CACNA2D3

Summary

CACNA2D3 (calcium voltage-gated channel auxiliary subunit alpha2delta 3, HGNC:15460) is a protein-coding gene on chromosome 3p21.1-p14.3, encoding Voltage-dependent calcium channel subunit alpha-2/delta-3 (Q8IZS8). The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.

This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.

Source: NCBI Gene 55799 — RefSeq curated summary.

At a glance

• GWAS associations: 25
• Clinical variants (ClinVar): 293 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_018398

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15460
Approved symbol	CACNA2D3
Name	calcium voltage-gated channel auxiliary subunit alpha2delta 3
Location	3p21.1-p14.3
Locus type	gene with protein product
Status	Approved
Aliases	HSA272268, alpha2delta-3
Ensembl gene	ENSG00000157445
Ensembl biotype	protein_coding
OMIM	606399
Entrez	55799

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 protein_coding, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000468658, ENST00000471363, ENST00000471865, ENST00000474759, ENST00000477024, ENST00000478261, ENST00000478466, ENST00000490478, ENST00000492460, ENST00000958523, ENST00000958524, ENST00000958525

RefSeq mRNA: 1 — MANE Select: NM_018398 NM_018398

CCDS: CCDS54598

Canonical transcript exons

ENST00000474759 — 38 exons

Exon	Start	End
ENSE00001281116	54386715	54386774
ENSE00001308935	54503492	54503654
ENSE00002308552	54123513	54123594
ENSE00003458260	55007790	55007842
ENSE00003461369	54969800	54969844
ENSE00003464310	54642128	54642241
ENSE00003465583	55009388	55009443
ENSE00003483203	54887959	54888052
ENSE00003484998	54627787	54627876
ENSE00003498287	54880796	54880863
ENSE00003516145	54871539	54871622
ENSE00003531076	54885281	54885326
ENSE00003532393	54846393	54846467
ENSE00003551222	55073777	55073859
ENSE00003563825	54885489	54885586
ENSE00003566801	54968450	54968511
ENSE00003567955	54891355	54891450
ENSE00003576193	54879018	54879089
ENSE00003577248	55073445	55073557
ENSE00003587059	54838568	54838648
ENSE00003589659	54764218	54764351
ENSE00003604377	55074114	55074557
ENSE00003608688	55018206	55018317
ENSE00003614538	54816853	54816870
ENSE00003615590	54752599	54752677
ENSE00003615717	55004763	55004838
ENSE00003616073	54837159	54837230
ENSE00003621682	54899788	54899868
ENSE00003624595	54569954	54570104
ENSE00003625177	54987683	54987753
ENSE00003634233	54569795	54569855
ENSE00003638732	54581803	54581877
ENSE00003639361	54562800	54562931
ENSE00003649646	54984608	54984670
ENSE00003656138	54896749	54896870
ENSE00003663251	54320442	54320558
ENSE00003685481	54879350	54879411
ENSE00003848571	54122552	54122835

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 95.15.

FANTOM5 (CAGE): breadth broad, TPM avg 3.4794 / max 244.0114, expressed in 447 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36943	1.9499	401
36946	0.6924	89
36941	0.3340	156
36944	0.2505	83
36945	0.1738	61
36942	0.0622	32
202774	0.0165	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	95.15	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.53	gold quality
endothelial cell	CL:0000115	92.86	gold quality
right atrium auricular region	UBERON:0006631	90.63	gold quality
apex of heart	UBERON:0002098	88.29	gold quality
cardiac atrium	UBERON:0002081	88.24	gold quality
nucleus accumbens	UBERON:0001882	87.77	gold quality
superior frontal gyrus	UBERON:0002661	87.76	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.65	gold quality
prefrontal cortex	UBERON:0000451	87.14	gold quality
frontal cortex	UBERON:0001870	86.98	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.95	gold quality
right frontal lobe	UBERON:0002810	86.85	gold quality
postcentral gyrus	UBERON:0002581	86.78	gold quality
sperm	CL:0000019	86.59	gold quality
caudate nucleus	UBERON:0001873	86.48	gold quality
primary visual cortex	UBERON:0002436	86.46	gold quality
gastrocnemius	UBERON:0001388	86.17	gold quality
orbitofrontal cortex	UBERON:0004167	86.06	gold quality
neocortex	UBERON:0001950	86.03	gold quality
muscle of leg	UBERON:0001383	86.02	gold quality
Brodmann (1909) area 46	UBERON:0006483	85.50	gold quality
parietal lobe	UBERON:0001872	85.39	gold quality
monocyte	CL:0000576	85.32	gold quality
putamen	UBERON:0001874	85.31	gold quality
cerebral cortex	UBERON:0000956	85.25	gold quality
mononuclear cell	CL:0000842	84.97	gold quality
telencephalon	UBERON:0001893	84.80	gold quality
leukocyte	CL:0000738	84.78	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	1973.82
E-CURD-119	yes	1880.35
E-HCAD-35	yes	88.23
E-HCAD-25	yes	77.12
E-CURD-112	yes	13.68
E-GEOD-83139	yes	4.15
E-ANND-3	no	6.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

70 targeting CACNA2D3, 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-513A-5P	100.00	69.77	2465
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 16)

• This publication primarily discusses the alpha2/delta 4 subunit, but also contains cDNA data relating to the gene described in this record. (PMID:12181424)
• did not detect submicroscopic deletion or duplication nor sequence alteration in either CACNA2D3 or WNT5A in ZLS-affected individuals (PMID:17937436)
• Loss of CACNA2D3 expression through aberrant promoter hypermethylation may contribute to gastric carcinogenesis. (PMID:18588891)
• In humans, study found single-nucleotide polymorphisms in alpha2delta3 that are associated with reduced acute heat pain sensitivity in healthy volunteers and chronic postsurgical back pain. (PMID:21074052)
• High CACNA2D3 gene expression is assiciated with glioblastoma multiforme. (PMID:22395973)
• Expression of CACNA2D3 mRNA is regulated in breast cancer cell lines by methylation in the CpG island located in the 5’ regulatory region of the gene. (PMID:22644305)
• CACNA2D3 polymorphism rs1375515 plays important role in iron status and is associated with the levels of iron-related biomarkers, as well as with iron clinical phenotypes (normal, iron de fi cient and anaemic). (PMID:23324578)
• CACNA2D3 is a novel tumor suppressor gene responsible for the 3p21 deletion event that plays a critical suppressing role in the development and progression of esophageal squamous cell carcinoma. (PMID:23560067)
• CACNA2D3-mediated increase in intracellular calcium (Ca2+) can induce mitochondrial-mediated apoptosis. (PMID:23649311)
• The risk of developing anaemia is increased in reproductive age women carriers of A allele of rs1868505 (CACNA2D3) and/or T allele of rs13194491 (HIST1H2BJ). (PMID:26460247)
• Findings demonstrate the tumor suppressive role of CACNA2D3 in gliomas. CACNA2D3 operates via Ca 2thorn signaling and the activation of non-canonical Wnt signaling to inhibit cell proliferation and motility and induce apoptosis. (PMID:27583705)
• Nine of the 32 (28.1%) iCCA patients had gene mutations at chromosome 3p, totaling 11 mutations across five genes. Those included five (15.6%) BAP1 mutations, two each (6.3%) of CACNA2D3 and RASSF1 mutations, and one each (3.1%) of ATG7 and PLCD1 mutations. Six (18.8%) cases had concurrent loss of chromosome 3p and gene mutations. (PMID:29122566)
• CNS sensitisation was associated with a common genetic variant near the calcium channel gene CACNA2D3 at genome-wide significance. (PMID:31378653)
• The authors show that ventricular alpha2delta3 expression is low in healthy mice and humans, but significantly elevated in ventricular muscles from DM1 patients with conduction defects. (PMID:31829940)
• A two-stage genome-wide association study identifies novel germline genetic variations in CACNA2D3 associated with radiotherapy response in nasopharyngeal carcinoma. (PMID:36624463)
• Remote ischemic preconditioning reduces mitochondrial apoptosis mediated by calpain 1 activation in myocardial ischemia-reperfusion injury through calcium channel subunit Cacna2d3. (PMID:38151212)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cacna2d3	ENSDARG00000078760
danio_rerio	CACNA2D3	ENSDARG00000106018
mus_musculus	Cacna2d3	ENSMUSG00000021991
rattus_norvegicus	Cacna2d3	ENSRNOG00000031287
drosophila_melanogaster	stj	FBGN0261041
caenorhabditis_elegans		WBGENE00006772

Paralogs (4): CACNA2D2 (ENSG00000007402), CACNA2D4 (ENSG00000151062), CACNA2D1 (ENSG00000153956), CACHD1 (ENSG00000158966)

Protein

Protein identifiers

Voltage-dependent calcium channel subunit alpha-2/delta-3 — Q8IZS8 (reviewed: Q8IZS8)

Alternative names: Voltage-gated calcium channel subunit alpha-2/delta-3

All UniProt accessions (4): Q8IZS8, B4DSF6, C9JAV5, F8WAV4

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) but not T-type (CACNA1G).

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. Only detected in brain. Not present in lung, testis, aorta, spleen, jejunum, ventricular muscle and kidney (at protein level). According to PubMed:11687876, it is brain-specific, while according to PubMed:11245980, it is widely expressed.

Post-translational modifications. N-glycosylated. May be proteolytically processed into subunits alpha-2-3 and delta-3 that are disulfide-linked. It is however unclear whether such cleavage really takes place in vivo and has a functional role.

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. In contrast to CACNA2D1 and CACNA2D2, it does not bind gabapentin, an antiepileptic drug.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q8IZS8-1	1	yes
Q8IZS8-2	2
Q8IZS8-3	3

RefSeq proteins (1): NP_060868* (*=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: PF08399, PF08473, PF13768

UniProt features (24 total): glycosylation site 5, splice variant 4, chain 3, binding site 3, topological domain 2, domain 2, signal peptide 1, modified residue 1, disulfide bond 1, transmembrane region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZS8-F1	83.30	0.41

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): 262; 264; 266

Post-translational modifications (1): 924

Disulfide bonds (1): 412–1055

Glycosylation sites (5): 166, 309, 553, 632, 793

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-112308	Presynaptic depolarization and calcium channel opening
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System

MSigDB gene sets: 270 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MODULE_255, KEGG_MAPK_SIGNALING_PATHWAY, GCANCTGNY_MYOD_Q6, MODULE_317, MEF2_02, AAAYRNCTG_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, CAGCTG_AP4_Q5, EFC_Q6, SREBP1_02, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CONTRACTION, IRF7_01, CDP_01

GO Biological Process (6): regulation of presynapse organization (GO:0099174), cellular response to insulin-like growth factor stimulus (GO:1990314), 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 (5): 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-2 pathways:

Category	Pathways
Transmission across Chemical Synapses	1
Neuronal System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of synapse organization	1
presynapse organization	1
cellular response to peptide hormone stimulus	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
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

1316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CACNA2D3	CACNB2	Q08289	822
CACNA2D3	CACNA1A	P78510	817
CACNA2D3	CACNB1	Q02641	778
CACNA2D3	CACNG1	Q06432	713
CACNA2D3	CACNB3	P54284	679
CACNA2D3	CACNA1E	Q15878	679
CACNA2D3	CACNB4	O00305	657
CACNA2D3	CACNA1D	Q01668	643
CACNA2D3	CACNA1H	O95180	623
CACNA2D3	CACNA1B	Q00975	619
CACNA2D3	CACNA1C	Q13936	617
CACNA2D3	CACNA2D1	P54289	581
CACNA2D3	CACNA2D2	Q9NY47	516
CACNA2D3	ATP2A1	O14983	510
CACNA2D3	CACNG6	Q9BXT2	487

IntAct

8 interactions, top by confidence:

A	B	Type	Score
CACNA2D3	TCOF1	psi-mi:“MI:0915”(physical association)	0.400
PSCA	METTL15	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
CEACAM8	PRRT4	psi-mi:“MI:0914”(association)	0.350
SFSWAP	U2SURP	psi-mi:“MI:0914”(association)	0.350
CACNA2D3	GPAA1	psi-mi:“MI:0914”(association)	0.350
CACNA2D3	RAD51C	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): CACNA2D3 (Proximity Label-MS), APOE (Affinity Capture-MS), CACNA2D3 (Affinity Capture-MS), CACNA2D3 (Affinity Capture-MS), CACNA2D3 (Affinity Capture-MS), SPCS1 (Affinity Capture-MS), PAGE2B (Affinity Capture-MS), CACNA2D3 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS), BAG6 (Affinity Capture-MS), YME1L1 (Affinity Capture-MS), CACNA2D3 (Affinity Capture-RNA)

ESM2 similar proteins: A0A078BQP2, A8XP97, B5AJT2, B5AJT3, B5AJT4, C6KYS2, E9NA96, G5ECE8, G5EDW5, G5EGM1, M9PE65, O16715, O44386, O55159, O73798, O77636, P34358, P34374, P78536, P90754, P90755, P91550, Q03600, Q18253, Q18331, Q19127, Q19187, Q20826, Q23316, Q24247, Q25410, Q3UWA6, Q5BI42, Q5QQ54, Q5RJF7, Q75QW1, Q7JKY3, Q7Z3S7, Q8CFG5, Q8I4N4

Diamond homologs: A1A5Q7, A2VE29, A6NCI4, A6X935, O02668, P19823, P19827, P56652, P79263, P97278, P97279, P97280, Q06033, Q0VCM5, Q14624, Q29052, Q3T052, Q5RB37, Q5RER0, Q61702, Q61703, Q61704, Q63416, Q6UXX5, Q86UX2, Q8BJD1, Q8CFG5, Q8IZS8, Q9GLY5, Q9Z1L5, Q5RJF7, Q7Z3S7, Q88KP1, G3XD24

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
CACNA2D3	“up-regulates quantity”	calcium(2+)	relocalization
CACNA2D3	down-regulates	Proliferation
CACNA2D3	up-regulates	Apoptosis
progesterone	“up-regulates quantity”	CACNA2D3
CACNA2D3	“up-regulates activity”	p38

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	206
Likely benign	25
Benign	12

Top pathogenic / likely-pathogenic (0)

SpliceAI

10140 predictions. Top by Δscore:

Variant	Effect	Δscore
3:54122831:TCCGT:T	donor_gain	1.0000
3:54122832:CCGT:C	donor_gain	1.0000
3:54122833:CGTG:C	donor_loss	1.0000
3:54122834:GT:G	donor_gain	1.0000
3:54122836:G:GA	donor_loss	1.0000
3:54122836:G:GG	donor_gain	1.0000
3:54122837:T:G	donor_loss	1.0000
3:54292942:A:G	donor_gain	1.0000
3:54320438:A:AG	acceptor_gain	1.0000
3:54320439:CAGA:C	acceptor_loss	1.0000
3:54320440:A:AG	acceptor_gain	1.0000
3:54320441:G:A	acceptor_loss	1.0000
3:54320441:G:GC	acceptor_gain	1.0000
3:54320441:GA:G	acceptor_gain	1.0000
3:54320441:GAA:G	acceptor_gain	1.0000
3:54320441:GAAA:G	acceptor_gain	1.0000
3:54320441:GAAAT:G	acceptor_gain	1.0000
3:54320540:G:GT	donor_gain	1.0000
3:54320554:TCAGG:T	donor_gain	1.0000
3:54320555:CAGG:C	donor_gain	1.0000
3:54320555:CAGGG:C	donor_loss	1.0000
3:54320556:AGG:A	donor_gain	1.0000
3:54320556:AGGG:A	donor_loss	1.0000
3:54320557:GG:G	donor_gain	1.0000
3:54320557:GGG:G	donor_gain	1.0000
3:54320558:GG:G	donor_gain	1.0000
3:54320558:GGT:G	donor_loss	1.0000
3:54320559:G:A	donor_loss	1.0000
3:54320559:G:GG	donor_gain	1.0000
3:54320559:G:T	donor_gain	1.0000

AlphaMissense

7266 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:54123523:T:A	W45R	1.000
3:54123523:T:C	W45R	1.000
3:54123525:G:C	W45C	1.000
3:54123525:G:T	W45C	1.000
3:54123526:G:C	A46P	1.000
3:54123527:C:A	A46D	1.000
3:54569843:G:T	R242M	1.000
3:54569854:T:A	W246R	1.000
3:54569854:T:C	W246R	1.000
3:54570039:G:C	A275P	1.000
3:54838589:G:A	G498R	1.000
3:54838589:G:C	G498R	1.000
3:54838590:G:A	G498E	1.000
3:54888024:T:A	W708R	1.000
3:54888024:T:C	W708R	1.000
3:54891405:T:C	L734P	1.000
3:54969833:T:A	C849S	1.000
3:54969833:T:C	C849R	1.000
3:54969834:G:A	C849Y	1.000
3:54969834:G:C	C849S	1.000
3:54984617:T:A	C856S	1.000
3:54984617:T:C	C856R	1.000
3:54984618:G:A	C856Y	1.000
3:54984618:G:C	C856S	1.000
3:54984619:T:G	C856W	1.000
3:54984624:T:C	L858P	1.000
3:54984639:G:A	G863E	1.000
3:54987699:G:A	G879D	1.000
3:55073473:A:C	S1006R	1.000
3:55073475:C:A	S1006R	1.000

dbSNP variants (sampled 300 via entrez): RS1000005979 (3:55007073 C>T), RS1000007515 (3:54815440 T>C), RS1000009949 (3:54131670 A>C), RS1000011537 (3:54970693 A>G), RS1000018129 (3:54310235 T>C), RS1000022572 (3:54904295 C>G,T), RS1000028458 (3:54932504 A>T), RS1000031120 (3:54855869 C>T), RS1000033751 (3:54287975 G>A,T), RS1000033770 (3:54394045 T>C,G), RS1000033893 (3:54203804 C>G,T), RS1000034290 (3:54298210 G>A), RS1000038678 (3:54815161 G>A,C), RS1000040415 (3:54271573 G>T), RS1000041684 (3:54583879 C>G)

Disease associations

OMIM: gene MIM:606399 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST001356_21	Gout	1.000000e-07
GCST001491_22	Immune response to smallpox vaccine (IL-6)	5.000000e-06
GCST002097_8	Coronary artery calcification	8.000000e-06
GCST002218_8	Endometrial cancer	8.000000e-06
GCST002983_2	Alzheimer’s disease (late onset)	2.000000e-06
GCST003542_189	Night sleep phenotypes	6.000000e-06
GCST003999_3	Nose size	6.000000e-11
GCST004185_10	Lung function (FEV1/FVC)	4.000000e-10
GCST004294_4	Nicotine dependence	4.000000e-08
GCST004749_99	Lung cancer in ever smokers	8.000000e-06
GCST005351_16	Carboplatin disposition in epthelial ovarian cancer	9.000000e-06
GCST005757_7	Dimensional psychopathology (Positive)	2.000000e-06
GCST005951_50	Body mass index	5.000000e-11
GCST006427_40	Depression in smokers	8.000000e-06
GCST006484_9	Type 2 diabetes	8.000000e-07
GCST006585_2585	Blood protein levels	1.000000e-08
GCST007430_95	Peak expiratory flow	6.000000e-10
GCST007431_84	Lung function (FEV1/FVC)	1.000000e-24
GCST007432_121	FEV1	5.000000e-08
GCST007692_98	Chronic obstructive pulmonary disease	9.000000e-11
GCST009379_251	Type 2 diabetes	6.000000e-09
GCST009674_1	Urinary uric acid excretion	4.000000e-07
GCST009818_3	Obsessive compulsive disorder severity	6.000000e-06
GCST011939_8	Takayasu arteritis	5.000000e-06
GCST90000047_44	Age at first sexual intercourse	5.000000e-11

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004723	coronary artery calcification
EFO:0004230	endometrial neoplasm
EFO:0004713	FEV/FVC ratio
EFO:0009097	positive domain measurement
EFO:0004340	body mass index
EFO:0009718	peak expiratory flow
EFO:0004314	forced expiratory volume
EFO:0004761	uric acid measurement
EFO:0007802	obsessive-compulsive symptom measurement
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

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

Molecules with ChEMBL bioactivity

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

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

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

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6806020	CACNA2D3, LRTM1		0.00	0
rs4505744	CACNA2D3		0.00	0
rs7427395	CACNA2D3		0.00	0
rs11130424	CACNA2D3		0.00	0

ChEMBL bioactivities

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

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

PubChem BioAssay actives

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

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
(+)-JQ1 compound	decreases expression	2
Lipopolysaccharides	decreases expression, affects cotreatment	2
Valproic Acid	affects cotreatment, increases expression, affects expression	2
Aflatoxin B1	affects methylation, decreases methylation	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	increases methylation	1
trichostatin A	increases expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
rofecoxib	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation, affects cotreatment, decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation, increases methylation	1
Air Pollutants	affects methylation, increases abundance	1
Copper	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Ibuprofen	affects expression	1
Methapyrilene	increases methylation	1
Nitrogen Oxides	affects methylation, increases abundance	1
Silicon Dioxide	decreases 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

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9AL	Ubigene HEK293 CACNA2D3 KO	Transformed cell line	Female
CVCL_D9Z1	Ubigene HeLa CACNA2D3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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