Is ACTRT2 p.Phe131Ile (c.391T>A) pathogenic?

ACTRT2 p.Phe131Ile (c.391T>A) is classified Uncertain significance in ACTRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). AlphaMissense: ambiguous (0.3693); Ultra-rare (popmax 0.0653%, afr).

How common is ACTRT2 p.Phe131Ile (c.391T>A) in the general population?

ACTRT2 p.Phe131Ile (c.391T>A) is ultra-rare (popmax 0.0653%, afr) (gnomAD).

What do computational predictors say about ACTRT2 p.Phe131Ile (c.391T>A)?

AlphaMissense predicts ambiguous (score 0.3693) — an in-silico prediction, not a clinical call.

ACTRT2 p.Phe131Ile

c.391T>A · rs563201125 · VCV3142798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3693 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0653%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3693	ambiguous
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -9.26	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,130 bp · p 0.66 · regional, not allelic
Overall
CADD	23.8	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 0.0653% African / African-American · 49/75,068 alleles

Filtering AF 0.0506% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0455%

Overall 0.00384% 62/1,613,490 alleles · ultra-rare exomes 39/1,461,166 · genomes 23/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0653%	1,532
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0032%	31,250
Admixed American	0.00167%	60,032
European (non-Finnish)	0.000593%	168,575

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.Phe131Ile
Coding: c.391T>A
MANE Select: NM_080431
dbSNP: rs563201125
Type: single nucleotide variant
Location: chr1:3022077 (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.Ala224Asp 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

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-phe131ile (accessed [today's date]).

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