TRPC4

Chr 13

transient receptor potential cation channel subfamily C member 4

Also known as: HTRP-4, HTRP4, TRP4

NCBI Gene: 7223ENSG00000133107UniProt: Q9UBN4OMIM: 603651

The protein forms a receptor-activated calcium-permeable cation channel that regulates endothelial permeability, vasodilation, and neurotransmitter release. Mutations cause generalized epilepsy with photosensitivity, with inheritance pattern not yet clearly established. The gene shows significant constraint against loss-of-function variants (LOEUF 0.373), suggesting that complete loss of protein function may be poorly tolerated.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.37
Clinical Summary— TRPC4
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.
📋
ClinVar Variants
52 unique Pathogenic / Likely Pathogenic· 90 VUS of 161 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.37LOEUF
pLI 0.482
Z-score 4.87
OE 0.22 (0.14–0.37)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.61Z-score
OE missense 0.68 (0.62–0.74)
353 obs / 520.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.22 (0.14–0.37)
0≤0.351.4
Missense OE0.68 (0.62–0.74)
0≤0.61.4
Synonymous OE1.07
0≤1.21.6
LoF obs/exp: 10 / 45.5Missense obs/exp: 353 / 520.7Syn Z: -0.83
DN
0.7034th %ile
GOF
0.82top 10%
LOF
0.3745th %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.

ClinVar Variant Classifications

161 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic52
VUS90
Likely Benign3
Benign2
52
Pathogenic
90
VUS
3
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
51
0
52
Likely Pathogenic
0
0
0
0
0
VUS
0
85
5
0
90
Likely Benign
0
1
1
1
3
Benign
0
0
0
2
2
Total186573147

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

View in ClinVar →

Protein Context — Lollipop Plot

TRPC4 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Expression of pH-Sensitive TRPC4 in Common Skin Tumors
Kurz B et al.·Int J Mol Sci
2023
Pharmacological Differences between Native Homomeric Transient Receptor Potential Canonical Type 4 Channels and Heteromeric Transient Receptor Potential Canonical Type 1/4 Channels in Lateral Septal Neurons
Phelan KD et al.·Pharmaceuticals (Basel)
2023
Targeting Nociceptive Neurons and Transient Receptor Potential Channels for the Treatment of Migraine
Cohen CF et al.·Int J Mol Sci
2023
Analysis of the Effect of the TRPC4/TRPC5 Blocker, ML204, in Sucrose-Induced Metabolic Imbalance
Araújo MC et al.·Pharmaceuticals (Basel)
2023
Inhibition of Canonical Transient Receptor Potential Channels 4/5 with Highly Selective and Potent Small-Molecule HC-070 Alleviates Mechanical Hypersensitivity in Rat Models of Visceral and Neuropathic Pain
Jalava N et al.·Int J Mol Sci
2023Functional
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
TRPC4/5 inhibitors: Phase I results and proof of concept studies.
Grimm S et al.·Eur Arch Psychiatry Clin Neurosci
2025Review
Ca(2+) Influx through TRPC Channels Is Regulated by Homocysteine-Copper Complexes.
Chen GL et al.·Biomolecules
2023
Efficacy, Tolerability, and Safety of TRPC4/5 Inhibitor BI 1358894 in Patients With Major Depressive Disorder and Inadequate Response to Antidepressants: A Phase 2 Randomized, Placebo-Controlled, Parallel Group, Dose-Ranging Trial.
Shelton RC et al.·J Clin Psychiatry
2025Clinical trial
Inhibition of TRPC4 channel activity in colonic myocytes by tricyclic antidepressants disrupts colonic motility causing constipation.
Jeong B et al.·J Cell Mol Med
2022
Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice.
Just S et al.·PLoS One
2018
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients