Is ACTA2 p.Phe23Leu (c.69T>G) pathogenic?

ACTA2 p.Phe23Leu (c.69T>G) is classified Uncertain significance in ACTA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-17). AlphaMissense: likely pathogenic (0.9984); Very rare (popmax 8.48e-05%, nfe).

How common is ACTA2 p.Phe23Leu (c.69T>G) in the general population?

ACTA2 p.Phe23Leu (c.69T>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ACTA2 p.Phe23Leu (c.69T>G)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

ACTA2 p.Phe23Leu

c.69T>G · VCV4908653

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -12.39	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 -0.96	GERP -4
Regional constraint	o/e 0.47	unconstrained · MANE · 14 kb · p 5.8e-32 · regional, not allelic
Overall
CADD	20.7	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,932 alleles

Overall 6.84e-05% 1/1,461,728 alleles · very rare

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.Phe23Leu
Coding: c.69T>G
MANE Select: NM_001613
Type: single nucleotide variant
Location: chr10:88948862 (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

Similar variants

ACTA2 p.Phe23Ile Uncertain significance ★ ⚠ same residue
ACTA2 p.Arg118Gln Pathogenic/Likely pathogenic ★★ same type
ACTA2 p.Arg149Cys Pathogenic ★★ same type
ACTA2 p.Arg149Leu Pathogenic/Likely pathogenic ★★ same type
ACTA2 p.Arg179Cys Pathogenic ★★ same type
ACTA2 p.Arg179His Pathogenic ★★ same type
ACTA2 p.Arg198Cys Pathogenic/Likely pathogenic ★★ same type
ACTA2 p.Arg198His Pathogenic/Likely pathogenic ★★ same type

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-phe23leu (accessed [today's date]).

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