CACNA1H

Chr 16AD

calcium voltage-gated channel subunit alpha1 H

Also known as: CACNA1HB, Cav3.2, ECA6, EIG6, HALD4

NCBI Gene: 8912 ENSG00000196557 UniProt: O95180 OMIM: 607904

The protein forms the pore-forming alpha-1 subunit of voltage-dependent T-type calcium channels, controlling calcium ion influx into cells upon membrane depolarization. Mutations cause childhood absence epilepsy, idiopathic generalized epilepsy, and familial hyperaldosteronism type IV through an autosomal dominant inheritance pattern. The pathogenic mechanism involves gain-of-function effects that disrupt normal calcium channel activity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.503 OMIM phenotypes

Clinical Summary— CACNA1H

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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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Clinical Trials

2 active or recruiting trials — 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

Moderate LoF intolerance

LoF Constraint?

0.50LOEUF

pLI 0.000

Z-score 5.35

OE 0.38 (0.28–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-2.36Z-score

OE missense 1.17 (1.13–1.22)

1717 obs / 1462.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.38 (0.28–0.50)

0≤0.351.4

Missense OE?1.17 (1.13–1.22)

0≤0.61.4

Synonymous OE?1.65

0≤1.21.6

LoF obs/exp: 32 / 85.3Missense obs/exp: 1717 / 1462.9Syn Z: -13.03

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCACNA1H-related epilepsy, childhood absence, susceptibility toOTHERAD

This gene — mechanism propensity

0.78top 25%

GOF

0.87top 5%

LOF

0.2679th %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 · 1 literature citation

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.

Literature Evidence

GOFRecently, a new autosomal-dominant form of familial PA, FH-IV, associated with mutations in the CACNA1H gene, was described in patients with hypertension and PA before the age of 10years.1

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

References