CACNB4

Summary

CACNB4 (calcium voltage-gated channel auxiliary subunit beta 4, HGNC:1404) is a protein-coding gene on chromosome 2q23.3, encoding Voltage-dependent L-type calcium channel subunit beta-4 (O00305). The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit mem….

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.

Source: NCBI Gene 785 — RefSeq curated summary.

At a glance

• Gene–disease (curated): episodic ataxia type 5 (Supportive, GenCC) — +3 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 322 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 35
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000726

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1404
Approved symbol	CACNB4
Name	calcium voltage-gated channel auxiliary subunit beta 4
Location	2q23.3
Locus type	gene with protein product
Status	Approved
Aliases	EJM4
Ensembl gene	ENSG00000182389
Ensembl biotype	protein_coding
OMIM	601949
Entrez	785

Gene structure

Transcript identifiers

Ensembl transcripts: 74 — 36 protein_coding, 19 nonsense_mediated_decay, 16 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000201943, ENST00000360283, ENST00000397327, ENST00000427385, ENST00000434468, ENST00000439467, ENST00000470066, ENST00000475848, ENST00000534999, ENST00000539935, ENST00000635731, ENST00000635738, ENST00000635743, ENST00000635803, ENST00000635835, ENST00000635890, ENST00000635904, ENST00000635930, ENST00000636108, ENST00000636129, ENST00000636130, ENST00000636350, ENST00000636380, ENST00000636390, ENST00000636442, ENST00000636496, ENST00000636507, ENST00000636598, ENST00000636617, ENST00000636664, ENST00000636721, ENST00000636762, ENST00000636773, ENST00000636785, ENST00000636810, ENST00000636831, ENST00000636834, ENST00000636901, ENST00000636947, ENST00000637007, ENST00000637132, ENST00000637216, ENST00000637217, ENST00000637232, ENST00000637284, ENST00000637309, ENST00000637312, ENST00000637319, ENST00000637330, ENST00000637418, ENST00000637436, ENST00000637479, ENST00000637491, ENST00000637514, ENST00000637530, ENST00000637535, ENST00000637547, ENST00000637550, ENST00000637622, ENST00000637762, ENST00000637765, ENST00000637773, ENST00000637779, ENST00000637828, ENST00000637884, ENST00000637913, ENST00000637942, ENST00000637956, ENST00000638005, ENST00000638040, ENST00000638056, ENST00000638083, ENST00000638091, ENST00000638150

RefSeq mRNA: 11 — MANE Select: NM_000726 NM_000726, NM_001005746, NM_001005747, NM_001145798, NM_001320722, NM_001330113, NM_001330114, NM_001330115, NM_001330116, NM_001330117, NM_001330118

CCDS: CCDS46426, CCDS46427, CCDS46428, CCDS54409, CCDS82520, CCDS82521, CCDS82522, CCDS82523

Canonical transcript exons

ENST00000539935 — 14 exons

Exon	Start	End
ENSE00001317962	152098330	152098413
ENSE00001365932	151832771	151839379
ENSE00001623528	151870531	151870611
ENSE00002373569	151869177	151869235
ENSE00003473133	151876426	151876556
ENSE00003486847	151880800	151880922
ENSE00003566065	151870842	151870861
ENSE00003584059	151883251	151883370
ENSE00003692082	151872417	151872493
ENSE00003715884	151855224	151855375
ENSE00003722321	151841903	151842088
ENSE00003722582	151860711	151860820
ENSE00003725322	151853448	151853543
ENSE00003796041	152098949	152099044

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 95.44.

FANTOM5 (CAGE): breadth broad, TPM avg 3.8906 / max 272.7187, expressed in 523 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31302	1.2407	285
31298	0.9638	138
31299	0.5555	143
31303	0.5332	255
31304	0.1630	88
31305	0.1437	55
31306	0.0933	40
31297	0.0641	35
31300	0.0575	33
31307	0.0527	30

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	95.44	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.91	gold quality
primary visual cortex	UBERON:0002436	90.63	gold quality
frontal pole	UBERON:0002795	90.54	gold quality
cerebellar cortex	UBERON:0002129	90.41	gold quality
cerebellar hemisphere	UBERON:0002245	90.23	gold quality
cerebellum	UBERON:0002037	90.19	gold quality
occipital lobe	UBERON:0002021	90.18	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.34	gold quality
postcentral gyrus	UBERON:0002581	89.01	gold quality
paraflocculus	UBERON:0005351	88.99	gold quality
parietal lobe	UBERON:0001872	88.95	gold quality
prefrontal cortex	UBERON:0000451	87.70	gold quality
superior frontal gyrus	UBERON:0002661	87.14	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.96	gold quality
nucleus accumbens	UBERON:0001882	85.33	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.31	gold quality
calcaneal tendon	UBERON:0003701	85.01	gold quality
lateral globus pallidus	UBERON:0002476	84.82	gold quality
frontal cortex	UBERON:0001870	84.79	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.77	gold quality
endothelial cell	CL:0000115	84.29	silver quality
cortical plate	UBERON:0005343	84.24	gold quality
putamen	UBERON:0001874	84.21	gold quality
neocortex	UBERON:0001950	84.21	gold quality
caudate nucleus	UBERON:0001873	84.10	gold quality
entorhinal cortex	UBERON:0002728	84.05	gold quality
buccal mucosa cell	CL:0002336	83.86	gold quality
substantia nigra pars compacta	UBERON:0001965	83.80	gold quality
telencephalon	UBERON:0001893	82.99	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	64.59
E-HCAD-35	yes	61.61
E-ANND-3	yes	9.55
E-GEOD-137537	yes	8.54

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 10)

• The novel nucleotide substitution T87C (D29D)in CACNB4 was observed in 2 migrainous vertigo patients and was not present in control DNA samples. (PMID:16866717)
• No pathogenic mutation were identified in CACNB4. (PMID:18446307)
• plays a role in neurotransmitter release. (PMID:18712068)
• proband identified with severe myoclonic epilepsy in infancy heterozygous for de novo SCN1A nonsense mutation & CACNB4 missense mutation (R468Q); greater Ca(v)2.1 currents caused by the mutation may increase neurotransmitter release in excitatory neurons (PMID:18755274)
• The Ca2+ channel beta4c subunit interacts with heterochromatin protein 1 gama via a PXVXL binding motif. (PMID:21220418)
• CACNB4 is associated with acute lung injury in mice (PMID:21297076)
• Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy (PMID:22892567)
• Genome-wide association studies identify CACNB4 mutation releated to juvenile myoclonic epilepsy. (PMID:23756480)
• The nuclear targeting properties of the truncated beta(4b(1-481)) subunit in tsA-201 cells, skeletal myotubes, and in hippocampal neurons, were investigated. (PMID:24875574)
• The homozygous CACNB4 p.(Leu126Pro) variant underlies the severe neurological phenotype in the two siblings. (PMID:32176688)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cacnb4a	ENSDARG00000009738
mus_musculus	Cacnb4	ENSMUSG00000017412
rattus_norvegicus	Cacnb4	ENSRNOG00000007666
drosophila_melanogaster	Ca-beta	FBGN0287724
caenorhabditis_elegans	ccb-1	WBGENE00000368
caenorhabditis_elegans	ccb-2	WBGENE00021125

Paralogs (3): CACNB1 (ENSG00000067191), CACNB2 (ENSG00000165995), CACNB3 (ENSG00000167535)

Protein

Protein identifiers

Voltage-dependent L-type calcium channel subunit beta-4 — O00305 (reviewed: O00305)

Alternative names: Calcium channel voltage-dependent subunit beta 4

All UniProt accessions (46): O00305, A0A1B0GTA9, A0A1B0GTF6, A0A1B0GTH0, A0A1B0GTK1, A0A1B0GTL1, A0A1B0GTN2, A0A1B0GTN8, A0A1B0GTP5, A0A1B0GTP6, A0A1B0GTS4, A0A1B0GTX2, A0A1B0GTX6, A0A1B0GTX8, A0A1B0GU05, A0A1B0GU07, A0A1B0GU32, A0A1B0GU42, A0A1B0GU53, A0A1B0GUI5, A0A1B0GUI8, A0A1B0GUJ7, A0A1B0GUK3, A0A1B0GUK4, A0A1B0GUM9, A0A1B0GUU5, A0A1B0GUU8, A0A1B0GUW8, A0A1B0GV16, A0A1B0GVB2, A0A1B0GVF0, A0A1B0GVG1, A0A1B0GVP7, A0A1B0GVT6, A0A1B0GVU5, A0A1B0GW58, A0A1B0GW63, A0A1B0GW81, A0A1B0GWF9, A0A1B0GWG5, A0A1B0GXG0, A0A1C7CYX2, C9J224, E7DBM8, E7EN11, H0Y476

UniProt curated annotations — full annotation on UniProt →

Function. The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting.

Subunit / interactions. The L-type calcium channel is composed of four subunits: alpha-1, alpha-2, beta and gamma. Interacts with FASLG. Interacts with CBARP.

Tissue specificity. Expressed predominantly in the cerebellum and kidney.

Disease relevance. Epilepsy, idiopathic generalized 9 (EIG9) [MIM:607682] A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Disease susceptibility is associated with variants affecting the gene represented in this entry. Juvenile myoclonic epilepsy 6 (EJM6) [MIM:607682] A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue. Disease susceptibility is associated with variants affecting the gene represented in this entry. Episodic ataxia 5 (EA5) [MIM:613855] A disorder characterized by episodes of vertigo and ataxia that last for several hours. Interictal examination show spontaneous downbeat and gaze-evoked nystagmus, mild dysarthria and truncal ataxia. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Unable to interact with the alpha-1 subunit.

Similarity. Belongs to the calcium channel beta subunit family.

Isoforms (4)

UniProt ID	Names	Canonical?
O00305-1	1, 4b	yes
O00305-2	2, 4a
O00305-3	3
O00305-4	4, 4d

RefSeq proteins (11): NP_000717, NP_001005746, NP_001005747, NP_001139270, NP_001307651, NP_001317042, NP_001317043, NP_001317044, NP_001317045, NP_001317046, NP_001317047 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000584	VDCC_L_bsu	Family
IPR001452	SH3_domain	Domain
IPR008145	GK/Ca_channel_bsu	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR046937	CAB1-4_N_A-dom	Domain

Pfam: PF00625, PF12052

UniProt features (27 total): modified residue 6, sequence conflict 4, splice variant 3, region of interest 3, compositionally biased region 3, strand 2, helix 2, chain 1, domain 1, sequence variant 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2D46	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00305-F1	72.29	0.49

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (6): 411, 448, 506, 508, 39, 183

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-112308	Presynaptic depolarization and calcium channel opening
R-HSA-419037	NCAM1 interactions
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1266738	Developmental Biology
R-HSA-375165	NCAM signaling for neurite out-growth
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 427 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_ACID_SECRETION, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_PEPTIDE, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_ADULT_BEHAVIOR, GOZGIT_ESR1_TARGETS_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_EXOCYTOSIS, REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH, GOBP_THYMUS_DEVELOPMENT, GOBP_NEUROTRANSMITTER_TRANSPORT

GO Biological Process (26): calcium ion transport (GO:0006816), gamma-aminobutyric acid signaling pathway (GO:0007214), chemical synaptic transmission (GO:0007268), neuromuscular junction development (GO:0007528), adult walking behavior (GO:0007628), negative regulation of cell population proliferation (GO:0008285), gamma-aminobutyric acid secretion (GO:0014051), neuronal action potential propagation (GO:0019227), synaptic transmission, glutamatergic (GO:0035249), cAMP metabolic process (GO:0046058), spleen development (GO:0048536), thymus development (GO:0048538), Peyer’s patch development (GO:0048541), T cell receptor signaling pathway (GO:0050852), detection of light stimulus involved in visual perception (GO:0050908), muscle cell development (GO:0055001), calcium ion transmembrane transport (GO:0070588), positive regulation of protein localization to nucleolus (GO:1904751), cellular response to leukemia inhibitory factor (GO:1990830), negative regulation of G1/S transition of mitotic cell cycle (GO:2000134), regulation of synaptic vesicle exocytosis (GO:2000300), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), regulation of membrane potential (GO:0042391), nervous system process (GO:0050877), regulation of presynaptic cytosolic calcium ion concentration (GO:0099509)

GO Molecular Function (6): calcium channel regulator activity (GO:0005246), protein kinase binding (GO:0019901), voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levels (GO:0099626), voltage-gated calcium channel activity (GO:0005245), calcium channel activity (GO:0005262), protein binding (GO:0005515)

GO Cellular Component (9): cytosol (GO:0005829), plasma membrane (GO:0005886), voltage-gated calcium channel complex (GO:0005891), cytoplasmic side of plasma membrane (GO:0009898), nuclear speck (GO:0016607), synapse (GO:0045202), presynapse (GO:0098793), glutamatergic synapse (GO:0098978), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Transmission across Chemical Synapses	1
NCAM signaling for neurite out-growth	1
Neuronal System	1
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
hematopoietic or lymphoid organ development	2
calcium channel activity	2
cellular anatomical structure	2
synapse	2
metal ion transport	1
cell-cell signaling	1
GABA receptor activity	1
anterograde trans-synaptic signaling	1
synapse organization	1
adult locomotory behavior	1
walking behavior	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
gamma-aminobutyric acid transport	1
acid secretion	1
transmission of nerve impulse	1
nervous system process	1
action potential propagation	1
chemical synaptic transmission	1
purine ribonucleotide metabolic process	1
cyclic purine nucleotide metabolic process	1
gland development	1
mucosa-associated lymphoid tissue development	1
antigen receptor-mediated signaling pathway	1
visual perception	1
detection of light stimulus involved in sensory perception	1
muscle cell differentiation	1
cell development	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
positive regulation of protein localization to nucleus	1
protein localization to nucleolus	1
regulation of protein localization to nucleolus	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
G1/S transition of mitotic cell cycle	1
negative regulation of mitotic cell cycle phase transition	1
negative regulation of cell cycle G1/S phase transition	1
regulation of G1/S transition of mitotic cell cycle	1

Protein interactions and networks

STRING

1324 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CACNB4	CACNA1A	P78510	929
CACNB4	EFHC1	Q5JVL4	874
CACNB4	CACNA2D2	Q9NY47	866
CACNB4	CLCN2	P51788	800
CACNB4	GUK1	Q16774	790
CACNB4	GABRD	O14764	770
CACNB4	CACNG2	Q9Y698	754
CACNB4	KCNA1	Q09470	752
CACNB4	SLC1A3	P43003	748
CACNB4	CACNA2D1	P54289	736
CACNB4	GABRA1	P14867	726
CACNB4	KCNQ2	O43526	714
CACNB4	EPHB2	P29323	684
CACNB4	CACNA2D3	Q8IZS8	657
CACNB4	CACNA1B	Q00975	648

IntAct

21 interactions, top by confidence:

A	B	Type	Score
CACNB4	EFHC2	psi-mi:“MI:0915”(physical association)	0.720
CACNB4	CCDC102B	psi-mi:“MI:0915”(physical association)	0.560
CACNB4	CTBP2	psi-mi:“MI:0915”(physical association)	0.560
CACNB4	CACNB3	psi-mi:“MI:0914”(association)	0.530
CACNB3	CACNB4	psi-mi:“MI:0914”(association)	0.530
CACNB4	FASLG	psi-mi:“MI:0407”(direct interaction)	0.440
CACNA1C	CACNB4	psi-mi:“MI:0914”(association)	0.350
CACNB4	IDE	psi-mi:“MI:0914”(association)	0.350
CACNB4	CCDC102B	psi-mi:“MI:0915”(physical association)	0.000
CACNB4	EFHC2	psi-mi:“MI:0915”(physical association)	0.000
CACNB4	CTBP2	psi-mi:“MI:0915”(physical association)	0.000
CACNB4	MED31	psi-mi:“MI:0915”(physical association)	0.000
CACNB4	PTN	psi-mi:“MI:0915”(physical association)	0.000
CACNB4	TBL3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (21): EFHC2 (Two-hybrid), CACNB3 (Affinity Capture-MS), COLGALT2 (Affinity Capture-MS), TBL3 (Two-hybrid), MED31 (Two-hybrid), PTN (Two-hybrid), CACNB4 (Two-hybrid), CACNB4 (Two-hybrid), EFHC2 (Two-hybrid), CACNB4 (Reconstituted Complex), CACNA1A (Reconstituted Complex), CACNB4 (Affinity Capture-Western), IDE (Affinity Capture-MS), CACNB3 (Affinity Capture-MS), COLGALT2 (Affinity Capture-MS)

ESM2 similar proteins: A6QLK2, A6QNT8, D3ZMY7, D4A055, F1QH17, O00305, O35431, O95486, O95487, P40692, P49902, P54288, P56223, P97679, Q01973, Q0VGM9, Q13330, Q16514, Q1RMS5, Q3SWT1, Q3T174, Q3U2P1, Q3UNW5, Q3V1L4, Q5EBF1, Q5PYH5, Q5RA22, Q5RB16, Q5RE34, Q5RJZ1, Q5ZIZ4, Q61187, Q62599, Q6AY57, Q6DKB0, Q6H1L8, Q6IRE4, Q7ZWU5, Q80W47, Q80YA3

Diamond homologs: D4A055, O00305, P19517, P54283, P54284, P54285, P54286, P54287, P54288, Q02641, Q08289, Q8CC27, Q8R0S4, Q8R3Z5, Q8VGC3, Q9MZL3, Q9MZL5, Q9MZL7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

322 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	190
Likely benign	44
Benign	50

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
374311	NM_000726.5(CACNB4):c.610del (p.Gln204fs)	Pathogenic
1027429	NM_000726.5(CACNB4):c.615A>T (p.Lys205Asn)	Likely pathogenic
4278043	NM_000726.5(CACNB4):c.241G>A (p.Ala81Thr)	Likely pathogenic

SpliceAI

2917 predictions. Top by Δscore:

Variant	Effect	Δscore
2:151839378:CT:C	acceptor_gain	1.0000
2:151841897:CAATA:C	donor_loss	1.0000
2:151841898:AATAC:A	donor_loss	1.0000
2:151841899:ATACC:A	donor_loss	1.0000
2:151841900:TACCT:T	donor_loss	1.0000
2:151841901:A:AT	donor_loss	1.0000
2:151841902:CCTG:C	donor_gain	1.0000
2:151841902:CCTGT:C	donor_loss	1.0000
2:151841904:TGTA:T	donor_gain	1.0000
2:151842085:TTTC:T	acceptor_gain	1.0000
2:151842086:TTC:T	acceptor_gain	1.0000
2:151842086:TTCC:T	acceptor_loss	1.0000
2:151842087:TCCTG:T	acceptor_loss	1.0000
2:151842089:C:CC	acceptor_gain	1.0000
2:151842089:C:CG	acceptor_loss	1.0000
2:151842090:T:A	acceptor_loss	1.0000
2:151855373:CCGCT:C	acceptor_gain	1.0000
2:151855374:CGCT:C	acceptor_gain	1.0000
2:151855376:C:CC	acceptor_gain	1.0000
2:151855377:T:C	acceptor_gain	1.0000
2:151855377:T:TC	acceptor_gain	1.0000
2:151860820:CCTA:C	acceptor_gain	1.0000
2:151872023:T:TA	donor_gain	1.0000
2:151880919:TGGA:T	acceptor_gain	1.0000
2:151880923:C:CC	acceptor_gain	1.0000
2:151883246:CTCA:C	donor_loss	1.0000
2:151883247:TCAC:T	donor_loss	1.0000
2:151883248:CAC:C	donor_loss	1.0000
2:151883249:A:AC	donor_gain	1.0000
2:151883249:AC:A	donor_gain	1.0000

AlphaMissense

3390 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:151842021:A:G	L395P	1.000
2:151842054:A:T	L384H	1.000
2:151842069:A:C	L379W	1.000
2:151842069:A:G	L379S	1.000
2:151853484:T:A	Q360H	1.000
2:151853484:T:G	Q360H	1.000
2:151853517:T:A	R349S	1.000
2:151853517:T:G	R349S	1.000
2:151853518:C:A	R349I	1.000
2:151853518:C:G	R349T	1.000
2:151853530:A:C	L345W	1.000
2:151853530:A:G	L345S	1.000
2:151855249:A:T	V332D	1.000
2:151855258:G:C	P329R	1.000
2:151855258:G:T	P329Q	1.000
2:151855264:A:G	L327S	1.000
2:151855279:A:G	L322P	1.000
2:151855293:A:C	N317K	1.000
2:151855293:A:T	N317K	1.000
2:151855312:A:C	L311R	1.000
2:151855312:A:G	L311P	1.000
2:151855312:A:T	L311H	1.000
2:151855315:A:T	V310D	1.000
2:151855318:A:T	V309D	1.000
2:151855337:C:G	A303P	1.000
2:151855344:A:C	F300L	1.000
2:151855344:A:T	F300L	1.000
2:151855346:A:G	F300L	1.000
2:151860782:G:T	A266D	1.000
2:151860795:C:G	D262H	1.000

dbSNP variants (sampled 300 via entrez): RS1000002253 (2:151860350 C>A), RS1000010020 (2:151941863 A>G), RS1000018004 (2:151852218 T>A), RS1000028559 (2:151896632 C>G), RS1000032799 (2:152076498 T>C,G), RS1000033293 (2:151860122 T>C), RS1000040610 (2:151940450 T>C), RS1000053617 (2:151983036 T>A), RS1000058748 (2:152039791 C>T), RS1000076774 (2:152088941 C>A), RS1000079163 (2:151997000 G>A,C,T), RS1000082442 (2:152037390 C>G), RS1000091255 (2:152029121 G>A), RS1000092457 (2:151851268 A>G,T), RS1000100751 (2:152078207 T>C)

Disease associations

OMIM: gene MIM:601949 | disease phenotypes: MIM:600669, MIM:108600, MIM:607682, MIM:613855, MIM:254770, MIM:606904

GenCC curated gene-disease

Disease	Classification	Inheritance
episodic ataxia type 5	Supportive	Autosomal dominant
juvenile myoclonic epilepsy	Supportive	Autosomal dominant
epilepsy, idiopathic generalized, susceptibility to, 9	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
epilepsy	Refuted	AD

Mondo (7): idiopathic generalized epilepsy (MONDO:0005579), spastic ataxia (MONDO:0017845), epilepsy, idiopathic generalized, susceptibility to, 9 (MONDO:0011892), episodic ataxia type 5 (MONDO:0013464), epilepsy (MONDO:0005027), epilepsy, juvenile myoclonic, susceptibility to, 6 (MONDO:0800271), juvenile myoclonic epilepsy (MONDO:0009696)

Orphanet (3): Spastic ataxia (Orphanet:316226), Juvenile myoclonic epilepsy (Orphanet:307), Episodic ataxia type 5 (Orphanet:211067)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000153	Abnormality of the mouth
HP:0000496	Abnormality of eye movement
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000718	Aggressive behavior
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001336	Myoclonus
HP:0002069	Bilateral tonic-clonic seizure
HP:0002078	Truncal ataxia
HP:0002121	Generalized non-motor (absence) seizure
HP:0002131	Episodic ataxia
HP:0002133	Status epilepticus
HP:0002172	Postural instability
HP:0002197	Generalized-onset seizure
HP:0002321	Vertigo
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002392	EEG with polyspike wave complexes
HP:0003621	Juvenile onset
HP:0003829	Typified by incomplete penetrance
HP:0007000	Morning myoclonic jerks
HP:0007193	Bilateral tonic-clonic seizure on awakening
HP:0007207	Photosensitive tonic-clonic seizure
HP:0007270	Atypical absence seizure
HP:0010532	Paroxysmal vertigo
HP:0010818	Generalized tonic seizure
HP:0010850	EEG with spike-wave complexes
HP:0011147	Typical absence seizure

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002181_1	Adverse response to chemotherapy in breast cancer (alopecia)	2.000000e-09
GCST003469_11	Response to cognitive-behavioural therapy in anxiety disorder	4.000000e-06
GCST005588_14	Idiopathic dilated cardiomyopathy	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007820	cognitive behavioural therapy
EFO:0009094	idiopathic dilated cardiomyopathy

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D020190	Myoclonic Epilepsy, Juvenile	C10.228.140.490.375.130.670; C10.228.140.490.493.063.670
C562694	Epilepsy, Idiopathic Generalized (supp.)
C566601	Episodic Ataxia, Type 5 (supp.)
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2363032 (PROTEIN COMPLEX GROUP)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 67,947 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1428	NIMODIPINE	4	32,587
CHEMBL95	TACRINE	4	35,360

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3768652	CACNB4		0.00	0

ChEMBL bioactivities

58 potent at pChembl≥5 of 75 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.82	IC50	1.5	nM	CHEMBL3891844
8.72	IC50	1.9	nM	CHEMBL3890624
8.62	IC50	2.4	nM	CHEMBL3973392
8.57	IC50	2.7	nM	CHEMBL3891844
8.52	IC50	3	nM	CHEMBL3919024
8.51	IC50	3.1	nM	CHEMBL3919898
8.35	IC50	4.5	nM	CHEMBL3965812
8.23	IC50	5.9	nM	CHEMBL3906126
8.22	IC50	6	nM	CHEMBL3890916
8.15	IC50	7	nM	CHEMBL3940577
8.14	IC50	7.2	nM	CHEMBL3969562
8.12	IC50	7.6	nM	CHEMBL3937280
8.12	IC50	7.6	nM	CHEMBL3965812
8.10	IC50	8	nM	CHEMBL3983323
8.05	IC50	9	nM	CHEMBL3942512
8.03	IC50	9.4	nM	CHEMBL3922498
8.01	IC50	9.7	nM	CHEMBL3897303
7.96	IC50	11	nM	CHEMBL3948329
7.92	IC50	12	nM	CHEMBL3898359
7.85	IC50	14	nM	CHEMBL3911369
7.85	IC50	14	nM	CHEMBL3913505
7.85	IC50	14	nM	CHEMBL3936725
7.82	IC50	15	nM	CHEMBL3984596
7.82	IC50	15	nM	CHEMBL3902376
7.67	IC50	21.5	nM	CHEMBL3952905
7.62	IC50	24	nM	CHEMBL3972896
7.58	IC50	26	nM	CHEMBL3889804
7.55	IC50	28	nM	CHEMBL3958844
7.55	IC50	28	nM	CHEMBL3973382
7.52	IC50	30	nM	CHEMBL3978200
7.52	IC50	30	nM	CHEMBL3985660
7.51	IC50	31	nM	CHEMBL3896861
7.51	IC50	31	nM	CHEMBL3951956
7.50	IC50	31.4	nM	CHEMBL3962403
7.44	IC50	36	nM	CHEMBL3953976
7.44	IC50	36	nM	CHEMBL3925140
7.41	IC50	39	nM	CHEMBL3900691
7.39	IC50	41	nM	CHEMBL3930781
7.30	IC50	50	nM	CHEMBL3921840
7.21	IC50	62	nM	CHEMBL3956991
7.17	IC50	67	nM	CHEMBL3965293
7.09	IC50	81	nM	CHEMBL3958264
7.07	IC50	85	nM	CHEMBL3964411
7.01	IC50	98.5	nM	CHEMBL3953031
6.40	IC50	400	nM	CHEMBL3974355
6.10	IC50	800	nM	CHEMBL3734797
5.75	IC50	1800	nM	CHEMBL4228929
5.66	IC50	2200	nM	CHEMBL4226021
5.52	IC50	3000	nM	CHEMBL4228209
5.52	IC50	3000	nM	CHEMBL4224773

PubChem BioAssay actives

13 with measured affinity, of 101 total; 13 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-tert-butyl-8-[[[(1S,2S)-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropanecarbonyl]amino]methyl]-5-[3-(trifluoromethoxy)phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxamide	1262825: Inhibition of voltage-gated calcium channel (unknown origin)	ic50	0.8000	uM
5-methyl-1-[(2-nitrophenyl)methyl]-3-(piperidin-1-ylmethyl)indole	1392176: Inhibition of KCl-induced cytosolic voltage gated calcium channel opening in human SH-SY5Y cells by Fluo-4 AM dye based fluorescence assay	ic50	1.8000	uM
1-[(3-chlorophenyl)methyl]-5-methyl-3-(piperidin-1-ylmethyl)indole	1392176: Inhibition of KCl-induced cytosolic voltage gated calcium channel opening in human SH-SY5Y cells by Fluo-4 AM dye based fluorescence assay	ic50	2.2000	uM
5-methyl-1-[(3-nitrophenyl)methyl]-3-(piperidin-1-ylmethyl)indole	1392176: Inhibition of KCl-induced cytosolic voltage gated calcium channel opening in human SH-SY5Y cells by Fluo-4 AM dye based fluorescence assay	ic50	3.0000	uM
1-[(4-chlorophenyl)methyl]-5-methyl-3-(piperidin-1-ylmethyl)indole	1392176: Inhibition of KCl-induced cytosolic voltage gated calcium channel opening in human SH-SY5Y cells by Fluo-4 AM dye based fluorescence assay	ic50	3.0000	uM
1-benzyl-5-methyl-3-(piperidin-1-ylmethyl)indole	1392176: Inhibition of KCl-induced cytosolic voltage gated calcium channel opening in human SH-SY5Y cells by Fluo-4 AM dye based fluorescence assay	ic50	3.4000	uM
5-methyl-1-[(4-methylphenyl)methyl]-3-(piperidin-1-ylmethyl)indole	1392176: Inhibition of KCl-induced cytosolic voltage gated calcium channel opening in human SH-SY5Y cells by Fluo-4 AM dye based fluorescence assay	ic50	3.6000	uM
1-[(4-fluorophenyl)methyl]-5-methyl-3-(piperidin-1-ylmethyl)indole	1392176: Inhibition of KCl-induced cytosolic voltage gated calcium channel opening in human SH-SY5Y cells by Fluo-4 AM dye based fluorescence assay	ic50	4.8000	uM
N-heptyl-16,18-dioxo-17-azapentacyclo[6.6.5.02,7.09,14.015,19]nonadeca-2,4,6,9,11,13-hexaene-1-carboxamide	1612587: Inhibition of K+-induced voltage gated calcium channel opening in human SH-SY5Y cells assessed as decrease in Ca2+ level after 10 mins by Fluo-4 dye-based fluorescence assay	ic50	9.0000	uM
ethyl 5-amino-4-(3-methoxyphenyl)-2-methyl-7,8,9,10-tetrahydro-6H-cyclohepta[b][1,8]naphthyridine-3-carboxylate	1653244: Inhibition of VGCC (unknown origin)	ic50	9.0000	uM
ethyl 5-amino-4-(3,4-dimethoxyphenyl)-2-methyl-7,8,9,10-tetrahydro-6H-cyclohepta[b][1,8]naphthyridine-3-carboxylate	1653244: Inhibition of VGCC (unknown origin)	ic50	9.0000	uM
propan-2-yl 5-amino-2-methyl-4-phenyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate	1653244: Inhibition of VGCC (unknown origin)	ic50	10.0000	uM
ethyl 5-amino-2-methyl-4-phenyl-6,7,8,9,10,11-hexahydrocycloocta[b][1,8]naphthyridine-3-carboxylate	1653244: Inhibition of VGCC (unknown origin)	ic50	10.0000	uM

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	3
Benzo(a)pyrene	affects methylation	2
Estradiol	affects binding, increases expression, affects expression	2
Valproic Acid	increases expression, affects expression	2
aristolochic acid I	decreases expression	1
sotorasib	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	increases expression	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
incobotulinumtoxinA	increases expression	1
trametinib	decreases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, affects expression	1
Arsenic	affects methylation	1
Asbestos	increases expression	1
Barium	affects transport	1
Chelating Agents	affects binding, increases expression	1
Copper	affects binding, increases expression	1

ChEMBL screening assays

13 unique, capped per target: 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3737861	Binding	Inhibition of voltage-gated calcium channel (unknown origin)	Discovery and Pharmacology of a Novel Class of Diacylglycerol Acyltransferase 2 Inhibitors. — J Med Chem

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D8I8	Ubigene HCT 116 CACNB4 KO	Cancer cell line	Male
CVCL_D9AQ	Ubigene HEK293 CACNB4 KO	Transformed cell line	Female
CVCL_D9Z4	Ubigene HeLa CACNB4 KO	Cancer cell line	Female
CVCL_SG54	HAP1 CACNB4 (-) 1	Cancer cell line	Male
CVCL_SG55	HAP1 CACNB4 (-) 2	Cancer cell line	Male
CVCL_YA27	IDG-HEK293T-CACNB4-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03590197	PHASE4	COMPLETED	Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy
NCT03940326	PHASE4	COMPLETED	Levetiracetam Versus Valproate in Idiopathic Generalized Tonic-clonic Seizures
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide