TRPM8
protein-codingtransient receptor potential cation channel subfamily M member 8, the group of Transient receptor potential cation channels
Gene summary
Predicted to enable ligand-gated calcium channel activity. Predicted to be involved in calcium ion transmembrane transport; positive regulation of cold-induced thermogenesis; and thermoception. Predicted to act upstream of or within calcium ion transport; intracellular calcium ion homeostasis; and response to cold. Located in plasma membrane. [provided by Alliance of Genome Resources, Jun 2026]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~102.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TRPM8 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_024080.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 4 | 7 | |||
| missense | 142 | 3 | 2 | 147 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 145 | 6 | 6 | 157 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_076985.4 | 24 | MANE Select | |
| Ensembl | ENSP00000323926.4 | 24 | MANE Select | |
| RefSeq | NP_001384535.1 | 21 | Standard | |
| RefSeq | NP_001384536.1 | 22 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
- Stimuli-sensing channels
- Ion channel transport
- Transport of small molecules
- TRP channels
Biological Process
- cellular calcium ion homeostasis
- response to cold
- detection of temperature stimulus
- thermoception
- protein homotetramerization
Molecular Function
- calcium channel activity
- protein binding
- protein homodimerization activity
Cellular Component
- endoplasmic reticulum membrane
- plasma membrane
- external side of plasma membrane
- integral component of membrane
- membrane raft
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000324695
- Coding exons
- 24
- Length
- 102124
- Individuals with no LoFs
- 125541
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 207
- Defined
- 125748
- p
- 0.000823
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.476 | 600 | 634 | 0.947 | 0.0000369 | 7324 |
| Missense (PolyPhen) | 174 | 208.47 | 0.83467 | 2412 | ||
| Synonymous | -0.0455 | 260 | 259 | 1.00 | 0.0000163 | 2081 |
| Loss of Function | 1.29 | 50 | 60.9 | 0.821 | 0.00000340 | 670 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0015 | 0.0015 | notable |
| Latino/Admixed American | 0.00078 | 0.00078 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.0019 | 0.0019 | notable |
| European (Non-Finnish) | 0.00052 | 0.00052 | rare |
| South Asian | 0.0016 | 0.0016 | notable |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor-activated non-selective cation channel involved in detection of sensations such as coolness, by being activated by cold temperature below 25 degrees Celsius. Activated by icilin, eucalyptol, menthol, cold and modulation of intracellular pH. Involved in menthol sensation. Permeable for monovalent cations sodium, potassium, and cesium and divalent cation calcium. Temperature sensing is tightly linked to voltage-dependent gating. Activated upon depolarization, changes in temperature resulting in graded shifts of its voltage-dependent activation curves. The chemical agonist menthol functions as a gating modifier, shifting activation curves towards physiological membrane potentials. Temperature sensitivity arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing. In prostate cancer cells, shows strong inward rectification and high calcium selectivity in contrast to its behavior in normal cells which is characterized by outward rectification and poor cationic selectivity. Plays a role in prostate cancer cell migration (PubMed:25559186). Isoform 2 and isoform 3 negatively regulate menthol- and cold-induced channel activity by stabilizing the closed state of the channel. {ECO:0000269|PubMed:15306801, ECO:0000269|PubMed:16174775, ECO:0000269|PubMed:22128173, ECO:0000269|PubMed:25559186}.;
Intolerance Scores
- LoFtool
- 0.756
- RVIS EVS
- -1.43
- RVIS percentile EVS
- 4.03
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.279
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | High | Medium | High |