CACNA1I

Summary

CACNA1I (calcium voltage-gated channel subunit alpha1 I, HGNC:1396) is a protein-coding gene on chromosome 22q13.1, encoding Voltage-dependent T-type calcium channel subunit alpha-1I (Q9P0X4). Voltage-sensitive calcium channels (VSCC) 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 an….

This gene encodes the pore-forming alpha subunit of a voltage gated calcium channel. The encoded protein is a member of a subfamily of calcium channels referred to as is a low voltage-activated, T-type, calcium channel. The channel encoded by this protein is characterized by a slower activation and inactivation compared to other T-type calcium channels. This protein may be involved in calcium signaling in neurons. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 8911 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with speech impairment and with or without seizures (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 39
• Clinical variants (ClinVar): 597 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 25
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_021096

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1396
Approved symbol	CACNA1I
Name	calcium voltage-gated channel subunit alpha1 I
Location	22q13.1
Locus type	gene with protein product
Status	Approved
Aliases	Cav3.3
Ensembl gene	ENSG00000100346
Ensembl biotype	protein_coding
OMIM	608230
Entrez	8911

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000401624, ENST00000402142, ENST00000404898, ENST00000407673, ENST00000471970

RefSeq mRNA: 2 — MANE Select: NM_021096 NM_001003406, NM_021096

CCDS: CCDS46710, CCDS46711

Canonical transcript exons

ENST00000402142 — 37 exons

Exon	Start	End
ENSE00000654773	39660344	39660437
ENSE00000654776	39661965	39662435
ENSE00000654777	39662776	39662876
ENSE00000654785	39664739	39664923
ENSE00000654791	39665881	39666006
ENSE00000654799	39672199	39672308
ENSE00000654817	39679107	39679445
ENSE00000654819	39679722	39679868
ENSE00001120831	39677987	39678108
ENSE00001120842	39672949	39673082
ENSE00001120859	39665498	39665624
ENSE00001120866	39663718	39663841
ENSE00001120873	39661108	39661310
ENSE00001120919	39640867	39641182
ENSE00001120937	39619310	39619407
ENSE00001321795	39680930	39681052
ENSE00001334092	39646569	39646881
ENSE00001334182	39670803	39670954
ENSE00001334208	39634565	39634724
ENSE00001356362	39684302	39684498
ENSE00001356366	39682496	39682661
ENSE00001541816	39658152	39658303
ENSE00001554061	39570753	39570988
ENSE00001563463	39649501	39649925
ENSE00001564114	39598151	39598262
ENSE00001564634	39647822	39647926
ENSE00001604897	39659433	39659550
ENSE00001624177	39658931	39659116
ENSE00001697081	39677341	39677419
ENSE00001707808	39673963	39674033
ENSE00001716204	39600520	39600653
ENSE00001746031	39664091	39664159
ENSE00001754664	39668292	39668381
ENSE00001773441	39659697	39659852
ENSE00001779902	39670038	39670230
ENSE00001916862	39685761	39689735
ENSE00003672143	39642797	39642889

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 84.05.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	84.05	gold quality
primary visual cortex	UBERON:0002436	83.75	gold quality
middle temporal gyrus	UBERON:0002771	83.64	silver quality
Brodmann (1909) area 46	UBERON:0006483	82.73	gold quality
type B pancreatic cell	CL:0000169	82.67	gold quality
entorhinal cortex	UBERON:0002728	81.73	gold quality
CA1 field of hippocampus	UBERON:0003881	81.43	silver quality
postcentral gyrus	UBERON:0002581	81.07	gold quality
superior frontal gyrus	UBERON:0002661	80.98	gold quality
olfactory bulb	UBERON:0002264	80.64	gold quality
diaphragm	UBERON:0001103	80.59	gold quality
triceps brachii	UBERON:0001509	80.59	gold quality
endothelial cell	CL:0000115	80.49	silver quality
gluteal muscle	UBERON:0002000	80.19	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	79.88	gold quality
occipital lobe	UBERON:0002021	79.61	gold quality
parietal lobe	UBERON:0001872	78.98	gold quality
right frontal lobe	UBERON:0002810	78.51	gold quality
frontal cortex	UBERON:0001870	78.32	gold quality
prefrontal cortex	UBERON:0000451	77.92	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	77.73	gold quality
right hemisphere of cerebellum	UBERON:0014890	77.65	gold quality
cerebellar hemisphere	UBERON:0002245	77.31	gold quality
neocortex	UBERON:0001950	77.29	gold quality
cerebellar cortex	UBERON:0002129	77.26	gold quality
cerebral cortex	UBERON:0000956	77.15	gold quality
Brodmann (1909) area 9	UBERON:0013540	76.88	gold quality
cerebellum	UBERON:0002037	76.81	gold quality
telencephalon	UBERON:0001893	75.68	gold quality
right adrenal gland cortex	UBERON:0035827	75.67	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

125 targeting CACNA1I, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-4525	99.94	64.38	675

Literature-anchored findings (GeneRIF, showing 19)

• Specific contribution of human T-type calcium channel isotypes (alpha(1G), alpha(1H) and alpha(1I)) to neuronal excitability. (PMID:11927664)
• intracellular regions after repeats I and IV play a role in gating interdependently, suggesting a direct interaction, and splice variation of Cav3.3 channels provides a mechanism for fine-tuning latency and duration of low-threshold spikes. (PMID:15254077)
• CatSper1 and CatSper2 can associate with and modulate the function of the Ca(v)3.3 channel, which might be important in the regulation of sperm function. (PMID:16740636)
• two distinct regions of the Cav3.3 channel are necessary and sufficient for complete M1 receptor-mediated channel inhibition (PMID:17535809)
• The sodium channel toxins tetrodotoxin and saxitoxin interact with the alpha-subunit of T-type Ca 2+ channels. (PMID:18591418)
• Ethanol primarily affects the CaV3.2 isoform of T-type Ca(2)+ channels, acting through protein kinase C. (PMID:23488970)
• Extracellular pressure increases [Ca(2+)]i via Cav3.3, driving a PKC-beta- IKK- IkB-NF-kB pathway that stimulates cancer cell proliferation (PMID:25454347)
• CaV3.1, CaV3.2 and CaV3.3 channels, are best recognized for their negative voltage of activation and inactivation thresholds that allow them to operate near the resting membrane potential of neurons. (PMID:26488564)
• analyses suggest that a single copy of Chr22: 39665939G > A CACNA1I has the capacity to disrupt CaV3.3 channel-dependent functions, including rebound bursting in TRN neurons, with potential implications for schizophrenia pathophysiology. (PMID:27756899)
• CACNA1I variant is associated with differential antiepileptic drug response in childhood absence epilepsy. (PMID:28165634)
• significant association exists between the CACNA1I gene and schizophrenia in the Uighur Chinese population (PMID:28725167)
• In gastric cancer, expression of all the CACNA (1G, 1H, 1I) genes was associated with overall survival (OS) among stage I-IV patients. By combining the three potential biomarkers, a TTCC signature was developed, which retained a significant association with OS both in stage IV and stage I-III patients. Alterations in CACNA gene expression are linked to tumour prognosis. (PMID:28846697)
• human Cav3.1, Cav3.2, and Cav3.3 T-type channels specifically associate with CaM at helix 2 of the gating brake in the I-II linker of the channels. (PMID:28972185)
• CACNA1I is a risk gene for schizophrenia in the Han Chinese population (PMID:29308060)
• low-voltage activation characteristics of CaV3.3 channels (PMID:29474447)
• Study identified an association between single nucleotide polymorphisms in CADM2 and Sensation Seeking and Drug Experimentation via single variant, gene- and transcriptome-based analyses; CADM2 has been previously implicated in numerous traits related to risk taking. In addition, we identified an association between variants in CACNA1I and Negative Urgency via single-variant and gene-based analyses. (PMID:30718321)
• Analysing an allelic series of rare missense variants of CACNA1I in a Swedish schizophrenia cohort. (PMID:34919654)
• Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense Variants in CACNA1H and CACNA1I Genes. (PMID:36786913)
• G protein beta subunits regulate Cav3.3 T-type channel activity and current kinetics via interaction with the Cav3.3 C-terminus. (PMID:38763272)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cacna1ia	ENSDARG00000070522
danio_rerio	cacna1ib	ENSDARG00000096307
danio_rerio		ENSDARG00000115741
mus_musculus	Cacna1i	ENSMUSG00000022416
rattus_norvegicus	Cacna1i	ENSRNOG00000060407

Paralogs (26): CACNA1G (ENSG00000006283), SCN4A (ENSG00000007314), CACNA1S (ENSG00000081248), 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), CACNA1E (ENSG00000198216)

Protein

Protein identifiers

Voltage-dependent T-type calcium channel subunit alpha-1I — Q9P0X4 (reviewed: Q9P0X4)

Alternative names: Voltage-gated calcium channel subunit alpha Cav3.3

All UniProt accessions (1): Q9P0X4

UniProt curated annotations — full annotation on UniProt →

Function. Voltage-sensitive calcium channels (VSCC) 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 channel gives rise to T-type calcium currents. T-type calcium channels belong to the ’low-voltage activated (LVA)’ group and are strongly blocked by nickel and mibefradil. A particularity of this type of channels is an opening at quite negative potentials, and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. Gates in voltage ranges similar to, but higher than alpha 1G or alpha 1H. Voltage-sensitive calcium channels (VSCC) 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 channel gives rise to T-type calcium currents. Voltage-sensitive calcium channels (VSCC) 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 channel gives rise to T-type calcium currents.

Subunit / interactions. Interacts with CATSPER1 and CATSPER2, leading to suppress T-type calcium channel activity.

Subcellular location. Membrane.

Tissue specificity. Brain specific.

Post-translational modifications. In response to raising of intracellular calcium, the T-type channels are activated by CaM-kinase II.

Disease relevance. Neurodevelopmental disorder with speech impairment and with or without seizures (NEDSIS) [MIM:620114] An autosomal dominant disorder with variable manifestations. Severely affected individuals have profound global developmental delay, hypotonia, delayed or absent walking, absent speech, feeding difficulties, cortical visual impairment, and onset of hyperexcitability and seizures in the first months or years of life. Some patients manifest a milder phenotype characterized by mild to moderate cognitive impairment and mild speech delay, usually without seizures. 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. CACNA1I subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9P0X4-1	1, Delta36b	yes
Q9P0X4-2	2
Q9P0X4-3	3, Alpha1I-a
Q9P0X4-4	4

RefSeq proteins (2): NP_001003406, NP_066919* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002077	VDCCAlpha1	Family
IPR005445	VDCC_T_a1	Family
IPR005821	Ion_trans_dom	Domain
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR050599	VDCC_alpha-1_subunit	Family

Pfam: PF00520

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (170 total): helix 54, topological domain 25, transmembrane region 24, strand 14, compositionally biased region 10, turn 9, region of interest 9, sequence variant 8, glycosylation site 5, repeat 4, site 4, splice variant 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7WLI	ELECTRON MICROSCOPY	3.3
7WLK	ELECTRON MICROSCOPY	3.6
7WLL	ELECTRON MICROSCOPY	3.6
7WLJ	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P0X4-F1	60.94	0.13

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): 357 (calcium ion selectivity and permeability); 821 (calcium ion selectivity and permeability); 1380 (calcium ion selectivity and permeability); 1678 (calcium ion selectivity and permeability)

Post-translational modifications (1): 1058

Glycosylation sites (5): 173, 244, 311, 1342, 1345

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-419037	NCAM1 interactions
R-HSA-445355	Smooth Muscle Contraction
R-HSA-1266738	Developmental Biology
R-HSA-375165	NCAM signaling for neurite out-growth
R-HSA-397014	Muscle contraction
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 184 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, KEGG_MAPK_SIGNALING_PATHWAY, REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH, RODRIGUES_NTN1_TARGETS_DN, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CALCIUM_ION_IMPORT, KYNG_DNA_DAMAGE_BY_GAMMA_RADIATION, REACTOME_SMOOTH_MUSCLE_CONTRACTION, GOBP_SLEEP, CCCNNGGGAR_OLF1_01, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_IMPORT_INTO_CELL, GOBP_NEURONAL_ACTION_POTENTIAL, GOBP_TRANSMEMBRANE_TRANSPORT, GOCC_VOLTAGE_GATED_CALCIUM_CHANNEL_COMPLEX

GO Biological Process (9): signal transduction (GO:0007165), neuronal action potential (GO:0019228), sleep (GO:0030431), 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)

GO Molecular Function (5): voltage-gated calcium channel activity (GO:0005245), high voltage-gated calcium channel activity (GO:0008331), monoatomic ion channel activity (GO:0005216), calcium channel activity (GO:0005262), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), voltage-gated calcium channel complex (GO:0005891), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
NCAM signaling for neurite out-growth	1
Muscle contraction	1
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
transport	2
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
action potential	1
transmission of nerve impulse	1
multicellular organismal process	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
calcium ion transport	1
monoatomic cation transmembrane transport	1
calcium channel activity	1
voltage-gated monoatomic cation channel activity	1
voltage-gated calcium channel activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
binding	1
membrane	1
cell periphery	1
calcium channel complex	1
plasma membrane protein complex	1
cellular anatomical structure	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

978 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CACNA1I	CAV3	P56539	813
CACNA1I	CACNA1H	O95180	782
CACNA1I	CACNB2	Q08289	643
CACNA1I	PCBD2	Q9H0N5	639
CACNA1I	CAV2	P51636	632
CACNA1I	CACNA1G	O43497	621
CACNA1I	CAV1	Q03135	570
CACNA1I	KCNIP3	Q9Y2W7	557
CACNA1I	GRIN2B	Q13224	524
CACNA1I	CACNA1C	Q13936	467
CACNA1I	KCND2	Q9NZV8	463
CACNA1I	KCND3	Q9UK17	462
CACNA1I	SCN1A	P35498	459
CACNA1I	KCNA2	P16389	456
CACNA1I	SCN8A	Q9UQD0	453

IntAct

10 interactions, top by confidence:

A	B	Type	Score
CATSPER1	CACNA1I	psi-mi:“MI:0915”(physical association)	0.620
CACNA1I	CATSPER1	psi-mi:“MI:0915”(physical association)	0.620
CATSPER1	CACNA1I	psi-mi:“MI:2364”(proximity)	0.620
CACNA1I	CATSPER2	psi-mi:“MI:0915”(physical association)	0.520
CATSPER2	CACNA1I	psi-mi:“MI:0915”(physical association)	0.520
ALB	CDC45	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): CACNA1I (Affinity Capture-MS), CACNA1I (Affinity Capture-MS), CACNA1I (Affinity Capture-MS), CACNA1I (Affinity Capture-MS)

ESM2 similar proteins: B1AWN6, C9D7C2, D0E0C2, O00555, O08562, O35505, O55017, O57483, O60840, O73700, O88420, O88457, P02719, P07293, P15381, P22002, P22316, P27732, P27884, P54282, P56698, P56699, P91645, P97445, Q00975, Q01668, Q01815, Q02294, Q02343, Q02485, Q02789, Q05152, Q07652, Q13698, Q13936, Q15858, Q15878, Q25452, Q28644, Q2XVR3

Diamond homologs: A2APX8, A2ASI5, B1AWN6, B1AYL1, C9D7C2, D0E0C2, O00555, O08562, O35505, O42398, O43497, O46669, O55017, O57483, O60840, O73700, O73705, O73706, O73707, O88420, O88427, O88457, O95180, P02719, P04774, P04775, P07293, P08104, P0DMA5, P15381, P15389, P15390, P22002, P22316, P27732, P27884, P35498, P35499, P35500, P54282

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	480
Likely benign	65
Benign	26

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1723156	NM_021096.4(CACNA1I):c.2579T>A (p.Ile860Asn)	Pathogenic
1723157	NM_021096.4(CACNA1I):c.2580C>G (p.Ile860Met)	Pathogenic
1723159	NM_021096.4(CACNA1I):c.4275G>A (p.Met1425Ile)	Pathogenic
3764750	NM_021096.4(CACNA1I):c.3474-2_3476del	Pathogenic
3899315	NM_021096.4(CACNA1I):c.3704A>C (p.Tyr1235Ser)	Likely pathogenic
4684984	NM_021096.4(CACNA1I):c.2059A>G (p.Met687Val)	Likely pathogenic

SpliceAI

7772 predictions. Top by Δscore:

Variant	Effect	Δscore
22:39598141:T:TA	acceptor_gain	1.0000
22:39598149:ACGT:A	acceptor_gain	1.0000
22:39598152:T:TA	acceptor_gain	1.0000
22:39598260:CAGGT:C	donor_loss	1.0000
22:39598261:AGGT:A	donor_loss	1.0000
22:39598262:GGT:G	donor_loss	1.0000
22:39598263:GTGA:G	donor_loss	1.0000
22:39598264:T:A	donor_loss	1.0000
22:39600509:T:A	acceptor_gain	1.0000
22:39600515:TGCA:T	acceptor_loss	1.0000
22:39600516:GCA:G	acceptor_loss	1.0000
22:39600517:CAGG:C	acceptor_loss	1.0000
22:39600518:A:AC	acceptor_loss	1.0000
22:39600519:G:A	acceptor_loss	1.0000
22:39600553:AT:A	acceptor_gain	1.0000
22:39600649:GCAGG:G	donor_gain	1.0000
22:39600651:AGGG:A	donor_loss	1.0000
22:39600652:GG:G	donor_gain	1.0000
22:39600652:GGGTA:G	donor_loss	1.0000
22:39600653:GG:G	donor_gain	1.0000
22:39600654:G:GA	donor_loss	1.0000
22:39615895:C:G	donor_gain	1.0000
22:39615906:G:GG	donor_gain	1.0000
22:39619304:CTGCA:C	acceptor_loss	1.0000
22:39619305:TGCA:T	acceptor_loss	1.0000
22:39619308:A:AG	acceptor_gain	1.0000
22:39619308:AG:A	acceptor_gain	1.0000
22:39619308:AGGAT:A	acceptor_gain	1.0000
22:39619309:G:GA	acceptor_gain	1.0000
22:39619309:GG:G	acceptor_gain	1.0000

AlphaMissense

14584 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:39598190:C:A	N92K	1.000
22:39598190:C:G	N92K	1.000
22:39598191:T:C	C93R	1.000
22:39598219:G:A	C102Y	1.000
22:39598248:T:A	C112S	1.000
22:39598248:T:C	C112R	1.000
22:39598249:G:C	C112S	1.000
22:39600619:T:A	W150R	1.000
22:39600619:T:C	W150R	1.000
22:39600632:A:T	D154V	1.000
22:39600652:G:A	G161R	1.000
22:39600652:G:C	G161R	1.000
22:39619375:T:C	L183P	1.000
22:39619378:G:C	R184T	1.000
22:39619378:G:T	R184M	1.000
22:39619381:C:A	P185H	1.000
22:39619381:C:G	P185R	1.000
22:39619384:T:A	L186H	1.000
22:39619384:T:C	L186P	1.000
22:39634577:T:C	L198P	1.000
22:39634586:T:C	L201P	1.000
22:39634589:T:C	L202P	1.000
22:39634592:T:C	L203P	1.000
22:39634628:T:A	L215H	1.000
22:39634628:T:C	L215P	1.000
22:39634630:T:C	C216R	1.000
22:39634632:C:G	C216W	1.000
22:39634654:G:C	G224R	1.000
22:39634655:G:A	G224D	1.000
22:39634663:G:C	G227R	1.000

dbSNP variants (sampled 300 via entrez): RS1000000546 (22:39598211 C>G,T), RS1000051128 (22:39642640 AATGTG>A), RS1000113553 (22:39674093 G>A), RS1000115813 (22:39574465 G>A), RS1000117101 (22:39606175 A>G), RS1000123232 (22:39673717 G>C), RS1000170524 (22:39577165 G>A), RS1000176331 (22:39607411 A>C), RS1000182093 (22:39684615 C>A,T), RS1000202473 (22:39680123 C>G), RS1000233062 (22:39684296 C>T), RS1000249807 (22:39668016 A>G), RS1000261867 (22:39611766 G>A), RS1000285934 (22:39646929 T>A), RS1000304981 (22:39661471 T>C,G)

Disease associations

OMIM: gene MIM:608230 | disease phenotypes: MIM:620114, MIM:192500

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with speech impairment and with or without seizures	Strong	Autosomal dominant
complex neurodevelopmental disorder	Moderate	Autosomal dominant

Mondo (3): neurodevelopmental disorder with speech impairment and with or without seizures (MONDO:0859313), familial long QT syndrome (MONDO:0019171), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000194	Open mouth
HP:0000365	Hearing impairment
HP:0000675	Macrodontia of permanent maxillary central incisor
HP:0000716	Depression
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001344	Absent speech
HP:0002020	Gastroesophageal reflux
HP:0002079	Hypoplasia of the corpus callosum
HP:0002188	Delayed CNS myelination
HP:0002267	Exaggerated startle response
HP:0002307	Drooling
HP:0002540	Inability to walk
HP:0003593	Infantile onset
HP:0003596	Middle age onset
HP:0003623	Neonatal onset
HP:0010536	Central sleep apnea
HP:0011344	Severe global developmental delay
HP:0011463	Childhood onset
HP:0011968	Feeding difficulties
HP:0012444	Brain atrophy
HP:0012471	Thick vermilion border
HP:0100704	Cerebral visual impairment

GWAS associations

39 associations (top):

Study	Trait	p-value
GCST001631_2	Schizophrenia	8.000000e-06
GCST001848_106	IgG glycosylation	2.000000e-06
GCST001848_127	IgG glycosylation	6.000000e-10
GCST001848_132	IgG glycosylation	2.000000e-15
GCST001848_216	IgG glycosylation	6.000000e-16
GCST001848_290	IgG glycosylation	5.000000e-10
GCST001848_311	IgG glycosylation	3.000000e-08
GCST001848_342	IgG glycosylation	2.000000e-10
GCST001848_399	IgG glycosylation	3.000000e-13
GCST001848_428	IgG glycosylation	3.000000e-09
GCST001848_444	IgG glycosylation	2.000000e-10
GCST001848_460	IgG glycosylation	1.000000e-10
GCST001848_477	IgG glycosylation	3.000000e-09
GCST001848_563	IgG glycosylation	1.000000e-24
GCST001848_592	IgG glycosylation	1.000000e-16
GCST001848_632	IgG glycosylation	9.000000e-24
GCST001848_74	IgG glycosylation	9.000000e-06
GCST001849_3	IgG glycosylation	3.000000e-08
GCST001849_5	IgG glycosylation	2.000000e-10
GCST001849_6	IgG glycosylation	9.000000e-06
GCST002408_17	Response to methotrexate in juvenile idiopathic arthritis	9.000000e-08
GCST004521_246	Autism spectrum disorder or schizophrenia	4.000000e-09
GCST004946_132	Schizophrenia	2.000000e-10
GCST005141_33	Cognitive ability (MTAG)	2.000000e-08
GCST005316_260	Intelligence (MTAG)	2.000000e-11
GCST005316_262	Intelligence (MTAG)	2.000000e-09
GCST005316_263	Intelligence (MTAG)	3.000000e-11
GCST005316_265	Intelligence (MTAG)	5.000000e-08
GCST005316_431	Intelligence (MTAG)	9.000000e-10
GCST006803_27	Schizophrenia	2.000000e-12

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005193	serum IgG glycosylation measurement
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0006946	behavioural disinhibition measurement
EFO:0009695	household income

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2362995 (PROTEIN FAMILY), CHEMBL2363032 (PROTEIN COMPLEX GROUP), CHEMBL5558 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 87,380 (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
CHEMBL45816	MIBEFRADIL	4	7,838
CHEMBL1684950	SUVECALTAMIDE	2	70
CHEMBL30008	FLUNARIZINE	2	11,439
CHEMBL4217292	APINOCALTAMIDE	2	37
CHEMBL3934636	ULIXACALTAMIDE	1	49

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3747178	CACNA1I		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 (13 total), top 13:

Ligand	Action	Affinity	Parameter
suvecaltamide	Inhibition	8.82	pIC50
ACT-709478	Inhibition	8.12	pIC50
TTA-A2	Pore blocker	7.5	pIC50
pimozide	Antagonist	7.5	pIC50
ulixacaltamide	Pore blocker	7.0	pIC50
TTA-P2	Pore blocker	7.0	pIC50
ML218	Pore blocker	6.5	pIC50
flunarizine	Antagonist	6.08	pIC50
anandamide	Antagonist	6.0	pIC50
mibefradil	Antagonist	5.8	pIC50
3β-OH	Antagonist	5.7	pIC50
ABT-639	Pore blocker	5.0	pIC50
Ni2+	Antagonist	4.1	pIC50

ChEMBL bioactivities

330 potent at pChembl≥5 of 350 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.12	IC50	0.76	nM	CHEMBL4203847
9.05	IC50	0.89	nM	CHEMBL4205005
9.04	IC50	0.92	nM	CHEMBL4216687
9.00	IC50	1	nM	CHEMBL4204507
8.96	IC50	1.1	nM	CHEMBL4204077
8.92	IC50	1.2	nM	CHEMBL4215974
8.92	IC50	1.2	nM	CHEMBL4205399
8.92	Ki	1.2	nM	CHEMBL1684954
8.89	IC50	1.3	nM	CHEMBL4208626
8.82	IC50	1.5	nM	SUVECALTAMIDE
8.82	IC50	1.5	nM	CHEMBL3891844
8.82	IC50	1.5	nM	CHEMBL4209481
8.80	IC50	1.6	nM	CHEMBL4209376
8.80	IC50	1.6	nM	CHEMBL4205399
8.77	IC50	1.7	nM	CHEMBL4208907
8.74	IC50	1.8	nM	CHEMBL4213335
8.74	IC50	1.8	nM	CHEMBL4203748
8.74	IC50	1.8	nM	CHEMBL4218161
8.74	IC50	1.8	nM	CHEMBL4207031
8.74	IC50	1.8	nM	CHEMBL4206509
8.74	IC50	1.8	nM	CHEMBL4203101
8.72	IC50	1.9	nM	CHEMBL3890624
8.72	IC50	1.9	nM	CHEMBL4212039
8.70	IC50	2	nM	CHEMBL3913893
8.70	IC50	2	nM	CHEMBL4208950
8.70	IC50	2	nM	CHEMBL4212176
8.68	IC50	2.1	nM	CHEMBL4207159
8.64	IC50	2.3	nM	CHEMBL4214862
8.62	IC50	2.4	nM	CHEMBL3973392
8.59	IC50	2.6	nM	CHEMBL4218608
8.57	IC50	2.7	nM	CHEMBL3891844
8.55	IC50	2.8	nM	CHEMBL4208413
8.55	IC50	2.8	nM	CHEMBL4207979
8.54	IC50	2.9	nM	CHEMBL4217227
8.54	IC50	2.9	nM	CHEMBL4207291
8.52	IC50	3	nM	CHEMBL3919024
8.51	IC50	3.1	nM	CHEMBL3919898
8.48	IC50	3.3	nM	CHEMBL4204295
8.47	IC50	3.4	nM	CHEMBL4216279
8.47	IC50	3.4	nM	CHEMBL4210292
8.46	IC50	3.5	nM	CHEMBL4204611
8.44	IC50	3.6	nM	CHEMBL4204873
8.44	IC50	3.6	nM	SUVECALTAMIDE
8.43	IC50	3.7	nM	CHEMBL1684954
8.40	IC50	4	nM	CHEMBL3906199
8.40	IC50	4	nM	CHEMBL3921765
8.40	IC50	4	nM	CHEMBL3936835
8.40	IC50	4	nM	CHEMBL3906825
8.40	IC50	4	nM	CHEMBL4211393
8.39	IC50	4.1	nM	CHEMBL4204573

PubChem BioAssay actives

281 with measured affinity, of 532 total; 50 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-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-(1-methylindazol-5-yl)acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0008	uM
N-[1-[(3,5-difluoro-4-methoxyphenyl)methyl]pyrazol-3-yl]-2-[4-(dimethylamino)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0009	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-[4-(dimethylamino)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0009	uM
2-[4-(dimethylamino)phenyl]-N-[1-[[4-(trifluoromethoxy)phenyl]methyl]pyrazol-3-yl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0010	uM
N-[1-[(4-chlorophenyl)methyl]pyrazol-3-yl]-2-[4-(dimethylamino)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0011	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-[4-(3-methyloxetan-3-yl)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0012	uM
N-[1-[(5,5-difluorooxan-2-yl)methyl]pyrazol-3-yl]-2-(4-propan-2-ylphenyl)acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0012	uM
2-(4-cyclopropylphenyl)-N-[(1R)-1-[5-(2,2,2-trifluoroethoxy)-2-pyridinyl]ethyl]acetamide	579239: Binding affinity to Cav3.3 alpha1i	ki	0.0012	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-[4-(3-fluorooxetan-3-yl)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0013	uM
N-[2-[(3,4-difluorophenyl)methyl]triazol-4-yl]-2-(1-methylindazol-5-yl)acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0015	uM
2-(4-propan-2-ylphenyl)-N-[(1R)-1-[5-(2,2,2-trifluoroethoxy)-2-pyridinyl]ethyl]acetamide	1316437: Inhibition of T-type calcium channel Cav3.3 (unknown origin) expressed in HEK293 cells assessed as calcium influx by Fluo-4-AM dye-based FLIPR assay	ic50	0.0015	uM
N-[1-[[4-(difluoromethoxy)phenyl]methyl]pyrazol-3-yl]-2-[4-(dimethylamino)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0016	uM
N-[1-[(5-cyano-2-pyridinyl)methyl]pyrazol-3-yl]-2-[3-methyl-4-(2,2,2-trifluoroethoxy)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0017	uM
N-[1-[(4-cyano-3-fluorophenyl)methyl]pyrazol-3-yl]-2-[4-(dimethylamino)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0018	uM
2-[4-(dimethylamino)phenyl]-N-[1-[(4-methylphenyl)methyl]pyrazol-3-yl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0018	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-(4-propan-2-ylphenyl)acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0018	uM
2-[4-(3,3-difluorocyclobutyl)phenyl]-N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0018	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-(1,3,3-trimethyl-2-oxoindol-5-yl)acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0018	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-[4-(2,2-dimethyl-1,3-dioxolan-4-yl)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0018	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-(1H-indol-6-yl)acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0019	uM
2-[4-(dimethylamino)phenyl]-N-[1-[(4-fluorophenyl)methyl]pyrazol-3-yl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0020	uM
N-[1-[(5-cyano-2-pyridinyl)methyl]pyrazol-3-yl]-2-[3-methyl-4-(trifluoromethoxy)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0020	uM
(3R,5S)-N,1-dibenzyl-3,5-dimethyl-3,5-dihydro-2H-1,4-benzodiazepine-4-carboxamide	1325730: Channel blocking activity at recombinant human CaV 3.3 channel expressed in HEK293 cells assessed as inhibition of Ca2+ flux preincubated for 3 mins followed by CaCl2 addition by fluo-4 dye-based FLIPR assay	ic50	0.0020	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-(1H-indol-5-yl)acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0021	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-[6-(3,3-difluoropyrrolidin-1-yl)-3-pyridinyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0023	uM
2-(4-tert-butylphenyl)-N-[1-[(5-cyano-2-pyridinyl)methyl]pyrazol-3-yl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0026	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0028	uM
2-[4-(dimethylamino)phenyl]-N-[1-[(3-methylphenyl)methyl]pyrazol-3-yl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0028	uM
N-[1-[(5-cyano-2-pyridinyl)methyl]pyrazol-3-yl]-2-[3-ethyl-4-(2,2,2-trifluoroethoxy)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0029	uM
N-(1-benzylpyrazol-3-yl)-2-[4-(dimethylamino)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0029	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-(1-methylpyrrolo[2,3-b]pyridin-5-yl)acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0033	uM
2-[4-(dimethylamino)phenyl]-N-[1-[(4-methoxyphenyl)methyl]pyrazol-3-yl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0034	uM
2-(4-propan-2-ylphenyl)-N-[1-[2-(2,2,2-trifluoroethoxy)ethyl]pyrazol-3-yl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0034	uM
N-[1-[(4-cyanophenyl)methyl]pyrazol-3-yl]-2-[4-(dimethylamino)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0035	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-[4-(oxetan-3-yloxy)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0036	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-[6-(dimethylamino)-3-pyridinyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0040	uM
(3R,5S)-N-benzyl-1-[(2,3-difluorophenyl)methyl]-3,5-dimethyl-3,5-dihydro-2H-1,4-benzodiazepine-4-carboxamide	1325730: Channel blocking activity at recombinant human CaV 3.3 channel expressed in HEK293 cells assessed as inhibition of Ca2+ flux preincubated for 3 mins followed by CaCl2 addition by fluo-4 dye-based FLIPR assay	ic50	0.0040	uM
(3R,5S)-N,1-dibenzyl-8-fluoro-3,5-dimethyl-3,5-dihydro-2H-pyrido[2,3-e][1,4]diazepine-4-carboxamide	1325730: Channel blocking activity at recombinant human CaV 3.3 channel expressed in HEK293 cells assessed as inhibition of Ca2+ flux preincubated for 3 mins followed by CaCl2 addition by fluo-4 dye-based FLIPR assay	ic50	0.0040	uM
(3R,5S)-1-[dideuterio(phenyl)methyl]-3,5-dimethyl-N-pyridin-3-yl-3,5-dihydro-2H-1,4-benzodiazepine-4-carboxamide	1325730: Channel blocking activity at recombinant human CaV 3.3 channel expressed in HEK293 cells assessed as inhibition of Ca2+ flux preincubated for 3 mins followed by CaCl2 addition by fluo-4 dye-based FLIPR assay	ic50	0.0040	uM
(3R,5S)-1-benzyl-8-fluoro-3,5-dimethyl-N-pyridin-3-yl-3,5-dihydro-2H-1,4-benzodiazepine-4-carboxamide	1325730: Channel blocking activity at recombinant human CaV 3.3 channel expressed in HEK293 cells assessed as inhibition of Ca2+ flux preincubated for 3 mins followed by CaCl2 addition by fluo-4 dye-based FLIPR assay	ic50	0.0040	uM
N-[1-[(5-cyano-2-pyridinyl)methyl]pyrazol-3-yl]-2-[3-methyl-4-(3,3,3-trifluoropropoxy)phenyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0041	uM
2-[4-(dimethylamino)phenyl]-N-[1-[(4-fluorophenyl)methyl]pyrazol-3-yl]propanamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0047	uM
(3R,5S)-1-[(3-fluorophenyl)methyl]-3,5-dimethyl-N-pyridin-3-yl-3,5-dihydro-2H-1,4-benzodiazepine-4-carboxamide	1325730: Channel blocking activity at recombinant human CaV 3.3 channel expressed in HEK293 cells assessed as inhibition of Ca2+ flux preincubated for 3 mins followed by CaCl2 addition by fluo-4 dye-based FLIPR assay	ic50	0.0050	uM
(3R,5S)-1-[(2-fluorophenyl)methyl]-3,5-dimethyl-N-pyridin-3-yl-3,5-dihydro-2H-1,4-benzodiazepine-4-carboxamide	1325730: Channel blocking activity at recombinant human CaV 3.3 channel expressed in HEK293 cells assessed as inhibition of Ca2+ flux preincubated for 3 mins followed by CaCl2 addition by fluo-4 dye-based FLIPR assay	ic50	0.0050	uM
2-(4-tert-butylphenyl)-N-[(1R)-1-(5-methoxy-2-pyridinyl)ethyl]acetamide	579239: Binding affinity to Cav3.3 alpha1i	ki	0.0050	uM
N-[(6-pyrrolidin-1-yl-3-pyridinyl)methyl]-2-[[4-(trifluoromethoxy)phenyl]methyl]-1,3-oxazole-4-carboxamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0052	uM
N-[1-[(3,4-difluorophenyl)methyl]pyrazol-3-yl]-2-[6-[(3S)-3-fluoropyrrolidin-1-yl]-3-pyridinyl]acetamide	1367823: Inhibition of recombinant Cav3.3 (unknown origin) expressed in HEK293 cells assessed as decrease in calcium flux preincubated for 3 mins followed by CaCl2 addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0054	uM
(3R,5S)-N-benzyl-3,5-dimethyl-1-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]-3,5-dihydro-2H-1,4-benzodiazepine-4-carboxamide	1325730: Channel blocking activity at recombinant human CaV 3.3 channel expressed in HEK293 cells assessed as inhibition of Ca2+ flux preincubated for 3 mins followed by CaCl2 addition by fluo-4 dye-based FLIPR assay	ic50	0.0060	uM
1-[(3R,5S)-1-benzyl-3,5-dimethyl-3,5-dihydro-2H-1,4-benzodiazepin-4-yl]-2-(1,3-thiazol-5-yl)ethanone	1325730: Channel blocking activity at recombinant human CaV 3.3 channel expressed in HEK293 cells assessed as inhibition of Ca2+ flux preincubated for 3 mins followed by CaCl2 addition by fluo-4 dye-based FLIPR assay	ic50	0.0060	uM
(3R,5S)-1-benzyl-N-[(4-methoxyphenyl)methyl]-3,5-dimethyl-3,5-dihydro-2H-1,4-benzodiazepine-4-carboxamide	1325730: Channel blocking activity at recombinant human CaV 3.3 channel expressed in HEK293 cells assessed as inhibition of Ca2+ flux preincubated for 3 mins followed by CaCl2 addition by fluo-4 dye-based FLIPR assay	ic50	0.0060	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression, affects expression, increases reaction, increases expression	4
Aflatoxin B1	decreases methylation, increases methylation	2
Genistein	affects cotreatment, increases expression	2
propionaldehyde	decreases expression	1
bisphenol A	decreases methylation	1
titanium dioxide	increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	increases abundance, affects methylation	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	affects methylation	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
Irinotecan	decreases expression	1
Barium	increases transport	1
Benzo(a)pyrene	affects methylation	1
Cannabinoids	affects methylation, increases abundance	1
Dexamethasone	affects cotreatment, increases expression	1
Methapyrilene	affects methylation	1
Silicon Dioxide	decreases expression	1
Valproic Acid	increases methylation	1
Okadaic Acid	increases expression	1

ChEMBL screening assays

56 unique, capped per target: 44 binding, 9 functional, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4331799	Binding	Inhibition of T-type calcium channel (unknown origin)	The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain. — Bioorg Med Chem
CHEMBL1225387	Functional	Antagonist activity at Cav3.3 alpha1i by depolarized FLIPR assay	Discovery and expanded SAR of 4,4-disubstituted quinazolin-2-ones as potent T-type calcium channel antagonists. — Bioorg Med Chem Lett
CHEMBL4180573	ADMET	Inhibition of recombinant human Cav3.3 expressed in HEK293 cells assessed as reduction in CaCl2-induced intracellular calcium flux incubated for 3 mins followed by CaCl2 stimulation by Fluo-4AM dye based FLIPR assay	Discovery and evaluation of Cav3.1-selective T-type calcium channel blockers. — 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_HC64	HEK293 Cav3.3	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort