Is TRPM2 p.Trp1411Arg (c.4231T>C) pathogenic?

TRPM2 p.Trp1411Arg (c.4231T>C) is classified Uncertain significance in TRPM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). AlphaMissense: likely pathogenic (0.6337); Ultra-rare (popmax 0.0293%, afr).

How common is TRPM2 p.Trp1411Arg (c.4231T>C) in the general population?

TRPM2 p.Trp1411Arg (c.4231T>C) is ultra-rare (popmax 0.0293%, afr) (gnomAD).

What do computational predictors say about TRPM2 p.Trp1411Arg (c.4231T>C)?

AlphaMissense predicts likely pathogenic (score 0.6337) — an in-silico prediction, not a clinical call.

TRPM2 p.Trp1411Arg

c.4231T>C · VCV3462102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6337 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0293%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6337	likely pathogenic
REVEL	0.208	benign-leaning
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 88 kb · p 0.67 · regional, not allelic
Overall
CADD	20.6	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 0.0293% African / African-American · 22/75,034 alleles

Filtering AF 0.0198% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00161% 26/1,613,734 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0293%	3,411
Remaining individualsnot grpmax-eligible	0.0032%	31,245
Admixed American	0.00167%	60,010
European (non-Finnish)	8.48e-05%	1,179,820

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.Trp1411Arg
Coding: c.4231T>C
MANE Select: NM_003307
Type: single nucleotide variant
Location: chr21:44439130 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 15 PDB
Residue 1411: the nudix hydrolase domain

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-trp1411arg (accessed [today's date]).

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