CACNA1E

Summary

CACNA1E (calcium voltage-gated channel subunit alpha1 E, HGNC:1392) is a protein-coding gene on chromosome 1q25.3, encoding Voltage-dependent R-type calcium channel subunit alpha-1E (Q15878). Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells.

Voltage-dependent calcium channels are multisubunit complexes consisting of alpha-1, alpha-2, beta, and delta subunits in a 1:1:1:1 ratio. These channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. This gene encodes the alpha-1E subunit of the R-type calcium channels, which belong to the ‘high-voltage activated’ group that maybe involved in the modulation of firing patterns of neurons important for information processing. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 777 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genetic developmental and epileptic encephalopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 2,530 total — 9 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 77
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001205293

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1392
Approved symbol	CACNA1E
Name	calcium voltage-gated channel subunit alpha1 E
Location	1q25.3
Locus type	gene with protein product
Status	Approved
Aliases	Cav2.3, BII, CACH6
Ensembl gene	ENSG00000198216
Ensembl biotype	protein_coding
OMIM	601013
Entrez	777

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000360108, ENST00000367570, ENST00000367573, ENST00000524607, ENST00000533229, ENST00000621791, ENST00000644521, ENST00000700187, ENST00000700188, ENST00000700189, ENST00000700190

RefSeq mRNA: 3 — MANE Select: NM_001205293 NM_000721, NM_001205293, NM_001205294

CCDS: CCDS53443, CCDS55664, CCDS55665

Canonical transcript exons

ENST00000367573 — 48 exons

Exon	Start	End
ENSE00000822800	181790445	181790556
ENSE00000822801	181794864	181795044
ENSE00001068612	181785318	181785418
ENSE00001068613	181755237	181755397
ENSE00001068615	181756925	181757126
ENSE00001068617	181783679	181783784
ENSE00001068620	181720783	181720855
ENSE00001068621	181720206	181720337
ENSE00001068622	181739147	181739253
ENSE00001068623	181755956	181756093
ENSE00001068624	181718055	181718167
ENSE00001068625	181758758	181758868
ENSE00001068626	181731175	181731231
ENSE00001068627	181784661	181784768
ENSE00001068628	181763406	181763531
ENSE00001068629	181737525	181737654
ENSE00001068633	181717093	181717302
ENSE00001068635	181733437	181733750
ENSE00001068636	181721758	181721875
ENSE00001068637	181781427	181781523
ENSE00001068638	181772066	181772231
ENSE00001068639	181732384	181733034
ENSE00001068641	181719751	181719863
ENSE00001068642	181762574	181762657
ENSE00001068643	181726065	181726162
ENSE00001068644	181771293	181771384
ENSE00001220042	181785713	181785819
ENSE00001304107	181796668	181796858
ENSE00001318856	181752143	181752239
ENSE00001324281	181736275	181736434
ENSE00001330057	181793665	181793793
ENSE00001657127	181724470	181724537
ENSE00001686159	181738367	181738426
ENSE00002247779	181757947	181758111
ENSE00002255553	181766546	181766611
ENSE00002336896	181750476	181750487
ENSE00002407384	181776101	181776228
ENSE00003479396	181579072	181579224
ENSE00003486289	181580595	181580776
ENSE00003522468	181577766	181577869
ENSE00003523461	181510477	181510582
ENSE00003655072	181511371	181511510
ENSE00003723910	181651338	181651441
ENSE00003728811	181715338	181715391
ENSE00003729869	181710954	181711069
ENSE00003734439	181798292	181808084
ENSE00003786388	181716040	181716129
ENSE00003843783	181483517	181484010

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 94.90.

FANTOM5 (CAGE): breadth broad, TPM avg 6.1336 / max 498.1723, expressed in 222 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7018	3.6825	177
6999	0.9987	83
7001	0.3067	61
7024	0.2325	79
7020	0.1807	69
7023	0.1295	63
6998	0.1187	32
7002	0.1038	39
7019	0.1027	61
7025	0.0785	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	94.90	gold quality
cortical plate	UBERON:0005343	94.56	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.33	gold quality
endothelial cell	CL:0000115	92.25	gold quality
entorhinal cortex	UBERON:0002728	90.34	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.04	gold quality
primary visual cortex	UBERON:0002436	85.94	gold quality
nucleus accumbens	UBERON:0001882	85.72	gold quality
superior frontal gyrus	UBERON:0002661	85.71	gold quality
postcentral gyrus	UBERON:0002581	85.31	gold quality
lateral globus pallidus	UBERON:0002476	84.80	gold quality
parietal lobe	UBERON:0001872	84.52	gold quality
ganglionic eminence	UBERON:0004023	83.74	gold quality
occipital lobe	UBERON:0002021	83.60	gold quality
prefrontal cortex	UBERON:0000451	81.70	gold quality
caudate nucleus	UBERON:0001873	81.56	gold quality
frontal cortex	UBERON:0001870	81.44	gold quality
putamen	UBERON:0001874	81.41	gold quality
cerebral cortex	UBERON:0000956	81.37	gold quality
temporal lobe	UBERON:0001871	80.90	gold quality
neocortex	UBERON:0001950	80.89	gold quality
Ammon’s horn	UBERON:0001954	80.68	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	80.01	gold quality
right frontal lobe	UBERON:0002810	79.23	gold quality
buccal mucosa cell	CL:0002336	79.06	gold quality
Brodmann (1909) area 9	UBERON:0013540	79.05	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.56	gold quality
anterior cingulate cortex	UBERON:0009835	77.51	gold quality
forebrain	UBERON:0001890	76.86	gold quality
brain	UBERON:0000955	75.60	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	62.44
E-ANND-3	yes	7.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NCOA3

miRNA regulators (miRDB)

411 targeting CACNA1E, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4650-5P	99.98	64.69	999

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 27)

• Review discusses the roles of Cav2.3-containing E-type Ca2+ channels which exhibit several subunit-specific features, trigger exocytosis and are also involved in long-term potentiation. (PMID:15845089)
• Full-length RGS3, RGS3T, and the core domain of RGS3 were equally effective in antagonizing inhibition of Ca(V)2.3 through M(2)R. (PMID:16855219)
• Neurokinin 1 receptorsmodulate CaV2.3 using three different signaling mechanisms: a fast inhibition mediated by Gbeta gamma, a slow inhibition mediated by Galpha(q/11), and a slow stimulation mediated by protein kinases C. (PMID:17050807)
• Amplification and overexpression of CACNA1E correlates with relapse in favorable histology Wilms’ tumors. (PMID:17189400)
• analysis of a three-dimensional homology model of Ca(V)2.3 based upon Kv1.2 where hydrophobic residues at positions facing Val(1720) in IS6, IIS6, and IIIS6 play a critical role in stabilizing the closed state in Ca(V)2.3 (PMID:17660294)
• A functional variant in CACNA1E contributes to type 2 diabetes susceptibility in Pima indians by affecting insulin action. (PMID:17720895)
• Genetic variation in the CACNA1E gene contributes to an increased risk of the development of type 2 diabetes by reducing insulin secretion. (PMID:17934712)
• These findings strongly suggest that both H179 and H183 in the IS3-IS4 loop are essential structural determinants required for nickel sensitive inhibition of the Cav2.3. (PMID:18037383)
• Swapping the I-II intracellular linker between L-type CaV1.2 and R-type CaV2.3 high-voltage gated calcium channels exchanges activation attributes. (PMID:20026913)
• Lack of high-voltage activated Cav2.3 channels results in a marked decrease in the sensitivity of transgenic animals to gamma-butyrolactone-induced absence epilepsy. (PMID:21482359)
• Ca(v)2.3 Ca2+ channel interacts with the G1-subunit of V-ATPase. (PMID:21691059)
• the II-III loop of the Ca(v)2.3 calcium channel binds APLP1 and that this binding promotes internalization of the channel (PMID:22178872)
• CACNA1E variants affect beta cell function in patients with newly diagnosed type 2 diabetes. (PMID:22427875)
• The C-terminus of human Ca(v)2.3 voltage-gated calcium channel interacts with alternatively spliced calmodulin-2 expressed in two human cell lines (PMID:22633975)
• quartet of leucine residues in the guanylate kinase domain of CaVbeta determines the plasma membrane density of the CaV2.3 channel. (PMID:22846999)
• CACNA1E gene single nucleotide polymorphisms may be involved in fentanyl sensitivity. (PMID:23940630)
• Data suggest that, in vascular smooth muscle cells, increase in cytosolic endothelin-1 (EDN1) induces sustained increase in nuclear Ca2+ via stimulation of R-type calcium channel (CACNA1E) present at the nuclear membrane. (PMID:25741585)
• Carriers of the minor G allele of the rs3845446 SNP exhibited enhanced pain-related phenotypes after gastrointestinal surgery. The pain-related phenotypes of carriers of the minor allele of this SNP after gastrointestinal surgery were opposite to such phenotypes after orthognathic surgery. (PMID:27480382)
• This study identified a polymorphism in exon 20 of the CACNA1E gene (Asp859Glu - rs35737760) that is more prevalent in hemiplegic and brain stem aura migraine. (PMID:28573794)
• The variants in CACNA1E as a cause of DEEs. (PMID:30343943)
• F0F1 ATP synthase regulates extracellular calcium influx in human neutrophils by interacting with Cav2.3 and modulates neutrophil accumulation in the lipopolysaccharide-challenged lung. (PMID:32019549)
• Cav2.3 R-type calcium channels: from its discovery to pathogenic de novo CACNA1E variants: a historical perspective. (PMID:32529299)
• De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures. (PMID:34702355)
• Direct inhibition of CaV2.3 by Gem is dynamin dependent and does not require a direct alfa/beta interaction. (PMID:34837834)
• Mutations and clinical significance of calcium voltage-gated channel subunit alpha 1E (CACNA1E) in non-small cell lung cancer. (PMID:35026540)
• Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability. (PMID:38081835)
• Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy: Two sides of the same coin or same side of two different coins? (PMID:38780451)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cacna1ea	ENSDARG00000062346
danio_rerio	cacna1eb	ENSDARG00000095614
mus_musculus	Cacna1e	ENSMUSG00000004110
rattus_norvegicus	Cacna1e	ENSRNOG00000002863

Paralogs (26): CACNA1G (ENSG00000006283), SCN4A (ENSG00000007314), CACNA1S (ENSG00000081248), CACNA1I (ENSG00000100346), CACNA1F (ENSG00000102001), NALCN (ENSG00000102452), SCN2A (ENSG00000136531), SCN7A (ENSG00000136546), CACNA1A (ENSG00000141837), SCN1A (ENSG00000144285), CACNA1B (ENSG00000148408), CACNA1C (ENSG00000151067), CATSPER3 (ENSG00000152705), SCN3A (ENSG00000153253), CACNA1D (ENSG00000157388), TPCN2 (ENSG00000162341), CATSPER2 (ENSG00000166762), SCN11A (ENSG00000168356), SCN9A (ENSG00000169432), CATSPER1 (ENSG00000175294), SCN5A (ENSG00000183873), SCN10A (ENSG00000185313), TPCN1 (ENSG00000186815), CATSPER4 (ENSG00000188782), CACNA1H (ENSG00000196557), SCN8A (ENSG00000196876)

Protein

Protein identifiers

Voltage-dependent R-type calcium channel subunit alpha-1E — Q15878 (reviewed: Q15878)

Alternative names: Brain calcium channel II, Calcium channel, L type, alpha-1 polypeptide, isoform 6, Voltage-gated calcium channel subunit alpha Cav2.3

All UniProt accessions (6): Q15878, A0A2R8Y7W1, A0A8V8TPE9, A0A8V8TPU6, E9PIE8, F8W9Z1

UniProt curated annotations — full annotation on UniProt →

Function. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells. They are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1E gives rise to R-type calcium currents. R-type calcium channels belong to the ‘high-voltage activated’ (HVA) group and are blocked by nickel. They are however insensitive to dihydropyridines (DHP). Calcium channels containing alpha-1E subunit could be involved in the modulation of firing patterns of neurons which is important for information processing. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells. They are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1E gives rise to R-type calcium currents.

Subunit / interactions. Interacts with EFHC1. Voltage-dependent calcium channels are multisubunit complexes, consisting of alpha-1, alpha-2, beta and delta subunits in a 1:1:1:1 ratio. The channel activity is directed by the pore-forming and voltage-sensitive alpha-1 subunit. In many cases, this subunit is sufficient to generate voltage-sensitive calcium channel activity. The auxiliary subunits beta and alpha-2/delta linked by a disulfide bridge regulate the channel activity.

Subcellular location. Membrane.

Tissue specificity. Expressed in neuronal tissues and in kidney.

Disease relevance. Developmental and epileptic encephalopathy 69 (DEE69) [MIM:618285] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE69 is an autosomal dominant form characterized by refractory seizures, hypotonia, and profoundly impaired development often associated with macrocephaly, hyperkinetic movements, and contractures. The disorder can sometimes result in early death. Some patients may have a favorable seizure response to topiramate medication. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Each of the four internal repeats contains five hydrophobic transmembrane segments (S1, S2, S3, S5, S6) and one positively charged transmembrane segment (S4). S4 segments probably represent the voltage-sensor and are characterized by a series of positively charged amino acids at every third position.

Similarity. Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1E subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q15878-1	1, Alpha-1E	yes
Q15878-2	2, Alpha-1E-1
Q15878-3	3, Alpha-1E-3

RefSeq proteins (3): NP_000712, NP_001192222, NP_001192223 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR002077	VDCCAlpha1	Family
IPR005449	VDCC_R_a1su	Family
IPR005821	Ion_trans_dom	Domain
IPR014873	VDCC_a1su_IQ	Domain
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR031649	GPHH_dom	Domain
IPR050599	VDCC_alpha-1_subunit	Family

Pfam: PF00520, PF08763, PF16905

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (256 total): helix 73, strand 31, topological domain 25, turn 25, transmembrane region 24, sequence variant 18, modified residue 13, compositionally biased region 10, region of interest 8, sequence conflict 7, binding site 7, repeat 4, site 4, glycosylation site 3, splice variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3BXL	X-RAY DIFFRACTION	2.3
7YG5	ELECTRON MICROSCOPY	3
7XLQ	ELECTRON MICROSCOPY	3.1
8EPL	ELECTRON MICROSCOPY	3.1
8EPM	ELECTRON MICROSCOPY	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15878-F1	60.56	0.06

Functional residue map

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

Catalytic / active sites (4): 309 (calcium ion selectivity and permeability); 657 (calcium ion selectivity and permeability); 1372 (calcium ion selectivity and permeability); 1663 (calcium ion selectivity and permeability)

Ligand- & substrate-binding residues (7): 426; 428; 430; 432; 1752; 1758; 1763

Post-translational modifications (13): 14, 19, 427, 440, 736, 745, 793, 815, 855, 947, 1097, 2094, 2113

Glycosylation sites (3): 254, 1566, 1571

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-112308	Presynaptic depolarization and calcium channel opening
R-HSA-422356	Regulation of insulin secretion
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1430728	Metabolism
R-HSA-163685	Integration of energy metabolism

MSigDB gene sets: 401 (showing top): BENPORATH_ES_WITH_H3K27ME3, ENK_UV_RESPONSE_KERATINOCYTE_UP, KEGG_MAPK_SIGNALING_PATHWAY, ATACCTC_MIR202, AAGCCAT_MIR135A_MIR135B, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, CACCAGC_MIR138, GGGTGGRR_PAX4_03, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, NFKB_Q6, GOBP_CALCIUM_ION_IMPORT

GO Biological Process (8): chemical synaptic transmission (GO:0007268), calcium ion import across plasma membrane (GO:0098703), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), calcium ion transmembrane transport (GO:0070588), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (9): voltage-gated calcium channel activity (GO:0005245), calcium ion binding (GO:0005509), high voltage-gated calcium channel activity (GO:0008331), voltage-gated monoatomic cation channel activity (GO:0022843), monoatomic ion channel activity (GO:0005216), monoatomic cation channel activity (GO:0005261), calcium channel activity (GO:0005262), gated channel activity (GO:0022836), metal ion binding (GO:0046872)

GO Cellular Component (6): plasma membrane (GO:0005886), voltage-gated calcium channel complex (GO:0005891), neuronal cell body (GO:0043025), synapse (GO:0045202), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Transmission across Chemical Synapses	1
Integration of energy metabolism	1
Neuronal System	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
monoatomic cation channel activity	2
channel activity	2
anterograde trans-synaptic signaling	1
calcium ion import	1
calcium ion transmembrane import into cytosol	1
inorganic cation import across plasma membrane	1
calcium ion import into cytosol	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
calcium channel activity	1
voltage-gated monoatomic cation channel activity	1
metal ion binding	1
voltage-gated calcium channel activity	1
voltage-gated monoatomic ion channel activity	1
monoatomic ion transmembrane transporter activity	1
monoatomic ion channel activity	1
monoatomic cation transmembrane transporter activity	1
calcium ion transmembrane transporter activity	1
cation binding	1
membrane	1
cell periphery	1
calcium channel complex	1
plasma membrane protein complex	1
somatodendritic compartment	1
cell body	1
cell junction	1
cellular anatomical structure	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

1994 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CACNA1E	EFHC1	Q5JVL4	831
CACNA1E	CACNA2D2	Q9NY47	800
CACNA1E	CACNA2D1	P54289	726
CACNA1E	CAV2	P51636	725
CACNA1E	CAV3	P56539	697
CACNA1E	CACNA2D3	Q8IZS8	679
CACNA1E	CACNG4	Q9UBN1	676
CACNA1E	CACNB1	Q02641	650
CACNA1E	CALM1	P02593	637
CACNA1E	CACNA1G	O43497	634
CACNA1E	CAV1	Q03135	609
CACNA1E	CACNG7	P62955	543
CACNA1E	SNAP25	P13795	528
CACNA1E	ANK2	Q01484	525
CACNA1E	CACNG1	Q06432	511

IntAct

3 interactions, top by confidence:

A	B	Type	Score
CACNA1E	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (11): EFHC1 (Affinity Capture-Western), HIST2H2BE (Proximity Label-MS), CACNA1E (Protein-peptide), PSMD1 (Cross-Linking-MS (XL-MS)), CACNA1E (Affinity Capture-MS), CACNA1E (Cross-Linking-MS (XL-MS)), VIM (Cross-Linking-MS (XL-MS)), CACNA1E (Affinity Capture-MS), CACNA1E (Co-fractionation), CACNA1E (Co-fractionation), GNB2 (Affinity Capture-Western)

ESM2 similar proteins: A2ARP9, B1AYL1, D0E0C2, F1LQQ7, O08562, O14234, O35505, O43497, O46669, O54898, O55017, O73700, O88457, P02719, P0DMA5, P15381, P15390, P22002, P27732, P50077, P56698, P56699, P59111, Q01118, Q02294, Q02343, Q07652, Q13936, Q15858, Q15878, Q28371, Q28644, Q61290, Q62205, Q62968, Q6AXP6, Q6QIY3, Q7RTX7, Q80W99, Q86XQ3

Diamond homologs: A2APX8, A2ASI5, B1AWN6, B1AYL1, D0E0C2, F1LQQ7, O00555, O08562, O46669, O73705, O73706, O73707, O88420, O88457, P02719, P04774, P04775, P08104, P0DMA5, P15389, P15390, P27884, P35498, P35499, P35500, P54282, P56699, P97445, Q01118, Q02789, Q05973, Q14524, Q15858, Q15878, Q20JQ7, Q28371, Q28644, Q2XVR3, Q2XVR4, Q2XVR5

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CACNA1E	“up-regulates quantity”	calcium(2+)	relocalization
CACNA1E	up-regulates	Excitatory_synaptic_transmission

Disease & clinical

Clinical variants and AI predictions

ClinVar

2530 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	19
Uncertain significance	816
Likely benign	1196
Benign	276

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1344625	NM_001205293.3(CACNA1E):c.2098G>A (p.Ala700Thr)	Pathogenic
1344627	NM_001205293.3(CACNA1E):c.4264A>T (p.Ile1422Phe)	Pathogenic
1344628	NM_001205293.3(CACNA1E):c.4274C>A (p.Thr1425Asn)	Pathogenic
1685598	NM_001205293.3(CACNA1E):c.3940A>C (p.Lys1314Gln)	Pathogenic
1703708	NM_001205293.3(CACNA1E):c.2104G>T (p.Ala702Ser)	Pathogenic
2574666	NM_001205293.3(CACNA1E):c.6658C>T (p.Gln2220Ter)	Pathogenic
3994432	NM_001205293.3(CACNA1E):c.1714C>T (p.Arg572Ter)	Pathogenic
4602858	NM_001205293.3(CACNA1E):c.3655C>T (p.Arg1219Ter)	Pathogenic
617451	NM_001205293.3(CACNA1E):c.2101A>G (p.Ile701Val)	Pathogenic
1183054	NM_001205293.3(CACNA1E):c.827G>A (p.Gly276Asp)	Likely pathogenic
1346057	NM_001205293.3(CACNA1E):c.2069G>T (p.Gly690Val)	Likely pathogenic
224995	NM_001205293.3(CACNA1E):c.2093T>C (p.Phe698Ser)	Likely pathogenic
2505203	NM_001205293.3(CACNA1E):c.1090C>T (p.Arg364Ter)	Likely pathogenic
2704715	NM_001205293.3(CACNA1E):c.638C>G (p.Ser213Cys)	Likely pathogenic
2710278	NM_001205293.3(CACNA1E):c.4389C>G (p.Asn1463Lys)	Likely pathogenic
2758877	NM_001205293.3(CACNA1E):c.1808_1812delinsGAGAA (p.Ile603_Ile604delinsArgGlu)	Likely pathogenic
3254659	NM_001205293.3(CACNA1E):c.3697G>A (p.Ala1233Thr)	Likely pathogenic
3262735	NM_001205293.3(CACNA1E):c.2105C>G (p.Ala702Gly)	Likely pathogenic
3606818	NM_001205293.3(CACNA1E):c.587G>A (p.Arg196Gln)	Likely pathogenic
4072024	NM_001205293.3(CACNA1E):c.901_904del (p.Thr301fs)	Likely pathogenic
422435	NM_001205293.3(CACNA1E):c.382G>A (p.Glu128Lys)	Likely pathogenic
427007	NM_001205293.3(CACNA1E):c.2104G>C (p.Ala702Pro)	Likely pathogenic
4277654	NM_001205293.3(CACNA1E):c.1055G>A (p.Gly352Glu)	Likely pathogenic
452778	NM_001205293.3(CACNA1E):c.661C>G (p.Leu221Val)	Likely pathogenic
4687986	NM_001205293.3(CACNA1E):c.4736G>C (p.Arg1579Pro)	Likely pathogenic
4838460	NM_001205293.3(CACNA1E):c.1031A>G (p.Asn344Ser)	Likely pathogenic
986059	NM_001205293.3(CACNA1E):c.4268T>C (p.Ile1423Thr)	Likely pathogenic
989253	NM_001205293.3(CACNA1E):c.4004A>T (p.Asp1335Val)	Likely pathogenic

SpliceAI

8242 predictions. Top by Δscore:

Variant	Effect	Δscore
1:181511369:A:AG	acceptor_gain	1.0000
1:181511370:G:GT	acceptor_gain	1.0000
1:181511507:GTGG:G	donor_gain	1.0000
1:181511508:TGG:T	donor_gain	1.0000
1:181511508:TGGG:T	donor_loss	1.0000
1:181511509:GG:G	donor_gain	1.0000
1:181511509:GGG:G	donor_gain	1.0000
1:181511510:GG:G	donor_gain	1.0000
1:181511510:GGT:G	donor_loss	1.0000
1:181511511:G:GG	donor_gain	1.0000
1:181511511:GTAA:G	donor_loss	1.0000
1:181511512:TAAG:T	donor_loss	1.0000
1:181577861:GGA:G	donor_gain	1.0000
1:181577870:G:GG	donor_gain	1.0000
1:181577898:C:G	donor_gain	1.0000
1:181579070:A:AG	acceptor_gain	1.0000
1:181579070:AG:A	acceptor_gain	1.0000
1:181579071:G:GG	acceptor_gain	1.0000
1:181579071:GG:G	acceptor_gain	1.0000
1:181579071:GGC:G	acceptor_gain	1.0000
1:181579071:GGCCT:G	acceptor_gain	1.0000
1:181579223:AGGTA:A	donor_loss	1.0000
1:181579224:GGTAG:G	donor_loss	1.0000
1:181579225:G:GG	donor_gain	1.0000
1:181579225:GT:G	donor_loss	1.0000
1:181580773:CAATG:C	donor_loss	1.0000
1:181580774:AATGT:A	donor_loss	1.0000
1:181580775:ATG:A	donor_loss	1.0000
1:181580776:TGTG:T	donor_loss	1.0000
1:181580777:G:GG	donor_gain	1.0000

AlphaMissense

15290 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:181510517:T:C	C103R	1.000
1:181511476:T:A	W160R	1.000
1:181511476:T:C	W160R	1.000
1:181511488:G:C	D164H	1.000
1:181511489:A:T	D164V	1.000
1:181577843:C:A	P197H	1.000
1:181577843:C:G	P197R	1.000
1:181577852:T:A	L200H	1.000
1:181577852:T:C	L200P	1.000
1:181579128:G:C	G225R	1.000
1:181580756:T:A	W311R	1.000
1:181580756:T:C	W311R	1.000
1:181580758:G:C	W311C	1.000
1:181580758:G:T	W311C	1.000
1:181651384:C:G	P333R	1.000
1:181651398:G:A	G338R	1.000
1:181651398:G:C	G338R	1.000
1:181651420:T:C	L345P	1.000
1:181651428:G:A	G348R	1.000
1:181651428:G:C	G348R	1.000
1:181710958:T:C	F354L	1.000
1:181710959:T:C	F354S	1.000
1:181710959:T:G	F354C	1.000
1:181710960:T:A	F354L	1.000
1:181710960:T:G	F354L	1.000
1:181710989:G:C	R364P	1.000
1:181711013:G:C	R372P	1.000
1:181711037:T:C	L380P	1.000
1:181711054:T:A	W386R	1.000
1:181711054:T:C	W386R	1.000

dbSNP variants (sampled 300 via entrez): RS1000002018 (1:181766470 C>A,T), RS1000006915 (1:181395794 C>T), RS1000010420 (1:181615541 A>T), RS1000019477 (1:181679669 G>A), RS1000026788 (1:181467392 CAT>C), RS1000038083 (1:181396144 C>T), RS1000038663 (1:181700847 C>T), RS1000040689 (1:181573396 C>G,T), RS1000065650 (1:181657130 T>A), RS1000078010 (1:181504366 G>A), RS1000083697 (1:181615294 A>T), RS1000090947 (1:181743179 G>A), RS1000092926 (1:181434210 G>A), RS1000096181 (1:181647224 A>T), RS1000110776 (1:181546551 A>G)

Disease associations

OMIM: gene MIM:601013 | disease phenotypes: MIM:618285, MIM:614959, MIM:308350, MIM:194200, MIM:119300

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 69	Definitive	Autosomal dominant
neurodevelopmental disorder	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Definitive	AD

Mondo (8): developmental and epileptic encephalopathy, 69 (MONDO:0032657), developmental and epileptic encephalopathy (MONDO:0100620), developmental and epileptic encephalopathy, 14 (MONDO:0013989), genetic developmental and epileptic encephalopathy (MONDO:0100062), Wolff-Parkinson-White syndrome (MONDO:0008685), van der Woude syndrome 1 (MONDO:0007333), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092)

Orphanet (3): Epilepsy of infancy with migrating focal seizures (Orphanet:293181), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

77 total (30 of 77 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000054	Micropenis
HP:0000070	Ureterocele
HP:0000110	Renal dysplasia
HP:0000175	Cleft palate
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000340	Sloping forehead
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000639	Nystagmus
HP:0000729	Autistic behavior
HP:0000752	Hyperactivity
HP:0000826	Precocious puberty
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001272	Cerebellar atrophy
HP:0001302	Pachygyria
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001500	Broad finger
HP:0001508	Failure to thrive
HP:0001537	Umbilical hernia

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002097_7	Coronary artery calcification	8.000000e-06
GCST002692_1	Body mass index (change over time)	3.000000e-06
GCST003563_9	Presence of antiphospholipid antibodies	1.000000e-06
GCST005232_144	Neuroticism	5.000000e-13
GCST005316_311	Intelligence (MTAG)	2.000000e-10
GCST006951_30	Feeling hurt	4.000000e-08
GCST007015_1	Lumbar spine bone mineral density (integral)	3.000000e-06
GCST008839_494	Height	1.000000e-08
GCST011140_2	Glucagon levels in response to oral glucose tolerance test (decremental area under the curve for 0-30 minutes)	2.000000e-06
GCST011382_7	Systemic mastocytosis	6.000000e-07

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0005937	longitudinal BMI measurement
EFO:0007660	neuroticism measurement
EFO:0004337	intelligence
EFO:0009599	feeling emotionally hurt measurement
EFO:0007620	volumetric bone mineral density
EFO:0008463	glucagon measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1687682 (SINGLE PROTEIN), 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 clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3845446	Dosage	3	fentanyl	Pain;Postoperative

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3845446	CACNA1E	3	0.50	1	fentanyl
rs12060765	CACNA1E		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — Voltage-gated calcium channels (Ca_V)

Most potent curated ligand interactions (9 total), top 9:

Ligand	Action	Affinity	Parameter
SNX482	Antagonist	8.0	pIC50
ω-PnTx3-3	Antagonist	7.9	pIC50
ω-phonetoxin-IIA	Antagonist	7.2	pKd
Pb2+	Antagonist	7.0	pIC50
DW13.3	Antagonist	7.0	pIC50
PnTx-3-6	Antagonist	6.9	pIC50
mibefradil	Pore blocker	6.4	pIC50
Cd2+	Antagonist	6.1	pIC50
Ni2+	Antagonist	4.6	pIC50

Binding affinities (BindingDB)

273 measured of 273 human assays (273 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(R)-N-ethyl-5-fluoro-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonamide	IC50	11.7 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonamide	IC50	13.5 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)imidazo[1,2-a]pyridine-6-sulfonamide	IC50	17.4 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-N-(1-(4-chlorophenyl)-2,2,2- trifluoroethyl)-N-methylimidazo[1,2- a]pyridine-3-sulfonamide	IC50	19.1 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-N-(1-(4-chlorophenyl)-2,2,2- trifluoroethyl)-N-ethylpyrimidine-5- sulfonamide	IC50	22.4 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-N-ethyl-5-fluoro-N-(2,2,2-trifluoro-1-(4- methoxyphenyl)ethyl)pyridine-3- sulfonamide	IC50	22.9 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-5-Cyano-N-ethyl-N-(2,2,2-trifluoro-1-(3- fluorophenyl)ethyl)pyridine-3-sulfonamide	IC50	23.4 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-[1,2,3]triazolo[1,5-a]pyridine-5-sulfonamide	IC50	25.1 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-cyano-N-methylpyridine-3-sulfonamide	IC50	25.7 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-cyano-N-(methyl-d3)pyridine-3-sulfonamide	IC50	28.2 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-N-(1-(4-chlorophenyl)-2,2,2- trifluoroethyl)-5-fluoro-N-methylpyridine-3- sulfonamide	IC50	30.2 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]pyridine-3-sulfonamide	IC50	30.2 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-5-Cyano-N-ethyl-N-(2,2,2-trifluoro-1-(p- tolyl)ethyl)pyridine-3-sulfonamide	IC50	30.9 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-N-Ethyl-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)imidazo[1,2-a]pyridine-7- sulfonamide	IC50	31.6 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-methyl-N-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]pyridine-3-sulfonamide	IC50	31.6 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-3-sulfonamide	IC50	32.4 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)imidazo[1,2-a]pyrimidine-3-sulfonamide	IC50	33.9 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-5-cyano-N-methyl-N-(2,2,2-trifluoro-1- (4-(trifluoromethyl)phenyl)ethyl)pyridine-3- sulfonamide	IC50	35.5 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl-1-d)-5-cyano-N-methylpyridine-3-sulfonamide	IC50	35.5 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-methyl-N-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]pyridine-7-sulfonamide	IC50	36.3 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-cyano-N-ethylpyridine-3-sulfonamide	IC50	37.2 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)imidazo[1,2-a]pyridine-3-sulfonamide (Example 186) and (R)—N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N-methylimidazo[1,2-a]pyridine-3-sulfonamide (Example 187)	IC50	38 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)imidazo[1,2-a]pyrazine-2-sulfonamide	IC50	39.8 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrazine-2-sulfonamide	IC50	39.8 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-5-Cyano-N-(2-fluoroethyl)-N-(2,2,2- trifluoro-1-(4-fluorophenyl)ethyl)pyridine-3- sulfonamide	IC50	40.7 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-methyl-N-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]pyridine-7-sulfonamide	IC50	46.8 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-N-(1-(3-chloro-4-fluorophenyl)-2,2,2- trifluoroethyl)-5-cyano-N-ethylpyridine-3- sulfonamide	IC50	46.8 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4- fluoro-3-methylphenyl)ethyl)pyridine-3- sulfonamide	IC50	49 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]pyridine-6-sulfonamidesulfonamide	IC50	50.1 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-N-ethyl-N-(2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethyl)- [1,2,4]triazolo[1,5-a]pyridine-7-sulfonamide	IC50	51.3 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
5-Cyano-N-ethyl-N-(2,2,2-trifluoro-1-(p- tolyl)ethyl)pyridine-3-sulfonamide	IC50	57.5 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-methyl-N-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)pyrimidine-5-sulfonamide	IC50	58.9 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidine-5-sulfonamide (Example 133) and (R)—N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N-ethylpyrimidine-5-sulfonamide (Example 134)	IC50	63.1 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-(1-(3-chlorophenyl)-2,2,2-trifluoroethyl)-5-cyano-N-ethylpyridine-3-sulfonamide (Example 251) and (S)—N-(1-(3-chlorophenyl)-2,2,2-trifluoroethyl)-5-cyano-N-ethylpyridine-3-sulfonamide (Example 252)	IC50	66.1 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-N-methyl-N-(2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethyl)imidazo[1,2- b]pyridazine-3-sulfonamide	IC50	67.6 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-methyl-N-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-[1,2,4]triazolo[1,5-a]pyridine-7-sulfonamide (Example 215) and (R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-[1,2,4]triazolo[1,5-a]pyridine-7-sulfonamide (Example 216)	IC50	70.8 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-N-ethyl-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyrimidine-5-sulfonamide	IC50	72.4 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-[1,2,4]triazolo[1,5-a]pyridine-7-sulfonamide (Example 137)	IC50	72.4 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-5-cyano-N-(1-(3,4-difluorophenyl)-2,2,2- trifluoroethyl)-N-ethylpyridine-3-sulfonamide	IC50	72.4 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
5-Cyano-N-ethyl-N-(2,2,2-trifluoro-1-(3- fluorophenyl)ethyl)pyridine-3-sulfonamide	IC50	77.6 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-methyl-N-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)pyridine-3-sulfonamide	IC50	81.3 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-5-Cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4- (trifluoromethoxy)phenyl)ethyl)pyridine-3- sulfonamide	IC50	87.1 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)imidazo[1,2-b]pyridazine-3-sulfonamide	IC50	91.2 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-5-(N-ethyl-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)sulfamoyl)nicotinamide	IC50	95.5 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
N-ethyl-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)tetrahydro-2H-pyran-4- sulfonamide	IC50	97.7 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-N-ethyl-2-methyl-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyrimidine-5-sulfonamide	IC50	97.7 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)—N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N-methylimidazo[1,2-a]pyrimidine-3-sulfonamide	IC50	100 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS
(R)-5-Cyano-N-methyl-N-(2,2,2-trifluoro-1- (4-fluorophenyl)ethyl)pyridine-3-sulfonamide	IC50	100 nM	US-20250115569: SULFONAMIDE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL CONDITIONS

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 102 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

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	5
bisphenol A	affects binding, decreases activity, increases reaction, decreases methylation, increases expression	3
Barium	increases transport, affects transport, decreases reaction	3
Benzo(a)pyrene	affects methylation, increases methylation, increases mutagenesis	2
ethyl-p-hydroxybenzoate	decreases expression	1
sodium arsenite	increases expression	1
cylindrospermopsin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
SNX 482	decreases reaction, increases transport	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Arsenic Trioxide	increases expression	1
Cadmium	decreases reaction, increases transport	1
Calcium	increases transport, decreases reaction	1
Estradiol	affects binding, decreases activity, increases reaction	1
Lead	affects expression	1
Menthol	decreases expression	1
Nickel	increases transport, decreases reaction	1
Niclosamide	increases expression	1
Sodium	increases transport	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases expression	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1686293	Binding	Inhibition of R-type Cav2.3 at -80 mV holding potential by tandard voltage-clamp electrophysiology assay	Pyridyl amides as potent inhibitors of T-type calcium channels. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B0KZ	192C	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
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)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
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
NCT07600736	PHASE2	RECRUITING	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Clinical Activity of ABS-1230 in Pediatric Participants With KCNT1-related Epilepsy
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT04727970	PHASE1	COMPLETED	Tricaprilin Infantile Spasms Pilot Study
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT07156201	PHASE1	RECRUITING	A Study to Investigate the Safety, Tolerability, and Pharmacokinetics of ABS-1230 Given Orally Compared With Placebo in Healthy Participants Aged 18 to 55 Years
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children