CACNA2D2

Summary

CACNA2D2 (calcium voltage-gated channel auxiliary subunit alpha2delta 2, HGNC:1400) is a protein-coding gene on chromosome 3p21.31, encoding Voltage-dependent calcium channel subunit alpha-2/delta-2 (Q9NY47). The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.

Calcium channels mediate the entry of calcium ions into the cell upon membrane polarization. This gene encodes the alpha-2/delta subunit of the voltage-dependent calcium channel complex. The complex consists of the main channel-forming subunit alpha-1, and auxiliary subunits alpha-2/delta, beta, and gamma. The auxiliary subunits function in the assembly and membrane localization of the complex, and modulate calcium currents and channel activation/inactivation kinetics. The subunit encoded by this gene undergoes post-translational cleavage to yield the extracellular alpha2 peptide and a membrane-anchored delta polypeptide. This subunit is a receptor for the antiepileptic drug, gabapentin. Mutations in this gene are associated with early infantile epileptic encephalopathy. Single nucleotide polymorphisms in this gene are correlated with increased sensitivity to opioid drugs. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 9254 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebellar atrophy with seizures and variable developmental delay (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 24
• Clinical variants (ClinVar): 1,248 total — 50 pathogenic, 29 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_006030

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1400
Approved symbol	CACNA2D2
Name	calcium voltage-gated channel auxiliary subunit alpha2delta 2
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0558, alpha2delta-2
Ensembl gene	ENSG00000007402
Ensembl biotype	protein_coding
OMIM	607082
Entrez	9254

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000266039, ENST00000360963, ENST00000423994, ENST00000424201, ENST00000429770, ENST00000479441, ENST00000483620, ENST00000487413, ENST00000940541, ENST00000940542, ENST00000941197, ENST00000941198

RefSeq mRNA: 5 — MANE Select: NM_006030 NM_001005505, NM_001174051, NM_001291101, NM_001410768, NM_006030

CCDS: CCDS33763, CCDS54588, CCDS63647, CCDS77748, CCDS93278

Canonical transcript exons

ENST00000424201 — 38 exons

Exon	Start	End
ENSE00000380897	50374737	50374813
ENSE00000769313	50370320	50370380
ENSE00000769314	50375644	50375705
ENSE00000769315	50375809	50375880
ENSE00000769316	50375963	50376034
ENSE00000769318	50376114	50376188
ENSE00000769319	50377467	50377541
ENSE00000769320	50377732	50377803
ENSE00000769321	50378008	50378097
ENSE00000769322	50378284	50378333
ENSE00000769323	50378915	50378993
ENSE00000769325	50379092	50379199
ENSE00000769326	50379432	50379590
ENSE00000769327	50379725	50379824
ENSE00000769328	50379968	50380018
ENSE00000769329	50380748	50380805
ENSE00000769330	50380995	50381126
ENSE00000769331	50384196	50384337
ENSE00000769332	50387568	50387612
ENSE00000769333	50394109	50394168
ENSE00000860756	50364888	50364970
ENSE00000860757	50365075	50365184
ENSE00000860759	50365633	50365688
ENSE00000860760	50365810	50365862
ENSE00000860761	50366011	50366163
ENSE00000860762	50366267	50366338
ENSE00000860763	50366578	50366625
ENSE00000860764	50366831	50366919
ENSE00000860765	50367011	50367109
ENSE00000860766	50367394	50367497
ENSE00000860767	50367642	50367704
ENSE00000860768	50367812	50367902
ENSE00000860769	50368138	50368235
ENSE00001862208	50362613	50364806
ENSE00003638383	50476118	50476199
ENSE00003642715	50365356	50365482
ENSE00003677935	50434313	50434429
ENSE00003906493	50503218	50503634

Expression profiles

Bgee: expression breadth ubiquitous, 218 present calls, max score 93.90.

FANTOM5 (CAGE): breadth broad, TPM avg 4.5592 / max 311.5871, expressed in 590 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42342	3.6688	542
42344	0.4483	251
42341	0.2478	152
42343	0.1943	119

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower lobe of lung	UBERON:0008949	93.90	gold quality
cerebellar vermis	UBERON:0004720	92.72	gold quality
superior vestibular nucleus	UBERON:0007227	91.63	gold quality
ventral tegmental area	UBERON:0002691	90.09	gold quality
upper lobe of lung	UBERON:0008948	89.71	gold quality
lung	UBERON:0002048	89.63	gold quality
upper lobe of left lung	UBERON:0008952	89.50	gold quality
right lung	UBERON:0002167	89.49	gold quality
vena cava	UBERON:0004087	89.29	silver quality
right hemisphere of cerebellum	UBERON:0014890	89.22	gold quality
cerebellum	UBERON:0002037	88.38	gold quality
cerebellar cortex	UBERON:0002129	88.07	gold quality
cerebellar hemisphere	UBERON:0002245	87.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.96	gold quality
type B pancreatic cell	CL:0000169	87.46	gold quality
medulla oblongata	UBERON:0001896	87.34	gold quality
substantia nigra pars reticulata	UBERON:0001966	87.16	gold quality
substantia nigra pars compacta	UBERON:0001965	87.15	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	87.10	gold quality
islet of Langerhans	UBERON:0000006	87.02	gold quality
paraflocculus	UBERON:0005351	86.59	gold quality
hypothalamus	UBERON:0001898	85.89	gold quality
lateral globus pallidus	UBERON:0002476	84.85	silver quality
visceral pleura	UBERON:0002401	84.71	gold quality
granulocyte	CL:0000094	84.54	gold quality
nucleus accumbens	UBERON:0001882	84.43	gold quality
cardiac atrium	UBERON:0002081	84.21	gold quality
right atrium auricular region	UBERON:0006631	84.09	gold quality
pons	UBERON:0000988	84.01	silver quality
primary visual cortex	UBERON:0002436	83.38	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	24.59
E-GEOD-130148	yes	9.90

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

124 targeting CACNA2D2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6785-5P	99.82	68.68	4428

Literature-anchored findings (GeneRIF, showing 7)

• single nucleotide polymorphism identified (PMID:11851383)
• role in apoptosis in non-small cell lung cancer cells via association with alterations of the intracellular calcium signaling and disruption of mitochondria membrane integrity (PMID:12555074)
• In mice, targeted disruption of Cacna2d2 led to growth retardation, reduced life span, ataxia, enhanced susceptibility to seizures, and cardiac abnormalities. Cacna2d2 may be involved in hereditary cerebellar ataxias and epileptic disorders in humans. (PMID:15331424)
• Although transgenic du(2J)/+ mice have a marked reduction in alpha2delta-2 protein, they show no fall in Purkinje somatic calcium currents or increase in cerebellar tyrosine hydroxylase gene expression. (PMID:17135419)
• CACNA2D2 deletion/methylation is associated with cervical disease progression. (PMID:21809394)
• The investigation of single nucleotide polymorphisms in three genes that have a functional impact on the opioid response: OPRM1, ABCB1 and the calcium channel complex subunit CACNA2D2, is reported. (PMID:23402298)
• show that the action of alpha2delta2 on tumor development occurs not only through a stimulation of proliferation (PMID:25619833)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cacna2d2b	ENSDARG00000078169
danio_rerio	cacna2d2a	ENSDARG00000103390
mus_musculus	Cacna2d2	ENSMUSG00000010066
rattus_norvegicus	Cacna2d2	ENSRNOG00000015835
drosophila_melanogaster	stj	FBGN0261041
caenorhabditis_elegans		WBGENE00006772

Paralogs (4): CACNA2D4 (ENSG00000151062), CACNA2D1 (ENSG00000153956), CACNA2D3 (ENSG00000157445), CACHD1 (ENSG00000158966)

Protein

Protein identifiers

Voltage-dependent calcium channel subunit alpha-2/delta-2 — Q9NY47 (reviewed: Q9NY47)

Alternative names: Voltage-gated calcium channel subunit alpha-2/delta-2

All UniProt accessions (3): Q9NY47, C9JE82, C9JVC9

UniProt curated annotations — full annotation on UniProt →

Function. The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-type calcium channel (CACNA1A), N-type (CACNA1B), L-type (CACNA1C OR CACNA1D) and possibly T-type (CACNA1G). Overexpression induces apoptosis.

Subunit / interactions. Dimer formed of alpha-2-2 and delta-2 chains; disulfide-linked. Voltage-dependent calcium channels are multisubunit complexes, consisting of alpha-1 (CACNA1), alpha-2 (CACNA2D), beta (CACNB) and delta (CACNA2D) subunits in a 1:1:1:1 ratio.

Subcellular location. Membrane.

Tissue specificity. Predominantly present in cerebellar cortex. Present in various lung tumor cell lines, while it is absent in normal lung (at protein level). Highly expressed in heart, lung, testis, pancreas and skeletal muscle. Also expressed in kidney, liver, placenta and brain.

Post-translational modifications. May be proteolytically processed into subunits alpha-2-2 and delta-2 that are disulfide-linked. It is however unclear whether such cleavage really takes place in vivo and has a functional role.

Disease relevance. Cerebellar atrophy with seizures and variable developmental delay (CASVDD) [MIM:618501] An autosomal recessive neurologic disorder characterized by cerebellar ataxia, atrophy of the cerebellar vermis, severe refractory seizures with early onset, and global developmental delay compatible with epileptic encephalopathy in most patients. Disease severity is variable and normal cognitive development has also been reported. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The MIDAS-like motif in the VWFA domain binds divalent metal cations and is required to promote trafficking of the alpha-1 (CACNA1) subunit to the plasma membrane by an integrin-like switch.

Miscellaneous. Binds gabapentin, an antiepileptic drug.

Similarity. Belongs to the calcium channel subunit alpha-2/delta family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9NY47-1	1, Alpha2delta-2a	yes
Q9NY47-2	2, Alpha2delta-2b
Q9NY47-3	3
Q9NY47-4	4
Q9NY47-5	5, Alpha2delta-2c

RefSeq proteins (5): NP_001005505, NP_001167522, NP_001278030, NP_001397697, NP_006021* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002035	VWF_A	Domain
IPR013608	VWA_N	Domain
IPR013680	VDCC_a2/dsu	Domain
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR051173	Ca_channel_alpha-2/delta	Family

Pfam: PF00092, PF08399, PF08473

UniProt features (31 total): glycosylation site 6, sequence variant 6, chain 3, binding site 3, splice variant 3, topological domain 2, domain 2, signal peptide 1, short sequence motif 1, disulfide bond 1, sequence conflict 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NY47-F1	81.48	0.47

Functional residue map

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

Ligand- & substrate-binding residues (3): 297; 299; 301

Disulfide bonds (1): 443–1098

Glycosylation sites (6): 386, 418, 507, 540, 624, 861

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-112308	Presynaptic depolarization and calcium channel opening
R-HSA-400042	Adrenaline,noradrenaline inhibits insulin secretion
R-HSA-422356	Regulation of insulin secretion
R-HSA-5576892	Phase 0 - rapid depolarisation
R-HSA-5576893	Phase 2 - plateau phase
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1430728	Metabolism
R-HSA-163685	Integration of energy metabolism
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction
R-HSA-9659379	Sensory processing of sound
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 270 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, VERHAAK_AML_WITH_NPM1_MUTATED_DN, REACTOME_ADRENALINE_NORADRENALINE_INHIBITS_INSULIN_SECRETION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, KEGG_MAPK_SIGNALING_PATHWAY, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_GROWTH, FOXO4_01, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, HESSON_TUMOR_SUPPRESSOR_CLUSTER_3P21_3, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, MODULE_66, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_MULTICELLULAR_ORGANISM_GROWTH

GO Biological Process (11): neuromuscular junction development (GO:0007528), organ growth (GO:0035265), regulation of multicellular organism growth (GO:0040014), positive regulation of organ growth (GO:0046622), muscle cell development (GO:0055001), rhythmic synaptic transmission (GO:0060024), regulation of neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0098696), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (3): voltage-gated calcium channel activity (GO:0005245), metal ion binding (GO:0046872), calcium channel activity (GO:0005262)

GO Cellular Component (6): plasma membrane (GO:0005886), voltage-gated calcium channel complex (GO:0005891), presynaptic active zone membrane (GO:0048787), GABA-ergic synapse (GO:0098982), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Cardiac conduction	2
Transmission across Chemical Synapses	1
Regulation of insulin secretion	1
Integration of energy metabolism	1
Sensory processing of sound	1
Neuronal System	1
Metabolism	1
Muscle contraction	1
Sensory Perception	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
synapse organization	1
multicellular organismal process	1
developmental growth	1
multicellular organism growth	1
regulation of developmental growth	1
regulation of multicellular organismal process	1
organ growth	1
regulation of organ growth	1
positive regulation of developmental growth	1
positive regulation of multicellular organismal process	1
muscle cell differentiation	1
cell development	1
modulation of chemical synaptic transmission	1
regulation of biological quality	1
neurotransmitter receptor localization to postsynaptic specialization membrane	1
regulation of protein localization to synapse	1
regulation of receptor localization to synapse	1
regulation of protein localization to cell periphery	1
regulation of protein localization to membrane	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
calcium channel activity	1
voltage-gated monoatomic cation channel activity	1
cation binding	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
membrane	1
cell periphery	1
calcium channel complex	1
plasma membrane protein complex	1
presynaptic membrane	1
presynaptic active zone	1
synaptic membrane	1
synapse	1
cellular anatomical structure	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

1268 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CACNA2D2	CACNB2	Q08289	927
CACNA2D2	CACNA1A	P78510	887
CACNA2D2	CACNB4	O00305	866
CACNA2D2	SESN3	P58005	844
CACNA2D2	CACNA1C	Q13936	842
CACNA2D2	SESN1	Q9Y6P5	828
CACNA2D2	CACNB1	Q02641	817
CACNA2D2	CACNG1	Q06432	816
CACNA2D2	CACNA1E	Q15878	800
CACNA2D2	CACNA1B	Q00975	793
CACNA2D2	CACNA1D	Q01668	745
CACNA2D2	CACNA1G	O43497	734
CACNA2D2	SESN2	P58004	670
CACNA2D2	CACNG4	Q9UBN1	652
CACNA2D2	CACNG7	P62955	645

IntAct

91 interactions, top by confidence:

A	B	Type	Score
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
INSL5	COCH	psi-mi:“MI:0914”(association)	0.530
SCGB1D4	EGFR	psi-mi:“MI:0914”(association)	0.530
CTSG	MANBA	psi-mi:“MI:0914”(association)	0.530
DIPK1A	TMEM259	psi-mi:“MI:0914”(association)	0.530
IGHA1	PLG	psi-mi:“MI:0914”(association)	0.350
M2	IPO5	psi-mi:“MI:0914”(association)	0.350
M2	AGPS	psi-mi:“MI:0914”(association)	0.350
TANK	CNOT1	psi-mi:“MI:0914”(association)	0.350
TNIP1	UMAD1	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	POTEF	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	POM121C	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	IGLON5	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
HLA-DPB1	TAPBP	psi-mi:“MI:0914”(association)	0.350
TMEM106A	QSOX1	psi-mi:“MI:0914”(association)	0.350
B3GAT2	FAM20B	psi-mi:“MI:0914”(association)	0.350
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
BTNL8	TMEM131L	psi-mi:“MI:0914”(association)	0.350
RNASE13	POTEF	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
BRICD5	POTEF	psi-mi:“MI:0914”(association)	0.350
PSCA	METTL15	psi-mi:“MI:0914”(association)	0.350
RLN1	RTL8C	psi-mi:“MI:0914”(association)	0.350
PATE1	MANBA	psi-mi:“MI:0914”(association)	0.350
TAFAZZIN	MANBA	psi-mi:“MI:0914”(association)	0.350

BioGRID (99): CACNA2D2 (Affinity Capture-Western), CACNA2D2 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), CACNA2D2 (Synthetic Lethality), CACNA2D2 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS)

ESM2 similar proteins: A1A4K5, A4IID1, A7XY94, O08532, O54890, O77836, P05106, P13806, P18614, P26009, P54289, P54290, Q00960, Q01097, Q13224, Q13822, Q3V3R4, Q4R854, Q5M854, Q5NVB3, Q5R1P3, Q5REP8, Q5VU97, Q64610, Q659X0, Q6BEA0, Q6EV76, Q6EV77, Q6GMK0, Q6GQI7, Q6GQK9, Q6IS24, Q6NYS8, Q6PDJ1, Q6PHS9, Q7TT15, Q80UG2, Q812G0, Q86X52, Q8BFR2

Diamond homologs: O08532, P13806, P54289, P54290, Q6PHS9, Q8CFG6, Q9NY47, Q88KP1, Q8CFG5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Beta defensins	5	17.7×	3e-03
Defensins	5	15.4×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1248 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	50
Likely pathogenic	29
Uncertain significance	451
Likely benign	636
Benign	44

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100785	NM_006030.4(CACNA2D2):c.1295del (p.Asn432fs)	Pathogenic
1074184	NM_006030.4(CACNA2D2):c.235dup (p.Gln79fs)	Pathogenic
1325389	NM_006030.4(CACNA2D2):c.829C>T (p.Arg277Ter)	Pathogenic
1352276	NM_006030.4(CACNA2D2):c.871_872del (p.Asp291fs)	Pathogenic
1369986	NM_006030.4(CACNA2D2):c.2920_2921del (p.Leu974fs)	Pathogenic
1398654	NM_006030.4(CACNA2D2):c.2281C>T (p.Arg761Ter)	Pathogenic
1434960	NM_006030.4(CACNA2D2):c.2920del (p.Leu974fs)	Pathogenic
1438980	NM_006030.4(CACNA2D2):c.843G>A (p.Trp281Ter)	Pathogenic
1453151	NM_006030.4(CACNA2D2):c.3223C>T (p.Gln1075Ter)	Pathogenic
1453307	NM_006030.4(CACNA2D2):c.2183del (p.Gly728fs)	Pathogenic
1457005	NC_000003.11:g.(?50513539)(50540854_?)del	Pathogenic
1526049	NM_006030.4(CACNA2D2):c.1701+2T>C	Pathogenic
1687585	NM_006030.4(CACNA2D2):c.1840del (p.Asp614fs)	Pathogenic
1805265	NM_006030.4(CACNA2D2):c.1126G>T (p.Glu376Ter)	Pathogenic
1962764	NM_006030.4(CACNA2D2):c.235C>T (p.Gln79Ter)	Pathogenic
2004098	NM_006030.4(CACNA2D2):c.2643dup (p.Leu882fs)	Pathogenic
2028993	NM_006030.4(CACNA2D2):c.3034C>T (p.Gln1012Ter)	Pathogenic
2100973	NM_006030.4(CACNA2D2):c.1162_1165del (p.Thr388fs)	Pathogenic
2106110	NM_006030.4(CACNA2D2):c.2646_2647del (p.Val884fs)	Pathogenic
2112011	NM_006030.4(CACNA2D2):c.107_177del (p.Pro36fs)	Pathogenic
2664675	NM_006030.4(CACNA2D2):c.3344del (p.Val1115fs)	Pathogenic
2701646	NM_006030.4(CACNA2D2):c.1996del (p.Leu666fs)	Pathogenic
2716913	NM_006030.4(CACNA2D2):c.1837del (p.Leu613fs)	Pathogenic
2745455	NM_006030.4(CACNA2D2):c.1298_1299del (p.Asn432_Tyr433insTer)	Pathogenic
2757448	NM_006030.4(CACNA2D2):c.3106del (p.His1036fs)	Pathogenic
2759836	NM_006030.4(CACNA2D2):c.1269_1270del (p.Phe424fs)	Pathogenic
2813025	NM_006030.4(CACNA2D2):c.2991_2994del (p.Ser998fs)	Pathogenic
2816330	NM_006030.4(CACNA2D2):c.2696dup (p.His899fs)	Pathogenic
2818776	NM_006030.4(CACNA2D2):c.1905C>G (p.Tyr635Ter)	Pathogenic
2829984	NM_006030.4(CACNA2D2):c.409_413dup (p.Asp139fs)	Pathogenic

SpliceAI

6670 predictions. Top by Δscore:

Variant	Effect	Δscore
3:50364886:A:AC	donor_gain	1.0000
3:50364887:C:CC	donor_gain	1.0000
3:50365136:C:CT	acceptor_gain	1.0000
3:50365139:C:CT	acceptor_gain	1.0000
3:50365139:C:T	acceptor_gain	1.0000
3:50365141:C:CT	acceptor_gain	1.0000
3:50365181:CAGC:C	acceptor_gain	1.0000
3:50365197:C:T	acceptor_gain	1.0000
3:50365629:CTA:C	donor_loss	1.0000
3:50365630:TA:T	donor_loss	1.0000
3:50365631:AC:A	donor_loss	1.0000
3:50365632:CCTG:C	donor_gain	1.0000
3:50365689:C:CA	acceptor_loss	1.0000
3:50365690:T:A	acceptor_loss	1.0000
3:50365695:C:CT	acceptor_gain	1.0000
3:50365699:C:CT	acceptor_gain	1.0000
3:50366004:GACTC:G	donor_loss	1.0000
3:50366005:ACTC:A	donor_loss	1.0000
3:50366006:CTCAC:C	donor_loss	1.0000
3:50366007:TCA:T	donor_loss	1.0000
3:50366008:CAC:C	donor_loss	1.0000
3:50366009:A:AC	donor_gain	1.0000
3:50366009:ACC:A	donor_loss	1.0000
3:50366010:C:CC	donor_gain	1.0000
3:50366010:CCA:C	donor_gain	1.0000
3:50366159:CCCAC:C	acceptor_gain	1.0000
3:50366160:CCAC:C	acceptor_gain	1.0000
3:50366160:CCACC:C	acceptor_gain	1.0000
3:50366161:CAC:C	acceptor_gain	1.0000
3:50366161:CACC:C	acceptor_gain	1.0000

AlphaMissense

7518 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:50366328:C:G	C890S	1.000
3:50366329:A:G	C890R	1.000
3:50366329:A:T	C890S	1.000
3:50367657:C:G	R768P	1.000
3:50376148:C:A	G556V	1.000
3:50376148:C:T	G556D	1.000
3:50378034:A:G	W485R	1.000
3:50378034:A:T	W485R	1.000
3:50378929:G:T	A442D	1.000
3:50378968:C:A	G429V	1.000
3:50378968:C:T	G429E	1.000
3:50378969:C:A	G429W	1.000
3:50378969:C:G	G429R	1.000
3:50378969:C:T	G429R	1.000
3:50378982:A:C	F424L	1.000
3:50378982:A:T	F424L	1.000
3:50378984:A:G	F424L	1.000
3:50379147:C:T	G402D	1.000
3:50379150:T:A	D401V	1.000
3:50379150:T:C	D401G	1.000
3:50379151:C:G	D401H	1.000
3:50379156:A:G	F399S	1.000
3:50379176:G:C	C392W	1.000
3:50379177:C:G	C392S	1.000
3:50379177:C:T	C392Y	1.000
3:50379178:A:T	C392S	1.000
3:50379451:G:T	A378D	1.000
3:50379463:C:T	G374D	1.000
3:50379588:G:C	F332L	1.000
3:50379588:G:T	F332L	1.000

dbSNP variants (sampled 300 via entrez): RS1000011575 (3:50465280 C>T), RS1000022429 (3:50459541 C>A,G,T), RS1000024408 (3:50439088 T>C), RS1000028417 (3:50376845 C>T), RS1000059433 (3:50436940 A>C,G), RS1000111801 (3:50457808 A>G), RS1000114148 (3:50391429 C>T), RS1000153461 (3:50466002 T>C,G), RS1000193906 (3:50450832 A>C), RS1000202470 (3:50475070 G>A,C), RS1000235350 (3:50382732 C>T), RS1000252113 (3:50505747 G>A), RS1000253877 (3:50483889 T>C,G), RS1000262804 (3:50441504 A>C), RS1000278352 (3:50401219 T>A,C,G)

Disease associations

OMIM: gene MIM:607082 | disease phenotypes: MIM:618501, MIM:244400

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebellar atrophy with seizures and variable developmental delay	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Moderate	AR

Mondo (4): developmental and epileptic encephalopathy (MONDO:0100620), early-infantile DEE (MONDO:0800491), cerebellar atrophy with seizures and variable developmental delay (MONDO:0032788), primary ciliary dyskinesia (MONDO:0016575)

Orphanet (3): Early infantile developmental and epileptic encephalopathy (Orphanet:1934), Primary ciliary dyskinesia (Orphanet:244), Early myoclonic encephalopathy (Orphanet:1935)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000486	Strabismus
HP:0000496	Abnormality of eye movement
HP:0000639	Nystagmus
HP:0000817	Reduced eye contact
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001290	Generalized hypotonia
HP:0001310	Dysmetria
HP:0001344	Absent speech
HP:0001999	Abnormal facial shape
HP:0002066	Gait ataxia
HP:0002072	Chorea
HP:0002540	Inability to walk
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0006855	Cerebellar vermis atrophy
HP:0008936	Axial hypotonia
HP:0012736	Profound global developmental delay
HP:0200134	Epileptic encephalopathy

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST003994_5	Age at voice drop	4.000000e-07
GCST004280_10	Diastolic blood pressure	2.000000e-10
GCST005316_126	Intelligence (MTAG)	3.000000e-08
GCST005860_2	Cholangiocarcinoma in primary sclerosing cholangitis (time to event)	4.000000e-06
GCST007094_31	Diastolic blood pressure	5.000000e-08
GCST007099_84	Systolic blood pressure	3.000000e-06
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST007565_129	Morning person	2.000000e-16
GCST007565_79	Morning person	4.000000e-14
GCST007576_377	Chronotype	2.000000e-16
GCST008058_280	Estimated glomerular filtration rate	4.000000e-07
GCST008526_23	Coffee consumption	2.000000e-06
GCST008843_1	Depressive symptom (appetite changes) (binary trait)	9.000000e-09
GCST008848_2	Depressive symptoms (sum-score)	1.000000e-09
GCST008849_3	Depressive symptoms (binary sum-score)	1.000000e-10
GCST008851_3	Depressive symptom (fatigue) (ordinal trait)	2.000000e-10
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13
GCST011125_4	Caffeine consumption from coffee	8.000000e-10
GCST90000025_936	Appendicular lean mass	3.000000e-12
GCST90020029_1182	Waist circumference adjusted for body mass index	2.000000e-08

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0007888	age at voice drop
EFO:0006336	diastolic blood pressure
EFO:0004337	intelligence
EFO:0006335	systolic blood pressure
EFO:0008328	chronotype measurement
EFO:0006781	coffee consumption measurement
EFO:0007006	depressive symptom measurement
EFO:0004346	neuroimaging measurement
EFO:0004980	appendicular lean mass
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002925	Ciliary Motility Disorders	C08.200; C09.150; C16.131.077.245.500; C16.320.184.500
D007619	Kartagener Syndrome	C08.127.384.500; C08.200.531; C08.695.501; C09.150.531; C14.240.400.280.500; C14.280.400.280.500; C16.131.077.245.500.531; C16.131.240.400.280.500; C16.131.740.501; C16.131.810.250.500; C16.320.184.500.531; C16.320.480

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363032 (PROTEIN COMPLEX GROUP), CHEMBL3896 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 94,021 (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
CHEMBL1059	PREGABALIN	4	26,074

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2236957	CACNA2D2		0.00	0

ChEMBL bioactivities

86 potent at pChembl≥5 of 103 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
8.00	IC50	10	nM	CHEMBL1801177
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
7.66	IC50	22	nM	CHEMBL1801206
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
7.23	IC50	59	nM	CHEMBL1801207
7.21	IC50	62	nM	CHEMBL3956991
7.17	IC50	67	nM	CHEMBL3965293
7.10	IC50	79	nM	CHEMBL1801179
7.09	IC50	81	nM	CHEMBL3958264
7.07	IC50	85	nM	CHEMBL3964411
7.07	IC50	85	nM	CHEMBL1801186
7.01	IC50	98.5	nM	CHEMBL3953031
7.00	Ki	99	nM	PREGABALIN

PubChem BioAssay actives

42 with measured affinity, of 138 total; 42 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
(3S)-1-[2-(4-ethoxyphenyl)-3,4-dimethylpyrazolo[3,4-d]pyridazin-7-yl]pyrrolidin-3-amine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.0100	uM
2-(4-ethoxyphenyl)-3,4-dimethyl-7-pyrrolidin-1-ylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.0220	uM
7-(azetidin-1-yl)-2-(4-ethoxyphenyl)-3,4-dimethylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.0590	uM
2-(4-ethoxyphenyl)-7-[(3R)-3-methoxypyrrolidin-1-yl]-3,4-dimethylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.0790	uM
2-(4-ethoxyphenyl)-7-[(3R)-3-fluoropyrrolidin-1-yl]-3,4-dimethylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.0850	uM
Pregabalin	1709033: Displacement of [3H]-gabapentin from human Cav alpha2delta2 expressed in HEK293 cell membranes incubated for 60 mins by scintillation counting method	ki	0.0990	uM
2-(4-ethoxyphenyl)-7-(3-methoxyazetidin-1-yl)-3,4-dimethylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.1260	uM
2-(4-ethoxyphenyl)-N,N,3,4-tetramethylpyrazolo[3,4-d]pyridazin-7-amine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.1580	uM
2-(4-ethoxy-2-fluorophenyl)-7-(3-methoxyazetidin-1-yl)-3,4-dimethylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.2000	uM
3,4-dimethyl-2-(4-propan-2-yloxyphenyl)-7-pyrrolidin-1-ylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.3160	uM
1-[2-(4-ethoxyphenyl)-3,4-dimethylpyrazolo[3,4-d]pyridazin-7-yl]piperidin-4-ol	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.3980	uM
3,4-dimethyl-7-pyrrolidin-1-yl-2-[4-(2,2,2-trifluoroethoxy)phenyl]pyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.3980	uM
2-(4-ethoxyphenyl)-N,3,4-trimethylpyrazolo[3,4-d]pyridazin-7-amine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.5370	uM
7-[(3R)-3-fluoropyrrolidin-1-yl]-3,4-dimethyl-2-[4-(2,2,2-trifluoroethoxy)phenyl]pyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.6310	uM
2-(2,4-dichlorophenyl)-3,4-dimethyl-7-pyrrolidin-1-ylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.6310	uM
2-[4-chloro-2-(trifluoromethoxy)phenyl]-3,4-dimethyl-7-pyrrolidin-1-ylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.7940	uM
7-(3,3-difluoropyrrolidin-1-yl)-2-(4-ethoxyphenyl)-3,4-dimethylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	0.7940	uM
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
2-(4-ethoxyphenyl)-3,4-dimethyl-7-piperidin-1-ylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	1.0000	uM
2-(4-ethoxyphenyl)-3,4-dimethyl-7-piperazin-1-ylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	1.0000	uM
7-(1,4-diazepan-1-yl)-2-(4-ethoxyphenyl)-3,4-dimethylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	1.0000	uM
2-(4-ethoxyphenyl)-3,4-dimethyl-7-(4-methylpiperazin-1-yl)pyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	1.0710	uM
(3R)-1-[2-(4-ethoxyphenyl)-3,4-dimethylpyrazolo[3,4-d]pyridazin-7-yl]pyrrolidin-3-ol	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	1.5850	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
3,4-dimethyl-7-pyrrolidin-1-yl-2-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	1.9950	uM
7-(3-methoxyazetidin-1-yl)-3,4-dimethyl-2-[4-(2,2,2-trifluoroethoxy)phenyl]pyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	1.9950	uM
7-(azepan-1-yl)-2-(4-ethoxyphenyl)-3,4-dimethylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	2.1310	uM
(6S)-13-(ethylamino)-8-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,8,12,14-tetrazatricyclo[8.4.0.02,6]tetradeca-1(14),10,12-trien-9-one	1709033: Displacement of [3H]-gabapentin from human Cav alpha2delta2 expressed in HEK293 cell membranes incubated for 60 mins by scintillation counting method	ki	2.1480	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
2-(ethylamino)-9-methyl-6-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-7,8-dihydropyrimido[4,5-e][1,4]diazepin-5-one	1709033: Displacement of [3H]-gabapentin from human Cav alpha2delta2 expressed in HEK293 cell membranes incubated for 60 mins by scintillation counting method	ki	2.9740	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
2-[4-chloro-2-(trifluoromethoxy)phenyl]-7-(3-methoxyazetidin-1-yl)-3,4-dimethylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	3.9810	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
2-(2,4-dichlorophenyl)-7-(3-methoxyazetidin-1-yl)-3,4-dimethylpyrazolo[3,4-d]pyridazine	604889: Binding affinity at voltage-gated calcium channel subunit alpha2delta2	ic50	6.3100	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

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
Daunorubicin	decreases expression	2
Doxorubicin	decreases expression	2
Mitoxantrone	decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
licochalcone B	increases expression	1
Gabapentin	affects binding	1
Arsenic Trioxide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	decreases methylation, increases abundance	1
Asbestos	decreases expression	1
Caffeine	increases phosphorylation	1
Carbamazepine	affects expression	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1
Diethylhexyl Phthalate	decreases expression, increases expression	1
Estradiol	affects binding, increases expression	1
Menthol	decreases expression	1
Methapyrilene	increases methylation	1
Rotenone	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1

ChEMBL screening assays

17 unique, capped per target: 17 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

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8I5	Ubigene HCT 116 CACNA2D2 KO	Cancer cell line	Male
CVCL_D9AK	Ubigene HEK293 CACNA2D2 KO	Transformed cell line	Female
CVCL_SG47	HAP1 CACNA2D2 (-) 1	Cancer cell line	Male
CVCL_SG48	HAP1 CACNA2D2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT04289467	PHASE2	RECRUITING	Treatment of Refractory Infantile Spasms With Fenfluramine
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT02871778	PHASE2	COMPLETED	Clearing Lungs With ENaC Inhibition in Primary Ciliary Dyskinesia
NCT07318974	PHASE2	ACTIVE_NOT_RECRUITING	Melatonin Therapy for Improving ICSI Outcomes in Women With Diminished Ovarian Reserve
NCT04727970	PHASE1	COMPLETED	Tricaprilin Infantile Spasms Pilot Study
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT05737485	PHASE1	COMPLETED	Study Evaluating the Safety and Tolerability of RCT1100 in Healthy and PCD Subjects
NCT06600425	PHASE1	COMPLETED	A Study to Assess the Safety, Tolerability, Ciliary Rescue, and Pharmacodynamics of RCT1100 in Adults With PCD
NCT06633757	PHASE1	COMPLETED	Study of Inhaled RCT1100 in Adults With PCD Caused by Pathogenic Mutations in the DNAI1 Gene to Measure Mucociliary Clearance
NCT03876444	PHASE2/PHASE3	UNKNOWN	Intravenous Methylprednisolone Versus Oral Prednisolone for Infantile Spasms
NCT05279118	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Ketogenic Diet vs ACTH for the Treatment of Children With West Syndrome
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT04302116	Not specified	RECRUITING	Vigabatrin With High Dose Prednisolone Combination Therapy vs Vigabatrin Alone for Infantile Spasm
NCT05538936	Not specified	COMPLETED	The Effect of Spa and Massage on Babies on Colic Symptoms
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06266234	Not specified	RECRUITING	Characterization by Automated System on Infantile Spasmes
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data
NCT07396883	Not specified	NOT_YET_RECRUITING	Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing
NCT07413211	Not specified	RECRUITING	Genetic Developmental and Epileptic Encephalopathy Natural History Study for Clinical Trial Readiness
NCT07531511	Not specified	NOT_YET_RECRUITING	SLC6A1-NDD Prospective Longitudinal Natural History Study
NCT07585643	Not specified	NOT_YET_RECRUITING	IBIS - Investigating Reliability of BIS and SEDLINE Monitoring in Children With Developmental and Epileptic Encephalopathies (DEE).
NCT00006191	Not specified	COMPLETED	Effect of Levetiracetam on Brain Excitability
NCT02960347	Not specified	COMPLETED	Examining the Efficacy of tDCS in the Attenuation of Epileptic Paroxysmal Discharges and Clinical Seizures
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT04901715	EARLY_PHASE1	COMPLETED	Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia II: Genotype to Phenotype
NCT00005650	Not specified	COMPLETED	Genetic Study of Patients With Primary Ciliary Dyskinesia
NCT00323167	Not specified	COMPLETED	Rare Genetic Disorders of the Breathing Airways
NCT00368446	Not specified	COMPLETED	Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease
NCT00450918	Not specified	COMPLETED	Evaluating Progression of and Diagnostic Tools for Primary Ciliary Dyskinesia in Children and Adolescents
NCT00608556	Not specified	COMPLETED	Dyskinesia, Heterotaxy and Congenital Heart Disease
NCT00686309	Not specified	UNKNOWN	Comparison of On-line and Off-line Measurements of Exhaled Nitric Oxide (NO)
NCT00722878	Not specified	COMPLETED	Long-term Lung Function and Disease Progression in Children With Early Onset Primary Ciliary Dyskinesia Lung Disease
NCT00739817	Not specified	UNKNOWN	Screening for Primary Ciliary Dyskinesia Using Nasal Nitric Oxide
NCT00783887	Not specified	COMPLETED	Diagnosis of Primary Ciliary Dyskinesia