CACNA1H

Chr 16AD

calcium voltage-gated channel subunit alpha1 H

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

NCBI Gene: 8912ENSG00000196557UniProt: O95180

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]

Primary Disease Associations & Inheritance

{Epilepsy, childhood absence, susceptibility to, 6}MIM #611942
{Epilepsy, idiopathic generalized, susceptibility to, 6}MIM #611942
Hyperaldosteronism, familial, type IVMIM #617027
AD
4270
ClinVar variants
0
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— CACNA1H
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
211 VUS of 4270 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-2.36Z-score
OE missense 1.17 (1.13–1.22)
1717 obs / 1462.9 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.38 (0.28–0.50)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.17 (1.13–1.22)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.65
0≤1.21.6
LoF obs/exp: 32 / 85.3Missense obs/exp: 1717 / 1462.9Syn Z: -13.03

ClinVar Variant Classifications

4270 submitted variants in ClinVar

ClinVar

Classification Summary

VUS211
Likely Benign133
Benign28
Conflicting5
211
VUS
133
Likely Benign
28
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
0
0
0
Likely Pathogenic
0
0
0
0
0
VUS
10
173
26
2
211
Likely Benign
0
16
55
62
133
Benign
0
6
2
20
28
Conflicting
—5
Total101958384377

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

View in ClinVar →

Protein Context — Lollipop Plot

CACNA1H · protein map & ClinVar variants

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

Gene2Phenotype Curations

CACNA1H-related epilepsy, childhood absence, susceptibility to

limited
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Epilepsy, childhood absence, susceptibility to, 6}

MIM #611942

Molecular basis of disorder known

{Epilepsy, idiopathic generalized, susceptibility to, 6}

MIM #611942

Molecular basis of disorder known

Hyperaldosteronism, familial, type IV

MIM #617027

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Calcium channelopathies and intellectual disability: a systematic review.
Kessi M et al.·Orphanet J Rare Dis
2021Review
Gene editing to prevent ventricular arrhythmias associated with cardiomyocyte cell therapy.
Marchiano S et al.·Cell Stem Cell
2023
The T-Type Calcium Channel CACNA1H is Required for Smooth Muscle Cytoskeletal Organization During Tracheal Tubulogenesis.
Liu Z et al.·Adv Sci (Weinh)
2024
Genetics of primary hyperaldosteronism.
Dutta RK et al.·Endocr Relat Cancer
2016Review
Genomics of benign adrenocortical tumors.
Jouinot A et al.·J Steroid Biochem Mol Biol
2019Review
Genetic variants and down-regulation of CACNA1H in pheochromocytoma.
Svahn F et al.·Endocr Relat Cancer
2024
A Novel Somatic Mutation of CACNA1H p.V1937M in Unilateral Primary Hyperaldosteronism.
Tseng CS et al.·Front Endocrinol (Lausanne)
2022
CACNA1H variants are not a cause of monogenic epilepsy.
Calhoun JD et al.·Hum Mutat
2020
Neuronal Cav3 channelopathies: recent progress and perspectives.
Lory P et al.·Pflugers Arch
2020Review
Pathogenesis of Primary Aldosteronism: Impact on Clinical Outcome.
Santana LS et al.·Front Endocrinol (Lausanne)
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Male Infertility

Efficacy Study of a Food Supplement With Myo-inositol, N-Acetyl-Cystein, Zinc and Vitamins on Sperm DNA Fragmentation

RECRUITING
NCT04959864Phase NAGYNOVStarted 2021-07-07
Isitol®Placebo
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07

External Resources

Links to major genomics databases and tools