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…

Primary Disease Associations & Inheritance

?Avascular necrosis of femoral head, primary, 2MIM #617383

[Sodium serum level QTL 1]MIM #613508

Brachyolmia type 3MIM #113500

Digital arthropathy-brachydactyly, familialMIM #606835

Hereditary motor and sensory neuropathy, type IIcMIM #606071

Metatropic dysplasiaMIM #156530

Neuronopathy, distal hereditary motor, autosomal dominant 8MIM #600175

Parastremmatic dwarfismMIM #168400

Scapuloperoneal spinal muscular atrophyMIM #181405

SED, Maroteaux typeMIM #184095

Spondylometaphyseal dysplasia, Kozlowski typeMIM #184252

UniProtBrachyolmia 3

UniProtCharcot-Marie-Tooth disease, axonal, autosomal dominant, type 2C

UniProtSpondyloepiphyseal dysplasia, Maroteaux type

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · TRPV4-related bone disorder · AD · ClinGen 2023
Definitive · neuromuscular disease · AD · ClinGen 2021
Definitive · spondylometaphyseal dysplasia, Kozlowski type · AD · G2P
Definitive · metatropic dysplasia · AD · G2P

+6 more curated pairs

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

485

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.06

LOEUF

GOF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in TRPV4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 77

923 rare PASS variants

Rare truncating (LoF)

1 in 500

137 rare PASS variants

Rare synonymous (reference)

1 in 57

524 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TRPV4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 91	1 in 510
South Asian	~43k	1 in 67	1 in 500
Remaining (unassigned)	~30k	1 in 60	1 in 600
European (Finnish)	~27k	1 in 150	1 in 2,700
Admixed American	~22k	1 in 49	1 in 270
African / African American	~21k	1 in 57	1 in 880
East Asian	~20k	1 in 69	1 in 1,600
Ashkenazi Jewish	~13k	1 in 180	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 54	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 15 coding exons well covered in gnomAD exomes and genomes.? see exons ↓