CACNB4
Chr 2ADcalcium voltage-gated channel auxiliary subunit beta 4
Also known as: CAB4, CACNLB4, EA5, EIG9, EJM, EJM4, EJM6
This protein functions as the beta subunit of voltage-dependent calcium channels, increasing peak calcium current, shifting voltage dependencies of activation and inactivation, and controlling alpha-1 subunit membrane targeting. Mutations cause episodic ataxia type 5 and increase susceptibility to idiopathic generalized epilepsy and juvenile myoclonic epilepsy with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (LOEUF 0.49), suggesting that complete loss of function is likely incompatible with normal development.
Refuted — evidence has disproved this relationship
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Moderately missense-constrained (top ~2.5%)
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
CACNB4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
External Resources
Links to major genomics databases and tools