Is TRPM2 c.1014+287C>A pathogenic?

TRPM2 c.1014+287C>A is classified Benign in TRPM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-19). Common (popmax 100%, mid) — too common for a highly-penetrant pathogenic allele.

TRPM2 c.1014+287C>A

Q: How common is TRPM2 c.1014+287C>A in the general population?

TRPM2 c.1014+287C>A is common (popmax 100%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs7276453 · VCV1278466

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 100%, mid) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +287	deep intronic (+287 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.79	GERP -1.9
Non-coding constraint	Z 2.93	1 kb window · o/e 0.82 · regional · uncalibrated
Overall
CADD	0.058	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 100% Middle Eastern · 294/294 alleles

Filtering AF 99.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.1%

Overall 99.4% 151,424/152,266 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	100%	1
Amishnot grpmax-eligible	100%	1
Middle Easterngrpmax	100%	1
East Asian	100%	1
European (non-Finnish)	100%	1
South Asian	100%	1
African / African-American	99.9%	1
Ashkenazi Jewishnot grpmax-eligible	99.6%	1
Remaining individualsnot grpmax-eligible	99.1%	1
Admixed American	95%	1

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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
Coding: c.1014+287C>A
MANE Select: NM_003307
dbSNP: rs7276453
Type: single nucleotide variant
Location: chr21:44378060 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 15 PDB

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-c-1014-plus-287c-a (accessed [today's date]).

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