Is TRPM2 p.Ile340Phe (c.1018A>T) pathogenic?

TRPM2 p.Ile340Phe (c.1018A>T) is classified Uncertain significance in TRPM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-09). AlphaMissense: ambiguous (0.5488); Very rare (popmax 0.00267%, afr).

How common is TRPM2 p.Ile340Phe (c.1018A>T) in the general population?

TRPM2 p.Ile340Phe (c.1018A>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TRPM2 p.Ile340Phe (c.1018A>T)?

AlphaMissense predicts ambiguous (score 0.5488) — an in-silico prediction, not a clinical call.

TRPM2 p.Ile340Phe

c.1018A>T · VCV3811010

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5488 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
AlphaMissense	0.5488	ambiguous
REVEL	0.391	indeterminate
SaProt	LLR -12.68	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 88 kb · p 0.67 · regional, not allelic
Overall
CADD	24.8	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 0.00267% African / African-American · 2/74,864 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,110 alleles · very rare

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: TRPM2
Protein: p.Ile340Phe
Coding: c.1018A>T
MANE Select: NM_003307
Type: single nucleotide variant
Location: chr21:44379000 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 15 PDB
Residue 340: an α-helix

Full TRPM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPM2 c.1932+141G>A Benign ★★ same type
TRPM2 c.1933-10T>C Benign ★★ same type
TRPM2 c.2322-35T>C Benign ★★ same type
TRPM2 c.2538+14C>T Benign ★★ same type
TRPM2 c.2962+96A>G Benign ★★ same type
TRPM2 c.3146+68T>C Benign ★★ same type
TRPM2 c.3147-20T>C Benign ★★ same type
TRPM2 c.3549+8C>T Likely benign ★★ 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/trpm2-p-ile340phe (accessed [today's date]).

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