TRPC3

Chr 4AD

transient receptor potential cation channel subfamily C member 3

Also known as: SCA41, TRP3

NCBI Gene: 7222 ENSG00000138741 UniProt: Q13507 OMIM: 602345

TRPC3 encodes a membrane protein that forms a receptor-activated calcium-permeable cation channel involved in cellular calcium signaling. Mutations cause autosomal dominant cerebellar ataxia and developmental delay, typically presenting in childhood with progressive neurological symptoms. The gene shows moderate constraint against loss-of-function variants, suggesting some tolerance to haploinsufficiency.

OMIM ResearchSummary from RefSeq, UniProt

MultiplemechanismADLOEUF 0.701 OMIM phenotype

Clinical Summary— TRPC3

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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

23 unique Pathogenic / Likely Pathogenic· 138 VUS of 253 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint

0.70LOEUF

pLI 0.000

Z-score 3.01

OE 0.47 (0.33–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

3.84Z-score

OE missense 0.52 (0.47–0.58)

267 obs / 511.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.47 (0.33–0.70)

0≤0.351.4

Missense OE0.52 (0.47–0.58)

0≤0.61.4

Synonymous OE0.88

0≤1.21.6

LoF obs/exp: 18 / 38.0Missense obs/exp: 267 / 511.6Syn Z: 1.37

0.75top 25%

GOF

0.82top 10%

LOF

0.2483th %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

DNprediction above median · 1 literature citation

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

DNThey observed that several members of the TRPC family are highly expressed in these neurons, and both calcium elevation and growth cone turning induced by BDNF were abolished by pharmacologic inhibition of TRPC channels, overexpression of a dominant-negative form of TRPC3 or TRPC6 (603652), or downrPMID:15758952

GOFA gain-of-function mutation (T635A) in the transient receptor potential (TRP) channel TRPC3 results in abnormal channel gating and causes cerebellar ataxia in the dominant Moonwalker (Mwk) mouse mutant.PMID:26112884

LOFTaken together, these data suggest that calcium metabolism abnormalities observed in WBS may be attributable to TFII-I haploinsufficiency and subsequent TRPC3 overexpression, thereby increasing both digestive and renal calcium absorption.PMID:22566418

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.