Is TRPM2 p.Arg413Trp (c.1237C>T) pathogenic?

TRPM2 p.Arg413Trp (c.1237C>T) is classified Uncertain significance in TRPM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-25). AlphaMissense: likely benign (0.1478); Ultra-rare (popmax 0.056%, afr).

How common is TRPM2 p.Arg413Trp (c.1237C>T) in the general population?

TRPM2 p.Arg413Trp (c.1237C>T) is ultra-rare (popmax 0.056%, afr) (gnomAD).

What do computational predictors say about TRPM2 p.Arg413Trp (c.1237C>T)?

AlphaMissense predicts likely benign (score 0.1478) — an in-silico prediction, not a clinical call.

TRPM2 p.Arg413Trp

c.1237C>T · VCV3462092

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1478 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.056%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1478	likely benign
REVEL	0.231	benign-leaning
SaProt	LLR -12.70	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.25, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 88 kb · p 0.67 · regional, not allelic
Overall
CADD	25.2	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 0.056% African / African-American · 42/75,038 alleles

Filtering AF 0.0425% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0378%

Overall 0.00756% 122/1,613,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.056%	1,787
East Asian	0.049%	2,040
Admixed American	0.0133%	7,499
Remaining individualsnot grpmax-eligible	0.0112%	8,927
European (non-Finnish)	0.00339%	29,499
South Asian	0.0033%	30,347

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.Arg413Trp
Coding: c.1237C>T
MANE Select: NM_003307
Type: single nucleotide variant
Location: chr21:44382739 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 15 PDB
Residue 413: a turn

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

Similar variants

TRPM2 p.Arg413Gln Uncertain significance ★ ⚠ same residue
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

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-arg413trp (accessed [today's date]).

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