Is TRPM2 p.Phe738Val (c.2212T>G) pathogenic?

TRPM2 p.Phe738Val (c.2212T>G) is classified Uncertain significance in TRPM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-10). AlphaMissense: ambiguous (0.4909); Very rare (popmax 0.00167%, amr).

How common is TRPM2 p.Phe738Val (c.2212T>G) in the general population?

TRPM2 p.Phe738Val (c.2212T>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TRPM2 p.Phe738Val (c.2212T>G)?

AlphaMissense predicts ambiguous (score 0.4909) — an in-silico prediction, not a clinical call.

TRPM2 p.Phe738Val

c.2212T>G · rs1348680795 · VCV3183284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4909	ambiguous
REVEL	0.235	benign-leaning
SaProt	LLR -6.78	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.28, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 88 kb · p 0.67 · regional, not allelic
Overall
CADD	23.5	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 0.00167% Admixed American · 1/59,954 alleles

Overall 6.2e-05% 1/1,612,160 alleles · very rare exomes 1/1,459,848 · genomes 0/152,312 · joint denominator

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.Phe738Val
Coding: c.2212T>G
MANE Select: NM_003307
dbSNP: rs1348680795
Type: single nucleotide variant
Location: chr21:44400262 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 15 PDB
Residue 738: 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-phe738val (accessed [today's date]).

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