TRPV4

Chr 12AD

transient receptor potential cation channel subfamily V member 4

Also known as: BCYM3, CMT2C, HMSN2C, OTRPC4, SMAL, SPSMA, SSQTL1, TRP12

NCBI Gene: 59341 ENSG00000111199 UniProt: Q9HBA0 OMIM: 605427

This protein functions as a calcium-permeable, nonselective cation channel that regulates systemic osmotic pressure. Mutations cause a spectrum of autosomal dominant disorders including skeletal dysplasias (spondylometaphyseal dysplasia, metatropic dysplasia, brachyolmia), peripheral neuropathies (hereditary motor and sensory neuropathy type IIC, distal hereditary motor neuronopathy), and digital arthropathy. The pathogenic mechanism involves gain-of-function mutations that disrupt normal calcium channel regulation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

GOFmechanismADLOEUF 1.0611 OMIM phenotypes

Clinical Summary— TRPV4

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Gene-Disease Validity (ClinGen)

TRPV4-related bone disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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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ClinVar Variants

19 unique Pathogenic / Likely Pathogenic· 278 VUS of 599 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TRPV4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.06LOEUF

pLI 0.000

Z-score 1.28

OE 0.77 (0.58–1.06)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

1.92Z-score

OE missense 0.77 (0.71–0.83)

418 obs / 544.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.77 (0.58–1.06)

0≤0.351.4

Missense OE0.77 (0.71–0.83)

0≤0.61.4

Synonymous OE1.00

0≤1.21.6

LoF obs/exp: 29 / 37.4Missense obs/exp: 418 / 544.2Syn Z: 0.03

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTRPV4-related metatropic dysplasiaOTHERAD

definitiveTRPV4-related spondylometaphyseal dysplasia, Kozlowski typeGOFAD

0.6744th %ile

GOF

0.80top 10%

LOF

0.3356th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). 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 · 1 literature citation

DNprediction above median

LOF1 literature citation

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.

Literature Evidence

GOFAccelerated osteoblastic differentiation in patient-derived dental pulp stem cells carrying a gain-of-function mutation of TRPV4 associated with metatropic dysplasia.PMID:31954514

LOFIn vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had reduced surface expression, as well as an impaired response to stimulus-dependent channel activity. These studies suggested that the mutations interfered with normal channel trafPMID:20037588

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