CACNB4

Chr 2AD

calcium voltage-gated channel auxiliary subunit beta 4

Also known as: CAB4, CACNLB4, EA5, EIG9, EJM, EJM4, EJM6

NCBI Gene: 785ENSG00000182389UniProt: O00305

This gene encodes a member of the beta subunit family of voltage-dependent calcium channel complex proteins. 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. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. The protein encoded by this locus plays an important role in calcium channel function by modulating G protein inhibition, increasing peak calcium current, controlling the alpha-1 subunit membrane targeting and shifting the voltage dependence of activation and inactivation. Certain mutations in this gene have been associated with idiopathic generalized epilepsy (IGE), juvenile myoclonic epilepsy (JME), and episodic ataxia, type 5. [provided by RefSeq, Aug 2016]

Primary Disease Associations & Inheritance

?Episodic ataxia, type 5MIM #613855
AD
{Epilepsy, idiopathic generalized, susceptibility to, 9}MIM #607682
AD
{Epilepsy, juvenile myoclonic, susceptibility to, 6}MIM #607682
AD
UniProtEpisodic ataxia 5
345
ClinVar variants
20
Pathogenic / LP
0.03
pLI score
1
Active trials
Clinical Summary— CACNB4
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.
📋
ClinVar Variants
20 Pathogenic / Likely Pathogenic· 193 VUS of 345 total submissions
💊
Clinical Trials
1 active or recruiting trial — 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.
0.49LOEUF
pLI 0.031
Z-score 3.77
OE 0.28 (0.17–0.49)
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.
2.69Z-score
OE missense 0.55 (0.49–0.63)
161 obs / 290.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.28 (0.17–0.49)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.55 (0.49–0.63)
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.0.89
0≤1.21.6
LoF obs/exp: 9 / 32.0Missense obs/exp: 161 / 290.2Syn Z: 0.86

ClinVar Variant Classifications

345 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic4
VUS193
Likely Benign60
Benign51
Conflicting17
16
Pathogenic
4
Likely Pathogenic
193
VUS
60
Likely Benign
51
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
15
0
16
Likely Pathogenic
0
2
2
0
4
VUS
1
103
86
3
193
Likely Benign
0
2
27
31
60
Benign
0
2
44
5
51
Conflicting
—17
Total210917439341

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

View 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.

Gene2Phenotype Curations

CACNB4-related juvenile myoclonic epilepsy

limited
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Episodic ataxia, type 5

MIM #613855

Molecular basis of disorder known

Autosomal dominant

{Epilepsy, idiopathic generalized, susceptibility to, 9}

MIM #607682

Molecular basis of disorder known

Autosomal dominant

{Epilepsy, juvenile myoclonic, susceptibility to, 6}

MIM #607682

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
[Hereditary episodic ataxia].
Riant F et al.·Rev Neurol (Paris)
2011Review
[Episodic ataxias].
Herrmann A et al.·Tidsskr Nor Laegeforen
2005Review
A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions.
Coste de Bagneaux P et al.·PLoS Genet
2020
Genetic paroxysmal neurological disorders featuring episodic ataxia and epilepsy.
Amadori E et al.·Eur J Med Genet
2022Review
Genetic Variants Associated with Episodic Ataxia in Korea.
Choi KD et al.·Sci Rep
2017
Atypical absence seizures and gene variants: A gene-based review of etiology, electro-clinical features, and associated epilepsy syndrome.
Zhao X et al.·Epilepsy Behav
2024Review
Migrainous vertigo: mutation analysis of the candidate genes CACNA1A, ATP1A2, SCN1A, and CACNB4.
von Brevern M et al.·Headache
2006
Central neurogenetic signatures of the visuomotor integration system.
Bueichekú E et al.·Proc Natl Acad Sci U S A
2020
Animal models of geriatric epilepsy.
Murphree LJ et al.·Int Rev Neurobiol
2007Review
Meta-analysis of microarray data to determine gene indicators involved in the cisplatin resistance in ovarian cancer.
Hashemi Sheikhshabani S et al.·Cancer Rep (Hoboken)
2023Meta-analysis
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
Alopecia

Evaluation of Scalp Cooling During Chemotherapy on Quality of Life and the Potential Role of Single Nucleotide Variations on Chemotherapy-Induced Alopecia and Hair Regrowth in the Appalachian Highlands Region

RECRUITING
NCT07422376Phase NACharles MaysStarted 2026-03-01
Paxman Scalp Cooling System

External Resources

Links to major genomics databases and tools