Is ACTRT2 p.Ala259Val (c.776C>T) pathogenic?

ACTRT2 p.Ala259Val (c.776C>T) is classified Uncertain significance in ACTRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-28). AlphaMissense: likely benign (0.1122); Ultra-rare (popmax 0.0165%, mid).

How common is ACTRT2 p.Ala259Val (c.776C>T) in the general population?

ACTRT2 p.Ala259Val (c.776C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ACTRT2 p.Ala259Val (c.776C>T)?

AlphaMissense predicts likely benign (score 0.1122) — an in-silico prediction, not a clinical call.

ACTRT2 p.Ala259Val

c.776C>T · rs746128345 · VCV2219585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1122 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1122	likely benign
REVEL	0.414	indeterminate
SaProt	LLR -11.56	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.22	donor gain · deltas
Constraint at this position
Conservation	phyloP 0.69	phastCons 0.17
Regional constraint	o/e 0.98	unconstrained · MANE · 1,130 bp · p 0.66 · regional, not allelic
Overall
CADD	22.7	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

Grpmax group 0.0165% Middle Eastern · 1/6,050 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00149% 24/1,612,808 alleles · ultra-rare exomes 24/1,460,550 · genomes 0/152,258 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,050
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00169%	58,999

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: ACTRT2
Protein: p.Ala259Val
Coding: c.776C>T
MANE Select: NM_080431
dbSNP: rs746128345
Type: single nucleotide variant
Location: chr1:3022462 (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.Ala259Gly Uncertain significance ★ ⚠ same residue
ACTRT2 p.Ala135Val Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala178Thr Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala224Asp Uncertain significance ★ ⚠ same type
ACTRT2 p.Ala23Val 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-ala259val (accessed [today's date]).

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