: LOEUF 0.472 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.43
Residue 272: a cross-link site

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

For Multisystemic smooth muscle dysfunction syndrome (Orphanet):

Inheritance: Unknown
Onset: Infancy

Similar variants

ACTA2 p.Glu272Gln Uncertain significance ★ ⚠ same residue
ACTA2 p.Glu272Ter 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
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-glu272asp (accessed [today's date]).

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