TRPV1

Chr 17

transient receptor potential cation channel subfamily V member 1

ENSG00000196689 UniProt: Q8NER1 OMIM: 602076

The protein encoded by this gene is a non-selective calcium-permeable cation channel that detects noxious chemical and thermal stimuli, serving as a receptor for capsaicin and temperatures above 42°C, and plays a role in inflammatory pain and hyperalgesia. Mutations in TRPV1 cause autosomal recessive episodic pain syndrome with autonomic dysfunction, characterized by recurrent episodes of severe pain associated with autonomic features. This gene is not highly constrained against loss-of-function variants based on population data.

OMIM ResearchSummary from RefSeq, UniProt

Non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli (PubMed:11050376, PubMed:11243859, PubMed:11226139, PubMed:12077606). Seems to mediate proton influx and may be involved in intracellular acidosis in nociceptive neurons. Involved in mediation of inflammatory pain and hyperalgesia. Sensitized by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases, which involves PKC isozymes and PCL. Activated by vanilloids, like capsaicin, and temperatures higher than 42 degrees Celsius (PubMed:37117175). Upon activation, exhibits a time- and Ca(2+)-dependent outward rectification, followed by a long-lasting refractory state. Mild extracellular acidic pH (6.5) potentiates channel activation by noxious heat and vanilloids, whereas acidic conditions (pH <6) directly activate the channel. Can be activated by endogenous compounds, including 12-hydroperoxytetraenoic acid and bradykinin. Acts as ionotropic endocannabinoid receptor with central neuromodulatory effects. Triggers a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamine in the hippocampus and nucleus accumbens by affecting AMPA receptors endocytosis

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.08

Clinical Summary— TRPV1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.08LOEUF

pLI 0.000

Z-score 1.14

OE 0.80 (0.59–1.08)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.47Z-score

OE missense 0.94 (0.87–1.02)

475 obs / 504.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.80 (0.59–1.08)

0≤0.351.4

Missense OE?0.94 (0.87–1.02)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 29 / 36.5Missense obs/exp: 475 / 504.5Syn Z: -1.43

This gene — mechanism propensity

0.6743th %ile

GOF

0.79top 10%

LOF

0.3454th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction 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.