Is ACTRT3 p.Arg370Ile (c.1109G>T) pathogenic?

ACTRT3 p.Arg370Ile (c.1109G>T) is classified Uncertain significance in ACTRT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: ambiguous (0.5114); Ultra-rare (popmax 0.0171%, mid).

How common is ACTRT3 p.Arg370Ile (c.1109G>T) in the general population?

ACTRT3 p.Arg370Ile (c.1109G>T) is ultra-rare (popmax 0.0171%, mid) (gnomAD).

What do computational predictors say about ACTRT3 p.Arg370Ile (c.1109G>T)?

AlphaMissense predicts ambiguous (score 0.5114) — an in-silico prediction, not a clinical call.

ACTRT3 p.Arg370Ile

c.1109G>T · rs2474265864 · VCV3142855

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5114 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5114	ambiguous
REVEL	0.237	benign-leaning
SaProt	LLR -12.22	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.37, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,085 bp · p 0.65 · regional, not allelic
Overall
CADD	25.6	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 0.0171% Middle Eastern · 1/5,846 alleles

Overall 0.000141% 2/1,413,812 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0171%	5,846
European (non-Finnish)	8.65e-05%	1,156,254

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.Arg370Ile
Coding: c.1109G>T
MANE Select: NM_032487
dbSNP: rs2474265864
Type: single nucleotide variant
Location: chr3:169767442 (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.Arg309Trp 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-arg370ile (accessed [today's date]).

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