Is TRPM8 p.Thr1069Ala (c.3205A>G) pathogenic?

TRPM8 p.Thr1069Ala (c.3205A>G) is classified Uncertain significance in TRPM8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.0643); Ultra-rare (popmax 0.0483%, amr).

How common is TRPM8 p.Thr1069Ala (c.3205A>G) in the general population?

TRPM8 p.Thr1069Ala (c.3205A>G) is ultra-rare (popmax 0.0483%, amr) (gnomAD).

What do computational predictors say about TRPM8 p.Thr1069Ala (c.3205A>G)?

AlphaMissense predicts likely benign (score 0.0643) — an in-silico prediction, not a clinical call.

TRPM8 p.Thr1069Ala

c.3205A>G · VCV4191871

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0643 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0643	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -5.96	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 9.3	GERP 4.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 44 kb · p 4.6e-05 · regional, not allelic
Overall
CADD	21.5	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 0.0483% Admixed American · 29/60,002 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.0018% 29/1,613,616 alleles · ultra-rare exomes 27/1,461,456 · genomes 2/152,160 · 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: TRPM8
Protein: p.Thr1069Ala
Coding: c.3205A>G
MANE Select: NM_024080
Type: single nucleotide variant
Location: chr2:234006927 (GRCh38)
Gene constraint: LOEUF 0.945 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.42 · 6 PDB
Residue 1069: an α-helix

Full TRPM8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPM8 p.Thr1069Arg Uncertain significance ★ ⚠ same residue
TRPM8 p.Arg247Thr Benign ★★ same type
TRPM8 p.Asn821Ser Benign ★★ same type
TRPM8 p.Glu545= Benign ★★ same type
TRPM8 p.Leu226= Benign ★★ same type
TRPM8 p.Met462Thr Benign ★★ ⚠ same type
TRPM8 p.Pro916= Benign ★★ same type
TRPM8 p.Ala1071Pro Uncertain significance ★ ⚠ 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/trpm8-p-thr1069ala (accessed [today's date]).

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