TRPM8

Chr 2

transient receptor potential cation channel subfamily M member 8

Also known as: LTRPC6, LTrpC-6, TRPP8, trp-p8

NCBI Gene: 79054ENSG00000144481UniProt: Q7Z2W7

TRPM8 encodes a calcium-permeable ion channel that detects cold temperatures below 23-28°C and is activated by cooling compounds like menthol, playing a central role in environmental temperature sensing and basal tear secretion. Mutations cause autosomal dominant or recessive disorders affecting temperature sensation and potentially other sensory functions. The gene shows low constraint against loss-of-function variants, suggesting complete loss may be tolerated in some contexts.

Summary from RefSeq, UniProt
Research Assistant →
2
Active trials
139
Pubs (1 yr)
40
P/LP submissions
0%
P/LP missense
1.04
LOEUF
GOF
Mechanism· predicted
Clinical Summary— TRPM8
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
40 unique Pathogenic / Likely Pathogenic· 146 VUS of 214 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.04LOEUF
pLI 0.000
Z-score 1.29
OE 0.82 (0.65–1.04)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.48Z-score
OE missense 0.95 (0.89–1.01)
600 obs / 633.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.82 (0.65–1.04)
0≤0.351.4
Missense OE0.95 (0.89–1.01)
0≤0.61.4
Synonymous OE1.00
0≤1.21.6
LoF obs/exp: 50 / 60.9Missense obs/exp: 600 / 633.7Syn Z: -0.05
DN
0.6163th %ile
GOF
0.6735th %ile
LOF
0.3165th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

214 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic2
VUS146
Likely Benign8
Benign8
38
Pathogenic
2
Likely Pathogenic
146
VUS
8
Likely Benign
8
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
38
0
38
Likely Pathogenic
0
0
2
0
2
VUS
0
138
8
0
146
Likely Benign
0
3
2
3
8
Benign
0
3
1
4
8
Total0144517202

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TRPM8 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Cold-Induced Pyroelectric Stimulation Enhances Implant Osteointegration via TRPM8 Activation.
Li K et al.·Adv Mater
2026
Dietary Caffeine, Cold Exposure, and the Estrogen-TRPM8 Axis: A Nutri-Environmental Model for Lower Urinary Tract Symptoms in the Menopause Transition: A Narrative Review.
Lee DH et al.·Nutrients
2026Review
Rewiring melanoma cell fate: TRPM8 modulators trigger apoptosis and boost NK cell cytotoxicity.
Sorrentino C et al.·Cell Death Dis
2026Open Access
TRPM8 Regulates Mitochondrial Ca2+-Dynamics, Temperature and Endoplasmic Reticulum-Mitochondrial Contact Points in T Cell.
Acharya TK et al.·J Cell Mol Med
2026Open Access
Pharmacological Blockade of TRPM8 Ion Channels Fails to Reduce Behavioral and Biological Markers of Acute Oral Pain in Irradiated C57BL/6J Mice.
Wheeler JJ et al.·Radiat Res
2026
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients