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

This gene encodes a member of the OSM9-like transient receptor potential channel (OTRPC) subfamily in the transient receptor potential (TRP) superfamily of ion channels. The encoded protein is a Ca2+-permeable, nonselective cation channel that is thought to be involved in the regulation of systemic osmotic pressure. Mutations in this gene are the cause of spondylometaphyseal and metatropic dysplasia and hereditary motor and sensory neuropathy type IIC. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

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

70 unique Pathogenic / Likely Pathogenic· 650 VUS of 1327 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 OE?0.77 (0.58–1.06)

0≤0.351.4

Missense OE?0.77 (0.71–0.83)

0≤0.61.4

Synonymous OE?1.00

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

This gene — mechanism propensity

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 · 91% of P/LP are missense

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.1

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 traf2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

1327 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35

Likely Pathogenic35

VUS650

Likely Benign438

Benign57

Conflicting87

Pathogenic

Likely Pathogenic

650

VUS

438

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	32	0	1	35
Likely Pathogenic	3	32	0	0	35
VUS	65	533	41	11	650
Likely Benign	2	20	155	261	438
Benign	1	3	49	4	57
Conflicting	—				87
Total	73	620	245	277	1,302

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap TRPV4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →