TRPV4

Chr 12AD

transient receptor potential cation channel subfamily V member 4

NCBI Gene: 59341 ENSG00000111199 UniProt: Q9HBA0

Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity (PubMed:16293632, PubMed:18695040, PubMed:18826956, PubMed:22526352, PubMed:23136043, PubMed:29899501). Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification (PubMed:18695040, PubMed:18826956, PubMed:29899501). Also activated by heat, low pH, citrate and phorbol esters (PubMed:16293632, PubMed:18695040, PubMed:18826956, PubMed:20037586, PubMed:21964574, PubMed:25256292). Increase of intracellular Ca(2+) potentiates currents. Channel activity seems to be regulated by a calmodulin-dependent mechanism with a negative feedback mechanism (PubMed:12724311, PubMed:18826956). Promotes cell-cell junction formation in skin keratinocytes and plays an important role in the formation and/or maintenance of functional intercellular barriers (By similarity). Acts as a regulator of intracellular Ca(2+) in synoviocytes (PubMed:19759329). Plays an obligatory role as a molecular component in the nonselective cation channel activation induced by 4-alpha-phorbol 12,13-didecanoate and hypotonic stimulation in synoviocytes and also regulates production of IL-8 (PubMed:19759329). Together with PKD2, forms mechano- and thermosensitive channels in cilium (PubMed:18695040). Negatively regulates expression of PPARGC1A, UCP1, oxidative metabolism and respiration in adipocytes (By similarity). Regulates expression of chemokines and cytokines related to pro-inflammatory pathway in adipocytes (By similarity). Together with AQP5, controls regulatory volume decrease in salivary epithelial cells (By similarity). Required for normal development and maintenance of bone and cartilage (PubMed:26249260). In its inactive state, may sequester DDX3X at the plasma membrane. When activated, the interaction between both proteins is affected and DDX3X relocalizes to the nucleus (PubMed:29899501). In neurons of the central nervous system, could play a role in triggering voluntary water intake in response to increased sodium concentration in body fluid (By similarity)

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

687

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

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

20 Pathogenic / Likely Pathogenic· 439 VUS of 687 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.92Z-score

OE missense 0.77 (0.71–0.83)

418 obs / 544.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.77 (0.58–1.06)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.77 (0.71–0.83)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00

0≤1.21.6

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

ClinVar Variant Classifications

687 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic14

VUS439

Likely Benign182

Benign25

Conflicting21

Pathogenic

Likely Pathogenic

439

VUS

182

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	3	0	6
Likely Pathogenic	2	10	1	1	14
VUS	38	347	46	8	439
Likely Benign	1	1	82	98	182
Benign	0	0	25	0	25
Conflicting	—				21
Total	41	361	157	107	687

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

View in ClinVar →

Protein Context — Lollipop Plot

TRPV4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TRPV4-related metatropic dysplasia

definitive

ADUndeterminedAltered Gene Product Structure

Dev. DisordersSkeletal

G2P ↗

missense variantinframe deletioninframe insertion

TRPV4-related spondylometaphyseal dysplasia, Kozlowski type

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkeletal

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 4; TRPV4

MIM #605427 · *

?Avascular necrosis of femoral head, primary, 2

MIM #617383