Is TRPM2 p.Ala677Val (c.2030C>T) pathogenic?

TRPM2 p.Ala677Val (c.2030C>T) is classified Uncertain significance in TRPM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-08). AlphaMissense: likely benign (0.0787); Ultra-rare (popmax 0.0165%, mid).

How common is TRPM2 p.Ala677Val (c.2030C>T) in the general population?

TRPM2 p.Ala677Val (c.2030C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TRPM2 p.Ala677Val (c.2030C>T)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

TRPM2 p.Ala677Val

c.2030C>T · rs200254205 · VCV3183281

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -7.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.12	GERP -3.6
Regional constraint	o/e 1.01	unconstrained · MANE · 88 kb · p 0.67 · regional, not allelic
Overall
CADD	16.23	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,054 alleles

Filtering AF 0.0029% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00245%

Overall 0.00361% 58/1,606,680 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,054
South Asian	0.0067%	14,925
African / African-American	0.00535%	18,678
European (non-Finnish)	0.00365%	27,372
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,506
Remaining individualsnot grpmax-eligible	0.00321%	31,124
Admixed American	0.00168%	59,400

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.Ala677Val
Coding: c.2030C>T
MANE Select: NM_003307
dbSNP: rs200254205
Type: single nucleotide variant
Location: chr21:44397844 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 15 PDB
Residue 677: 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-ala677val (accessed [today's date]).

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