Is TRPM2 p.Val166Ile (c.496G>A) pathogenic?

TRPM2 p.Val166Ile (c.496G>A) is classified Benign in TRPM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0706); Common (popmax 10.8%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about TRPM2 p.Val166Ile (c.496G>A)?

AlphaMissense predicts likely benign (score 0.0706) — an in-silico prediction, not a clinical call.

TRPM2 p.Val166Ile

Q: How common is TRPM2 p.Val166Ile (c.496G>A) in the general population?

TRPM2 p.Val166Ile (c.496G>A) is common (popmax 10.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.496G>A · rs45544142 · VCV777642

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0706 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0706	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -5.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.69	GERP -3.1
Regional constraint	o/e 1.01	unconstrained · MANE · 88 kb · p 0.67 · regional, not allelic
Overall
CADD	4.973	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 10.8% African / African-American · 8,094/74,838 alleles

Filtering AF 10.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.5%

Overall 0.579% 9,340/1,613,640 alleles · common exomes 4,607/1,461,734 · genomes 4,733/151,906 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.8%	9
Remaining individualsnot grpmax-eligible	0.691%	145
Admixed American	0.668%	150
Middle Eastern	0.429%	233
Ashkenazi Jewishnot grpmax-eligible	0.348%	287
East Asian	0.0892%	1,121
South Asian	0.0275%	3,641
European (non-Finnish)	0.0186%	5,388

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.Val166Ile
Coding: c.496G>A
MANE Select: NM_003307
dbSNP: rs45544142
Type: single nucleotide variant
Location: chr21:44366826 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 15 PDB
Residue 166: an α-helix; a UniProt-annotated variant site (in)

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-val166ile (accessed [today's date]).

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