Is ACTRT2 p.Ala224Asp (c.671C>A) pathogenic?

ACTRT2 p.Ala224Asp (c.671C>A) is classified Uncertain significance in ACTRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-31). AlphaMissense: ambiguous (0.5083); Absent from gnomAD v4.1.

How common is ACTRT2 p.Ala224Asp (c.671C>A) in the general population?

ACTRT2 p.Ala224Asp (c.671C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTRT2 p.Ala224Asp (c.671C>A)?

AlphaMissense predicts ambiguous (score 0.5083) — an in-silico prediction, not a clinical call.

ACTRT2 p.Ala224Asp

c.671C>A · rs1243739357 · VCV3142824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5083 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5083	ambiguous
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -13.09	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,130 bp · p 0.66 · regional, not allelic
Overall
CADD	24.2	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

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: ACTRT2
Protein: p.Ala224Asp
Coding: c.671C>A
MANE Select: NM_080431
dbSNP: rs1243739357
Type: single nucleotide variant
Location: chr1:3022357 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI 0.29 (gnomAD)
Structure: AlphaFold pLDDT 93.42

Full ACTRT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTRT2 p.Ala135Val Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala178Thr Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala23Val Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala259Gly Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala259Val Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala323Thr Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala361Thr Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala6Thr Uncertain significance ★ ⚠ 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/actrt2-p-ala224asp (accessed [today's date]).

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