Is ACTRT3 p.Arg309Trp (c.925C>T) pathogenic?

ACTRT3 p.Arg309Trp (c.925C>T) is classified Uncertain significance in ACTRT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely pathogenic (0.7836); Ultra-rare (popmax 0.0317%, nfe).

How common is ACTRT3 p.Arg309Trp (c.925C>T) in the general population?

ACTRT3 p.Arg309Trp (c.925C>T) is ultra-rare (popmax 0.0317%, nfe) (gnomAD).

What do computational predictors say about ACTRT3 p.Arg309Trp (c.925C>T)?

AlphaMissense predicts likely pathogenic (score 0.7836) — an in-silico prediction, not a clinical call.

ACTRT3 p.Arg309Trp

c.925C>T · rs138945719 · VCV2352009

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7836 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7836	likely pathogenic
REVEL	0.784	moderately pathogenic-leaning
SaProt	LLR -13.88	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 3.1	GERP -1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,085 bp · p 0.65 · regional, not allelic
Overall
CADD	22.5	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 0.0317% European (non-Finnish) · 374/1,179,880 alleles

Filtering AF 0.029% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0279%

Overall 0.0246% 397/1,613,544 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0336%	2,974
European (non-Finnish)grpmax	0.0317%	3,155
African / African-American	0.00267%	37,443

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ACTRT3
Protein: p.Arg309Trp
Coding: c.925C>T
MANE Select: NM_032487
dbSNP: rs138945719
Type: single nucleotide variant
Location: chr3:169767626 (GRCh38)
Gene constraint: LOEUF 1.242 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.47

Full ACTRT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTRT3 p.Ala108Val Uncertain significance ★ ⚠ same type
ACTRT3 p.Ala257Val Uncertain significance ★ ⚠ same type
ACTRT3 p.Ala315Val Uncertain significance ★ ⚠ same type
ACTRT3 p.Ala318Ser Uncertain significance ★ ⚠ same type
ACTRT3 p.Ala323Thr Uncertain significance ★ ⚠ same type
ACTRT3 p.Arg205Ser Uncertain significance ★ ⚠ same type
ACTRT3 p.Arg25Trp Uncertain significance ★ ⚠ same type
ACTRT3 p.Arg370Ile 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/actrt3-p-arg309trp (accessed [today's date]).

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