TRPC5

Chr X

transient receptor potential cation channel subfamily C member 5

ENSG00000072315 UniProt: Q9UL62 OMIM: 300334

The protein forms a receptor-activated non-selective calcium permeant cation channel that regulates neuronal calcium influx and controls hypothalamic-mediated behaviors including feeding, anxiety, socialization, and maternal care. Loss-of-function mutations cause autosomal dominant neurodevelopmental disorders with extremely high constraint scores indicating severe intolerance to protein-truncating variants. The pathogenic mechanism involves disrupted calcium signaling leading to impaired neuronal function and altered innate behaviors.

OMIM ResearchSummary from RefSeq, UniProt

MultiplemechanismLOEUF 0.17

Clinical Summary— TRPC5

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.17LOEUF

pLI 1.000

Z-score 4.72

OE 0.04 (0.01–0.17)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

3.27Z-score

OE missense 0.52 (0.47–0.59)

197 obs / 375.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.04 (0.01–0.17)

0≤0.351.4

Missense OE0.52 (0.47–0.59)

0≤0.61.4

Synonymous OE1.04

0≤1.21.6

LoF obs/exp: 1 / 27.9Missense obs/exp: 197 / 375.4Syn Z: -0.41

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedTRPC5-related neurodevelopmental disorderOTHERXLR

0.5081th %ile

GOF

0.7030th %ile

LOF

0.60top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.17

GOFprediction 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.