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): 348 total — 1 pathogenic, 2 likely-pathogenic (top 9% of genes corpus-wide)
• GTEx eGene: eQTL in 25 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 35
• ChEMBL bioactivity: 2 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.78 (unconstrained)
• MANE Select transcript: NM_000726
• Notable: 348 clinical variants but no curated precision-oncology (CIViC) evidence yet

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: 75 — 37 protein_coding, 19 nonsense_mediated_decay, 16 retained_intron, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000539935

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 1, TSL 4: 1, TSL 5: 64

ENST00000539935, ENST00000201943, ENST00000360283, ENST00000397327, ENST00000427385, ENST00000434468, ENST00000439467, ENST00000470066, ENST00000475848, ENST00000534999, 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, ENST00001138916

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.

Highest expression (Bgee): cerebellar vermis, lateral nuclear group of thalamus, primary visual cortex, frontal pole, cerebellar cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CACNB4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 25 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 26 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Not Sun Exposed Suprapubic	eqtl	2.7e-15	+0.34	2:151948921:G:T
Skin Sun Exposed Lower leg	eqtl	2.4e-14	+0.29	2:151980639:G:C
Esophagus Mucosa	eqtl	3.7e-10	-0.26	2:152039785:G:A
Testis	eqtl	3.4e-09	-0.13	2:152075773:A:T
Spleen	eqtl	2.0e-08	+1.08	2:152038939:G:A
Adipose Visceral Omentum	eqtl	6.3e-04	+0.16	2:152106846:T:G
Esophagus Gastroesophageal Junction	eqtl	8.6e-04	+0.19	2:151921671:C:T
Esophagus Muscularis	eqtl	9.8e-04	+0.17	2:151929717:A:C
Pituitary	eqtl	1.0e-03	-0.25	2:152036594:T:G
Nerve Tibial	eqtl	1.9e-03	-0.13	2:151980331:A:G
Artery Aorta	eqtl	2.4e-03	-0.16	2:152091632:T:C
Brain Cortex	eqtl	3.2e-03	+0.50	2:151942316:C:T
Cells EBV-transformed lymphocytes	sqtl	7.1e-03	+1.27	2:152280890:A:G
Pancreas	eqtl	8.1e-03	+0.47	2:152943694:T:C
Breast Mammary Tissue	eqtl	8.9e-03	+0.16	2:152049915:C:T
Colon Sigmoid	eqtl	1.2e-02	+0.23	2:152073610:T:C
Stomach	eqtl	1.4e-02	+0.53	2:151164274:CAG:C
Prostate	eqtl	1.5e-02	+0.88	2:151201581:T:C
Adipose Subcutaneous	eqtl	1.9e-02	+0.23	2:151762672:A:G
Adrenal Gland	eqtl	1.9e-02	+0.31	2:151999450:C:T

FANTOM5 promoters

showing 10 of 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

showing 100 of 284 tissues 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
cerebral cortex	UBERON:0000956	82.90	gold quality
pons	UBERON:0000988	82.88	gold quality
substantia nigra pars reticulata	UBERON:0001966	82.77	gold quality
Brodmann (1909) area 10	UBERON:0013541	82.55	gold quality
cingulate cortex	UBERON:0003027	81.99	gold quality
Brodmann (1909) area 46	UBERON:0006483	81.96	gold quality
anterior cingulate cortex	UBERON:0009835	81.84	gold quality
brain	UBERON:0000955	81.66	gold quality
central nervous system	UBERON:0001017	81.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.14	gold quality
forebrain	UBERON:0001890	81.01	gold quality
dorsal plus ventral thalamus	UBERON:0001897	80.56	gold quality
ventral tegmental area	UBERON:0002691	79.78	gold quality
right frontal lobe	UBERON:0002810	79.58	gold quality
tendon	UBERON:0000043	79.26	gold quality
corpus callosum	UBERON:0002336	79.15	gold quality
temporal lobe	UBERON:0001871	78.96	gold quality
orbitofrontal cortex	UBERON:0004167	78.44	gold quality
middle temporal gyrus	UBERON:0002771	78.14	gold quality
olfactory bulb	UBERON:0002264	77.64	gold quality
middle frontal gyrus	UBERON:0002702	76.34	silver quality
amygdala	UBERON:0001876	75.84	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.20	gold quality
Ammon’s horn	UBERON:0001954	74.94	gold quality
ganglionic eminence	UBERON:0004023	74.91	gold quality
superior vestibular nucleus	UBERON:0007227	74.65	gold quality
subthalamic nucleus	UBERON:0001906	74.53	gold quality
midbrain	UBERON:0001891	74.48	gold quality
substantia nigra	UBERON:0002038	74.28	gold quality
diaphragm	UBERON:0001103	74.04	gold quality
nipple	UBERON:0002030	73.59	gold quality
hypothalamus	UBERON:0001898	73.02	gold quality
globus pallidus	UBERON:0001875	73.00	silver quality
adrenal tissue	UBERON:0018303	72.49	gold quality
ventricular zone	UBERON:0003053	72.20	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	71.56	gold quality
inferior vagus X ganglion	UBERON:0005363	71.48	gold quality
spinal cord	UBERON:0002240	71.45	gold quality
medulla oblongata	UBERON:0001896	71.35	gold quality
medial globus pallidus	UBERON:0002477	71.34	silver quality
sural nerve	UBERON:0015488	71.27	gold quality
tonsil	UBERON:0002372	70.95	gold quality
upper leg skin	UBERON:0004262	70.76	silver quality
hair follicle	UBERON:0002073	70.66	gold quality
type B pancreatic cell	CL:0000169	70.12	gold quality
minor salivary gland	UBERON:0001830	69.68	gold quality
colonic epithelium	UBERON:0000397	69.51	silver quality
skin of abdomen	UBERON:0001416	69.45	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	68.67	gold quality
mucosa of paranasal sinus	UBERON:0005030	68.38	gold quality
mouth mucosa	UBERON:0003729	68.29	gold quality
saliva-secreting gland	UBERON:0001044	68.13	gold quality
mucosa of stomach	UBERON:0001199	68.01	gold quality
ascending aorta	UBERON:0001496	67.78	gold quality
thoracic aorta	UBERON:0001515	67.60	gold quality
vena cava	UBERON:0004087	67.51	gold quality
tendon of biceps brachii	UBERON:0008188	67.50	gold quality
dorsal root ganglion	UBERON:0000044	67.34	silver quality
descending thoracic aorta	UBERON:0002345	67.18	gold quality
vastus lateralis	UBERON:0001379	67.03	gold quality
tongue squamous epithelium	UBERON:0006919	66.96	gold quality
trigeminal ganglion	UBERON:0001675	66.64	gold quality
esophagus mucosa	UBERON:0002469	66.63	gold quality
quadriceps femoris	UBERON:0001377	66.10	gold quality
pituitary gland	UBERON:0000007	65.99	gold quality
aorta	UBERON:0000947	65.69	gold quality
monocyte	CL:0000576	65.66	gold quality
adenohypophysis	UBERON:0002196	65.66	gold quality
cardia of stomach	UBERON:0001162	65.61	gold quality
CA1 field of hippocampus	UBERON:0003881	65.48	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

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebellum	tissue	190.6	high
Cerebral cortex	tissue	116.6	high
Occipital cortex	tissue	116.6
Somatosensory cortex	tissue	112.3
Retrosplenial and cingulate cortex	tissue	86.2
Motor cortex	tissue	85.8
Hippocampal formation	tissue	85.0
Entorhinal cortex	tissue	85.0
Putamen	tissue	83.1
Prefrontal cortex	tissue	82.7
Retrosplenial cortex	tissue	79.4
Temporal cortex	tissue	77.9
Thalamus	tissue	77.4
Basal ganglia	tissue	76.2	medium
Midbrain	tissue	74.0
Superior colliculi	tissue	71.1
Olfactory bulb	tissue	68.9
Insular cortex	tissue	68.7
Frontal cortex	tissue	63.5
Ventral forebrain	tissue	60.3
Caudate putamen	tissue	60.0
Pons	tissue	55.6
Postcentral gyrus	tissue	51.0
Septum	tissue	47.2
Nucleus accumbens	tissue	36.1
Amygdala	tissue	35.2
Hypothalamus	tissue	31.1
Periaqueductal gray	tissue	28.8
Medulla oblongata	tissue	28.0
Substantia nigra	tissue	24.4
Spinal cord	tissue	20.6
Corpus callosum	tissue	19.1
Choroid plexus	tissue	16.0
Locus coeruleus	tissue	11.6
Hippocampus	tissue	11.6	high
Skin 1	tissue	6.9	low
Testis	tissue	2.1	medium
Lung	tissue	1.9	low
Prostate	tissue	1.9	low
Pituitary gland	tissue	1.8
Seminal vesicle	tissue	1.8	low
Retina	tissue	1.7
Breast	tissue	1.4	low
Esophagus	tissue	1.4	low
Urinary bladder	tissue	1.4	low
Thyroid gland	tissue	1.3	medium
Kidney	tissue	1.3	low
Thymus	tissue	1.1
Tonsil	tissue	1.0	medium
Salivary gland	tissue	0.9	low
Placenta	tissue	0.9	low
Gallbladder	tissue	0.8	low
Adrenal gland	tissue	0.7	medium
Adipose tissue	tissue	0.6	low
Bone marrow	tissue	0.6	low
Stomach 1	tissue	0.5	low
Vagina	tissue	0.5	low
Smooth muscle	tissue	0.5	low
Epididymis	tissue	0.5	low
Rectum	tissue	0.4	low

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Subiculum (51.7), Cerebellar cortex (50.3), Vermis (46.0), Flocculonodular lobe (43.1), Dorsal hippocampus (41.3).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 0.00137, LOEUF 0.778, missense Z 1.94 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000539935 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:151,839,122–151,841,952	115 / 128.8	0.89	no
2:151,841,953–152,098,368	299 / 471.7	0.63	no
2:152,098,369–152,099,011	50 / 47.5	1.05	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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:103301) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 54 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal gait	3
decreased body size	2
abnormal thymus involution	2
seizures	2
abnormal brain wave pattern	2
lethargy	2
abnormal head movements	1
pituitary gland hyperplasia	1
small spleen	1
enlarged lymph nodes	1
small thymus	1
abnormal motor neuron morphology	1
convulsive seizures	1
abnormal neuromuscular synapse morphology	1
absent corpus luteum	1
abnormal locomotor behavior	1
ataxia	1
circling	1
decreased locomotor activity	1
impaired coordination	1
abnormal posture	1
impaired righting response	1
impaired limb coordination	1
postnatal growth retardation	1
reduced fertility	1

+29 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q9MZL3	99.0%	Diamond
Oryctolagus cuniculus	P54286	97.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
STAM2	protein-coding	10254
FMNL2	protein-coding	114793
ARL5A	protein-coding	26225
ARL6IP6	protein-coding	151188
PRPF40A	protein-coding	55660
NEB	protein-coding	4703
RIF1	protein-coding	55183
TNFAIP6	protein-coding	7130
MIR4773-1	ncRNA	100616392
MIR4773-2	ncRNA	100616418

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): 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, O00305, 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 by resolution:

PDB	Title	Method	Resolution (Å)
2D46	Solution Structure of the Human Beta4a-A Domain	SOLUTION NMR

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes, Epilepsy

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

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)

Type	Positions
Phosphothreonine	411
Phosphoserine	448, 508, 39, 183
Omega-n-methylarginine	506

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

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

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 (11): calcium ion transport (GO:0006816), chemical synaptic transmission (GO:0007268), negative regulation of cell population proliferation (GO:0008285), positive regulation of muscle contraction (GO:0045933), calcium ion transmembrane transport (GO:0070588), positive regulation of protein localization to nucleolus (GO:1904751), 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 presynaptic cytosolic calcium ion concentration (GO:0099509)

GO Molecular Function (7): calcium channel regulator activity (GO:0005246), high voltage-gated calcium channel activity (GO:0008331), 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 (10): 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), T-tubule (GO:0030315), synapse (GO:0045202), presynapse (GO:0098793), glutamatergic synapse (GO:0098978), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

6 top-level categories:

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

49 GO namespaces:

Category	Terms
cellular anatomical structure	3
presynapse	2
calcium channel activity	2
synapse	2
metal ion transport	1
anterograde trans-synaptic signaling	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
muscle contraction	1
regulation of muscle contraction	1
positive regulation of multicellular organismal process	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
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
synaptic vesicle exocytosis	1
regulation of neurotransmitter secretion	1
regulation of regulated secretory pathway	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
regulation of cytosolic calcium ion concentration	1
neuron cellular homeostasis	1
ion channel regulator activity	1
voltage-gated calcium channel activity	1
kinase binding	1
regulation of presynaptic cytosolic calcium ion concentration	1
voltage-gated calcium channel activity involved in regulation of cytosolic calcium levels	1
voltage-gated monoatomic cation channel activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1
calcium channel complex	1
plasma membrane protein complex	1
plasma membrane	1
cytoplasmic side of membrane	1
nuclear ribonucleoprotein granule	1
sarcolemma	1
cell junction	1
transmembrane transporter complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 28 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
calcium ion transmembrane transport	BP	mutant phenotype
plasma membrane	CC	direct assay
synapse	CC	direct assay
voltage-gated calcium channel complex	CC	direct assay
calcium channel regulator activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,122 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CACNB4	CACNA1A	P78510	919
CACNB4	EFHC1	Q5JVL4	874
CACNB4	CACNA2D2	Q9NY47	838
CACNB4	GUK1	Q16774	781
CACNB4	CLCN2	P51788	779
CACNB4	GABRD	O14764	752
CACNB4	SLC1A3	P43003	731
CACNB4	KCNA1	Q09470	724
CACNB4	GABRA1	P14867	702
CACNB4	KCNQ2	O43526	697
CACNB4	CACNG2	Q9Y698	680
CACNB4	CACNA2D1	P54289	680
CACNB4	CACNA1B	Q00975	606
CACNB4	CACNG3	O60359	584
CACNB4	CACNG1	Q06432	552

IntAct

Human interaction partners of CACNB4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

10 partners by confidence:

Partner	Interaction type	MIscore	Records
EFHC2	physical association	0.720	6
CCDC102B	physical association	0.560	3
CTBP2	physical association	0.560	3
CACNB3	association	0.530	2
FASLG	direct interaction	0.440	1
CACNA1C	association	0.350	1
IDE	association	0.350	1
MED31	physical association	0.000	1
PTN	physical association	0.000	1
TBL3	physical association	0.000	1

BioGRID (22 interactions; top human partners by supporting records): CACNB3 (Affinity Capture-MS; 3 records), CACNA1A (Reconstituted Complex; 2 records), COLGALT2 (Affinity Capture-MS; 2 records), EFHC2 (Two-hybrid; 2 records), CBX3 (Reconstituted Complex), CCDC102B (Two-hybrid), CTBP2 (Two-hybrid), EEA1 (Cross-Linking-MS (XL-MS)), FASLG (Protein-peptide), IDE (Affinity Capture-MS), MED31 (Two-hybrid), NUDT21 (Affinity Capture-RNA), PARP10 (Proximity Label-MS), PTN (Two-hybrid), SNCA (Two-hybrid)

Disease & clinical

Genetic variants

Variant evidence for CACNB4: 348 ClinVar records (3 pathogenic / likely pathogenic); 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	201
Likely benign	58
Benign	45

Top pathogenic / likely-pathogenic (3)

Showing all 3 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1027429	NM_000726.5(CACNB4):c.615A>T (p.Lys205Asn)	Likely pathogenic	criteria provided, single submitter	1
4278043	NM_000726.5(CACNB4):c.241G>A (p.Ala81Thr)	Likely pathogenic	criteria provided, single submitter	1
374311	NM_000726.5(CACNB4):c.610del (p.Gln204fs)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore CACNB4’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 42 predictions of 2,367):

Position(s)	Effect	Δscore	Sites
2:151842089–151842090	acceptor_loss	1.0000	6
2:151855377	acceptor_gain	1.0000
2:151883250	donor_loss	1.0000	2
2:151883371–151883372	acceptor_loss	1.0000	6
2:152066294	acceptor_gain	1.0000
2:152098947–152098948	donor_loss	1.0000	4
2:151841901–151841902	donor_loss	0.9900	5
2:151860709–151860710	donor_loss	0.9900	6
2:151860821–151860822	acceptor_loss	0.9900	6
2:151872415–151872416	donor_loss	0.9900	5

AlphaMissense

1,808 missense substitutions predicted likely pathogenic (of 3,390 scored), across 374 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M237	9	0.995	1.000
M238	9	0.959	1.000
F95	8	0.999	1.000
D236	8	0.999	1.000
D312	8	0.998	0.999
D262	8	0.995	1.000
F243	8	0.993	0.999
F120	8	0.992	1.000
F300	8	0.992	1.000
H127	8	0.990	0.999
D314	8	0.990	0.999
S153	8	0.989	1.000
D244	8	0.988	0.997
F150	8	0.987	1.000
D376	8	0.985	0.999
D61	8	0.983	0.996
H390	8	0.982	0.998
N382	8	0.981	0.999
F250	8	0.974	0.998
M219	8	0.960	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:601949 | disease phenotypes: MIM:108600, MIM:607682

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
episodic ataxia type 5	Supportive	Autosomal dominant
juvenile myoclonic epilepsy	Supportive	Autosomal dominant
epilepsy, idiopathic generalized, susceptibility to, 9	Limited	Autosomal dominant	2

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
epilepsy	Refuted	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Brain channelopathy	green
Hypotonic infant	amber
Intellectual disability	amber
Leukodystrophy, childhood onset	amber
Paediatric disorders	amber
Paroxysmal central nervous system disorders	amber

Mondo (4): spastic ataxia (MONDO:0017845), epilepsy, idiopathic generalized, susceptibility to, 9 (MONDO:0011892), episodic ataxia type 5 (MONDO:0013464), juvenile myoclonic epilepsy (MONDO:0009696)

Orphanet (2): Spastic ataxia (Orphanet:316226), Juvenile myoclonic epilepsy (Orphanet:307)

HPO phenotypes

35 phenotypes (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
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0012000	EEG with generalized spikes
HP:0025709	Intermediate young adult onset
HP:0025710	Late young adult onset

GWAS associations

3 associations:

Study	Trait	p-value
GCST002181_1	Adverse response to chemotherapy in breast cancer (alopecia)	2e-9
GCST005588_14	Idiopathic dilated cardiomyopathy	4e-8
GCST003469_11	Response to cognitive-behavioural therapy in anxiety disorder	4e-6

EFO canonical traits (from GWAS)

2 canonical traits:

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

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D020190	Myoclonic Epilepsy, Juvenile	C10.228.140.490.375.130.670; C10.228.140.490.493.063.670
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

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 68,316 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

2 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1428	NIMODIPINE	4	32,766
CHEMBL95	TACRINE	4	35,550

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs3768652	antipsychotics	Efficacy	Genotypes AA + AC is associated with increased response to antipsychotics in people with Schizophrenia as compared to genotype CC.	PMID:30032160

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 expression, affects binding, increases expression	2
Valproic Acid	affects expression, increases 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	affects cotreatment, decreases expression	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	affects expression, increases abundance	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

7 cell lines: 5 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_F4SN	HyCyte SW620 stable cell line for hCXCR4 overexpression	Cancer cell line	Male
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)

Via MONDO — disease-level, not drug-specific.

showing 60 of 303 trials:

NCT	Phase	Status	Title
NCT03590197	Phase 4	COMPLETED	Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy
NCT03940326	Phase 4	COMPLETED	Levetiracetam Versus Valproate in Idiopathic Generalized Tonic-clonic Seizures
NCT00004637	Phase 4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	Phase 4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	Phase 4	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	Phase 4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	Phase 4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	Phase 4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	Phase 4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	Phase 4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	Phase 4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	Phase 4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	Phase 4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	Phase 4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	Phase 4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	Phase 4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	Phase 4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	Phase 4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	Phase 4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	Phase 4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	Phase 4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	Phase 4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	Phase 4	COMPLETED	RNS® System LTT Study
NCT00610532	Phase 4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	Phase 4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	Phase 4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	Phase 4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	Phase 4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	Phase 4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	Phase 4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	Phase 4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	Phase 4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	Phase 4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	Phase 4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	Phase 4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	Phase 4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	Phase 4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	Phase 4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	Phase 4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	Phase 4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	Phase 4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	Phase 4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy
NCT01309074	Phase 4	WITHDRAWN	Does Pregabalin Improve Symptoms of Anxiety in Patients With Epilepsy? A Comparison With Sertraline
NCT01318408	Phase 4	COMPLETED	Levetiracetam: The Anti-Convulsant of Choice for Elderly Patients With Dementia
NCT01498822	Phase 4	COMPLETED	Levetiracetam Versus Oxcarbazepine as Monotherapy to Evaluate Efficacy and Safety in Subjects With Newly or Recently Diagnosed Partial Epilepsy
NCT01546688	Phase 4	TERMINATED	A Study to Evaluate the Safety and Tolerability and Explore the Efficacy of Zonisamide as add-on Therapy in Elderly Patients With Refractory Partial Seizures
NCT01607346	Phase 4	TERMINATED	An Open Label Study to Evaluate the Effects of Ezogabine/Retigabine Added to Existing Anti-epileptic Drug(s) on Urinary Voiding Function in Subjects With Partial Onset Seizures
NCT01627860	Phase 4	COMPLETED	First Add-on vs. Mono-therapy Study of Topiramate in Neuro-Surgical Patients
NCT01689649	Phase 4	COMPLETED	A Study to Assess Tolerability and Efficacy of Topiramate Monotherapy in Recently Diagnosed Patients With Epilepsy
NCT01713777	Phase 4	COMPLETED	Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Chronic-Dose 4-Period Replicate Design
NCT01733394	Phase 4	COMPLETED	Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Single-Dose 6-Period Replicate Design (EQUIGEN Single-Dose Study)
NCT01804322	Phase 4	COMPLETED	Standardized Educational Plan for Epilepsy Patients With Comorbidities
NCT01932502	Phase 4	UNKNOWN	Evaluation of Onfi Conversion Therapy Replacing Clonazepam in Patients With Medically Refractory Epilepsy
NCT01995825	Phase 4	COMPLETED	Lamotrigine Bioequivalence
NCT02100644	Phase 4	COMPLETED	Valproate Dose Reduction and Its Clinical Evaluation by Introducing Lamotrigine in Japanese Women With Epilepsy - Single Arm, Multicenter, and Open-label Study
NCT02178995	Phase 4	COMPLETED	Methylphenidate Treatment of Attention Deficits in Epilepsy
NCT02205931	Phase 4	UNKNOWN	Ketogenic Diet in Infants With Epilepsy (KIWE)
NCT02362373	Phase 4	COMPLETED	Women With Epilepsy: a Pilot Study of PK and PD Anti-epileptic Drug Effects in Levonorgestrel Intrauterine System Users
NCT02404168	Phase 4	COMPLETED	BEEP Follow Up: Evaluation of Repeatability of Lamotrigine Pharmacokinetics in Epileptic Patients
NCT02429596	Phase 4	UNKNOWN	A Trial of Generic Substitution of Antiepileptic Drugs

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CACNB4 across ~30M SureChEMBL compounds — explore on Sugi Predict.