CACNA1A

Summary

CACNA1A (calcium voltage-gated channel subunit alpha1 A, HGNC:1388) is a protein-coding gene on chromosome 19p13.13, encoding Voltage-dependent P/Q-type calcium channel subunit alpha-1A (O00555). 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…. It is haploinsufficient (ClinGen: sufficient evidence).

Voltage-dependent calcium 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, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3’ UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6.

Source: NCBI Gene 773 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex movement disorder with or without neurodevelopmental features (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 4,515 total — 324 pathogenic, 211 likely-pathogenic
• Phenotypes (HPO): 221
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001127222

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1388
Approved symbol	CACNA1A
Name	calcium voltage-gated channel subunit alpha1 A
Location	19p13.13
Locus type	gene with protein product
Status	Approved
Aliases	Cav2.1, EA2, APCA, HPCA, FHM
Ensembl gene	ENSG00000141837
Ensembl biotype	protein_coding
OMIM	601011
Entrez	773

Gene structure

Transcript identifiers

Ensembl transcripts: 62 — 30 retained_intron, 22 protein_coding, 7 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000360228, ENST00000573710, ENST00000573891, ENST00000574822, ENST00000574974, ENST00000585802, ENST00000586190, ENST00000587451, ENST00000587525, ENST00000590205, ENST00000592864, ENST00000593160, ENST00000593267, ENST00000635727, ENST00000635742, ENST00000635786, ENST00000635895, ENST00000635917, ENST00000635988, ENST00000636012, ENST00000636022, ENST00000636058, ENST00000636074, ENST00000636389, ENST00000636473, ENST00000636549, ENST00000636610, ENST00000636670, ENST00000636768, ENST00000636816, ENST00000636966, ENST00000636974, ENST00000636984, ENST00000637004, ENST00000637117, ENST00000637168, ENST00000637276, ENST00000637297, ENST00000637432, ENST00000637475, ENST00000637485, ENST00000637616, ENST00000637625, ENST00000637692, ENST00000637736, ENST00000637769, ENST00000637774, ENST00000637777, ENST00000637809, ENST00000637819, ENST00000637832, ENST00000637927, ENST00000637952, ENST00000637966, ENST00000637981, ENST00000638009, ENST00000638029, ENST00000638114, ENST00000664864, ENST00000713788, ENST00000713789, ENST00000937071

RefSeq mRNA: 5 — MANE Select: NM_001127222 NM_000068, NM_001127221, NM_001127222, NM_001174080, NM_023035

CCDS: CCDS45998, CCDS45999, CCDS82300, CCDS82301, CCDS82302

Canonical transcript exons

ENST00000360228 — 47 exons

Exon	Start	End
ENSE00001247164	13452876	13453015
ENSE00001247385	13206442	13208053
ENSE00001666524	13455107	13455212
ENSE00004021275	13300550	13300656
ENSE00004021276	13308416	13308528
ENSE00004021277	13277069	13277128
ENSE00004021278	13235209	13235274
ENSE00004021279	13285068	13285206
ENSE00004021280	13335806	13335909
ENSE00004021281	13209312	13209498
ENSE00004021282	13317112	13317321
ENSE00004021284	13255095	13255259
ENSE00004021285	13212631	13212740
ENSE00004021286	13252991	13253101
ENSE00004021287	13330244	13330333
ENSE00004021288	13334378	13334493
ENSE00004021291	13230082	13230209
ENSE00004021292	13208756	13209009
ENSE00004021294	13286503	13286966
ENSE00004021295	13212384	13212522
ENSE00004021296	13365317	13365469
ENSE00004021297	13235614	13235730
ENSE00004021298	13227431	13227527
ENSE00004021299	13262734	13262833
ENSE00004021301	13283267	13283396
ENSE00004021302	13214501	13214608
ENSE00004021304	13224667	13224772
ENSE00004021305	13261450	13261610
ENSE00004021308	13257350	13257551
ENSE00004021309	13505932	13506479
ENSE00004021310	13308120	13308251
ENSE00004021311	13259564	13259701
ENSE00004021312	13303546	13303613
ENSE00004021313	13298544	13299353
ENSE00004021314	13371688	13371779
ENSE00004021315	13212103	13212216
ENSE00004021318	13332869	13332925
ENSE00004021319	13359606	13359799
ENSE00004021320	13231710	13231860
ENSE00004021324	13307782	13307854
ENSE00004021325	13210617	13210652
ENSE00004021326	13303767	13303884
ENSE00004021327	13275850	13275956
ENSE00004021328	13214233	13214333
ENSE00004021329	13312669	13312781
ENSE00004021330	13245182	13245265
ENSE00004021331	13234921	13235036

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 99.55.

FANTOM5 (CAGE): breadth broad, TPM avg 5.4439 / max 611.2807, expressed in 722 samples.

FANTOM5 promoters (25 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179506	2.3593	515
179524	0.7143	232
179503	0.2576	74
179508	0.2452	76
179521	0.2390	62
179505	0.1740	48
179501	0.1605	65
179487	0.1524	31
179489	0.1499	65
179485	0.1379	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	99.55	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.49	gold quality
cerebellar cortex	UBERON:0002129	99.40	gold quality
cerebellum	UBERON:0002037	99.25	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.88	gold quality
postcentral gyrus	UBERON:0002581	97.11	gold quality
parietal lobe	UBERON:0001872	96.89	gold quality
pons	UBERON:0000988	96.67	gold quality
primary visual cortex	UBERON:0002436	96.66	gold quality
superior frontal gyrus	UBERON:0002661	96.26	gold quality
occipital lobe	UBERON:0002021	96.02	gold quality
endothelial cell	CL:0000115	96.00	gold quality
middle temporal gyrus	UBERON:0002771	95.61	gold quality
buccal mucosa cell	CL:0002336	95.39	gold quality
entorhinal cortex	UBERON:0002728	95.39	gold quality
right frontal lobe	UBERON:0002810	95.24	gold quality
nucleus accumbens	UBERON:0001882	94.27	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.18	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.04	gold quality
CA1 field of hippocampus	UBERON:0003881	94.02	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.71	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.67	gold quality
temporal lobe	UBERON:0001871	93.29	gold quality
orbitofrontal cortex	UBERON:0004167	92.97	gold quality
caudate nucleus	UBERON:0001873	92.80	gold quality
putamen	UBERON:0001874	92.77	gold quality
telencephalon	UBERON:0001893	92.65	gold quality
cerebral cortex	UBERON:0000956	92.56	gold quality
frontal cortex	UBERON:0001870	92.37	gold quality
amygdala	UBERON:0001876	92.13	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	2725.71
E-GEOD-137537	yes	1035.86
E-GEOD-125970	yes	483.41
E-CURD-114	yes	454.86
E-GEOD-76312	yes	102.65
E-GEOD-86618	yes	95.51
E-GEOD-81547	yes	22.37
E-MTAB-7316	yes	14.39
E-MTAB-5061	yes	13.57
E-ANND-3	yes	8.95
E-HCAD-6	no	1009.29
E-MTAB-3929	no	35.81
E-HCAD-31	no	3.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EPAS1, NR1H4, SP1

miRNA regulators (miRDB)

90 targeting CACNA1A, 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-4795-3P	100.00	74.62	4024
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-5582-3P	99.86	72.48	4221

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• a pronounced loss of P/Q-type Ca(2+) channel function underlies the pathophysiology of EA-2 and PA. In contrast to other EA-2 mutations, AY1593/1594D and G293R form at least partially functional channels (PMID:11742003)
• Did not detect any linkage or association in these groups and conclude that if CACNA1A plays a role in typical migraine, it does not confer a major effect on the disease. (PMID:11803518)
• missense and mutations involved in episodic ataxia type 2 (PMID:11960817)
• first report confirming mutation in CACNA1A gene in familial hemiplegic migraine cases in Japan (PMID:11971066)
• uncovered two functional effects common to all familial hemiplegic migraine mutations analyzed: increase of single-channel Ca(2+) influx and decrease of maximal Ca(V)2.1 current density in neurons (PMID:12235360)
• novel SNPs within 25 kb of exon 8, defining the critical region of CACNA1A in predisposing to idiopathic generalized epilepsy (PMID:12461694)
• R192Q mutation reduces G-protein inhibition of P/Q-type Ca(2+) channels, probably by altering mechanisms by which Gbetagamma subunit binding induces change in channel gating. May contribute to migraine attacks. (PMID:12527722)
• Machado-Joseph disease and dentatorubral-pallidoluysian atrophy (DRPLA) mutations; SCA6 mutation was most frequently detected. (PMID:12542511)
• Trinucleotide repeat expansions in this protein are not as common in spinocerebellar ataxia as in SSCA8. (PMID:12545428)
• CACNA1A expressed in embryonic kidney 293T cells produces a 75 kDa C-terminal fragment in which resistance to proteolysis is rendered by an expanded polyglutamine tract, giving it a key role in the pathological mechanism of spinocerebellar ataxia type 6. (PMID:12676347)
• A novel insertion mutation of acetazolamide-responsive episodic ataxia in a Japanese family. (PMID:12736095)
• The T666M mutation is the most frequent CACNA1A mutation in familial hemiplegic migraine (PMID:12756131)
• novel CACNA1A mutation, IVS36-2A>G, at the 3’ acceptor splice site of intron 36 was identified by sequencing. (PMID:14530926)
• We report on a family with ataxia type 6 (SCA6) showing peculiar oculomotor symptoms. They carried the identical mutation (the number of expanded CAG repeat, 24) in the CACNA1A gene. (PMID:14534930)
• This study found that patients with congenital presynaptic failure of neuromuscle transmission and found sililarities with patients withEA-2 due to mutation in cacna1a. (PMID:14592859)
• Early cerebellar dysfunction in episodic ataxia type 2 results from the intrinsically abnormal properties of the CACNA1A channel rather than a degenerative process. (PMID:14681882)
• Functional analysis of a knockin mouse model of human R192Q pure FHM-1 mutation reveals a pure gain-of-function effect on Ca+ channel current, neurotransmission, and cortical spreading depression. (PMID:15003170)
• Distribution of CACNA1A haplotypes predisposing to spinocerebellar ataxia type 6 contributes to the geographical differences in prevalence of SCA6 in western Japan. (PMID:15026160)
• These results strongly suggest that ADCA families can be traced back to common ancestors in particular parts of the Netherlands. (PMID:15026782)
• CACNA1A gene is not associated with the more common migraine syndromes and is not one of the most common hemiplegic migraine genes. (PMID:15210532)
• The molecular architecture of CAG repeats in mutant SCA6 transcripts was studied. (PMID:15223312)
• This study identified a novel mutation of the CACNA1A gene, Ile1710thr, located in the domain IV-s5. (PMID:15240985)
• Concerted splicing of the P/Q channel’s main alpha1A subunit, at both an EF-hand-like domain and the channel C terminus, controls the form of Ca2+-dependent facilitation, an activity-dependent enhancement of channel opening triggered by calmodulin. (PMID:15254089)
• This paper identified a novel H1736L missense mutation in the CACNA1A gene associated with the EA2 phenotype. This mutation is localized near the pore-forming region of the P/Q-type Ca2+ channel. (PMID:15293273)
• Familial hemiplegic migraine type 1 mutations K1336E, W1684R, and V1696I alter Cav2.1 Ca2+ channel gating: evidence for beta-subunit isoform-specific effects. (PMID:15448138)
• A heterozygous nt 5404 T>C substitution in exon 33 was associated with co-occurrence of familial hemiplegic migraine and childhood epilepsy. (PMID:15452324)
• Impaired function of the mutant Ca2+ channels rendered them unable to prevent cell death. (PMID:15474358)
• Here, we report the characterization of two modes of gating of human CaV2.1 channels, the slow mode and the fast mode. (PMID:15504896)
• We show that the b gating mode produces reversible uncoupling of inactivation in human CaV2.1 channels. (PMID:15504897)
• Leaner mice carry a homozygous, autosomal recessive mutation in the CACNA1A gene encoding the Alpha1A subunit of P/Q-type calcium channels. Leaner cerebellar granule cells die via an apoptotic process and the peak time of neuronal death is P20. (PMID:15545010)
• This study have identified 2 novel truncating mutations of CACNA1A that are associated with interictal dystonia. (PMID:15710862)
• The unique combination of a particularly slow inactivation of mutant S218L CaV2.1 channel during cortical spreading depression and a somewhat low threshold of channel activation might lead to delayed severe cerebral edema and coma after minor head trauma. (PMID:15743764)
• most prevalent mutation, a threonine to methionine substitution at position 666, affects both ionic current and gating current associated with channel activation (PMID:15795222)
• presence of significant floccular atrophy compared with controls in both ataxin-2 and Ca(V)2.1 mutations (PMID:15826995)
• Mutated in patients with episodic ataxia type 2, suggested involvement outside the cerebellum. (PMID:15827025)
• In addition to altered channel function, the deficiency in protein misfolding and trafficking associated with the CACNA1A C287Y and G293R mutants may contribute to the slowly progressive cerebellar ataxia. (PMID:15985579)
• In a UK national study, the authors analyzed 15 index cases with typical EA2 and identified two unreported intronic CACNA1A mutations that predict aberrant splicing. (PMID:16043807)
• The authors describe a case of late-onset EA2 associated with the first multiple-base pair insertion in CACNA1A. Molecular expression revealed evidence of impaired calcium channel function. (PMID:16186543)
• Results indicate that for human P/Q-type Ca(2+) channels with the long-alpha(1A)-subunit isoform, both missense and nonsense episodic ataxia type 2 mutants indeed display prominent dominant-negative effects. (PMID:16306128)
• a patient with early onset, non fluctuating spinocerebellar ataxia carries a novel de novo missense mutation in this gene, p.R1664Q. (PMID:16325861)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cacna1ab	ENSDARG00000006923
danio_rerio	cacna1aa	ENSDARG00000037905
mus_musculus	Cacna1a	ENSMUSG00000034656
rattus_norvegicus	Cacna1a	ENSRNOG00000052707

Paralogs (26): CACNA1G (ENSG00000006283), SCN4A (ENSG00000007314), CACNA1S (ENSG00000081248), CACNA1I (ENSG00000100346), CACNA1F (ENSG00000102001), NALCN (ENSG00000102452), SCN2A (ENSG00000136531), SCN7A (ENSG00000136546), 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 P/Q-type calcium channel subunit alpha-1A — O00555 (reviewed: O00555)

Alternative names: Brain calcium channel I, Calcium channel, L type, alpha-1 polypeptide isoform 4, Voltage-gated calcium channel subunit alpha Cav2.1

All UniProt accessions (24): A0A087WW63, A0A1B0GTG6, A0A1B0GTI4, A0A1B0GTN7, A0A1B0GTW2, A0A1B0GU74, A0A1B0GU81, A0A1B0GUE5, A0A1B0GUM7, A0A1B0GUP3, A0A1B0GUS3, A0A1B0GVX1, A0A1C7CYY9, A0A384DVW2, A0A590UJK2, A0AAQ5BGX1, O00555, A0AAQ5BGX9, B5TYJ1, I3L2V5, I3L391, K7EIF8, K7EKF7, K7EQ95

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. The isoform alpha-1A gives rise to P and/or Q-type calcium currents. P/Q-type calcium channels belong to the ‘high-voltage activated’ (HVA) group and are specifically blocked by the spider omega-agatoxin-IVA (AC P54282). They are however insensitive to dihydropyridines (DHP).

Subunit / interactions. 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. Interacts (via C-terminal CDB motif) with CABP1 in the pre- and postsynaptic membranes. Interacts with the spider omega-agatoxin-IVA (AC P30288). Interacts with TSPOAP1.

Subcellular location. Cell membrane.

Tissue specificity. Brain specific; mainly found in cerebellum, cerebral cortex, thalamus and hypothalamus. Expressed in the small cell lung carcinoma cell line SCC-9. No expression in heart, kidney, liver or muscle. Purkinje cells contain predominantly P-type VSCC, the Q-type being a prominent calcium current in cerebellar granule cells.

Disease relevance. Spinocerebellar ataxia 6 (SCA6) [MIM:183086] Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA6 is an autosomal dominant cerebellar ataxia (ADCA), mainly caused by expansion of a CAG repeat in the coding region of CACNA1A. There seems to be a correlation between the repeat number and earlier onset of the disorder. The disease is caused by variants affecting the gene represented in this entry. Migraine, familial hemiplegic, 1 (FHM1) [MIM:141500] A subtype of migraine with aura associated with ictal hemiparesis and, in some families, cerebellar ataxia and atrophy. Migraine is a disabling symptom complex of periodic headaches, usually temporal and unilateral. Headaches are often accompanied by irritability, nausea, vomiting and photophobia, preceded by constriction of the cranial arteries. Migraine with aura is characterized by recurrent attacks of reversible neurological symptoms (aura) that precede or accompany the headache. Aura may include a combination of sensory disturbances, such as blurred vision, hallucinations, vertigo, numbness and difficulty in concentrating and speaking. The disease is caused by variants affecting the gene represented in this entry. Episodic ataxia 2 (EA2) [MIM:108500] An autosomal dominant disorder characterized by acetozolamide-responsive attacks of ataxia, migraine-like symptoms, interictal nystagmus, and cerebellar atrophy. The disease is caused by variants affecting the gene represented in this entry. Developmental and epileptic encephalopathy 42 (DEE42) [MIM:617106] 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. DEE42 inheritance is autosomal dominant. 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.

Polymorphism. The poly-Gln region of CACNA1A is polymorphic: 6 to 17 repeats in the normal population, expanded to about 21 to 30 repeats in SCA6. Repeat expansion has been reported also in a EA2 family.

Similarity. Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1A subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
O00555-8	1, 1A-1, BI-1-GGCAG	yes
O00555-2	2, 1A-2, BI-1
O00555-3	3, BI-1(V1)
O00555-4	4, BI-1(V1)-GGCAG
O00555-5	5, BI-1(V2)
O00555-6	6, BI-1(V2)-GGCAG

RefSeq proteins (5): NP_000059, NP_001120693, NP_001120694, NP_001167551, NP_075461 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002077	VDCCAlpha1	Family
IPR005448	CACNA1A	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 (278 total): helix 69, sequence variant 58, topological domain 25, transmembrane region 24, strand 23, compositionally biased region 16, turn 15, modified residue 15, sequence conflict 11, splice variant 8, repeat 4, region of interest 4, binding site 3, chain 1, site 1, glycosylation site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3BXK	X-RAY DIFFRACTION	2.55
8X93	ELECTRON MICROSCOPY	2.92
8X90	ELECTRON MICROSCOPY	2.95
8X91	ELECTRON MICROSCOPY	3.11

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00555-F1	58.34	0.05

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 (1): 1648 (binds to omega-aga-iva)

Ligand- & substrate-binding residues (3): 318; 667; 1459

Post-translational modifications (15): 409, 447, 450, 749, 752, 789, 1084, 1093, 1983, 2046, 2064, 2076, 2078, 2119, 2139

Glycosylation sites (1): 283

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: 773 (showing top): RNGTGGGC_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BENPORATH_ES_WITH_H3K27ME3, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, TGCGCANK_UNKNOWN, MODULE_169, GOBP_RESPONSE_TO_ACID_CHEMICAL, RORA1_01, ENK_UV_RESPONSE_KERATINOCYTE_UP, KEGG_MAPK_SIGNALING_PATHWAY, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, MAZ_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_PROTEIN_TARGETING

GO Biological Process (11): positive regulation of cytosolic calcium ion concentration (GO:0007204), chemical synaptic transmission (GO:0007268), modulation of chemical synaptic transmission (GO:0050804), calcium ion transmembrane transport (GO:0070588), calcium ion import across plasma membrane (GO:0098703), response to amyloid-beta (GO:1904645), cellular response to amyloid-beta (GO:1904646), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (8): amyloid-beta binding (GO:0001540), voltage-gated calcium channel activity (GO:0005245), high voltage-gated calcium channel activity (GO:0008331), syntaxin binding (GO:0019905), metal ion binding (GO:0046872), monoatomic ion channel activity (GO:0005216), calcium channel activity (GO:0005262), protein binding (GO:0005515)

GO Cellular Component (9): nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), voltage-gated calcium channel complex (GO:0005891), membrane (GO:0016020), cell projection (GO:0042995), neuronal cell body (GO:0043025), synapse (GO:0045202), 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
cellular anatomical structure	3
transport	2
regulation of biological quality	1
anterograde trans-synaptic signaling	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
calcium ion transport	1
monoatomic cation transmembrane transport	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
response to nitrogen compound	1
response to oxygen-containing compound	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to amyloid-beta	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
peptide binding	1
calcium channel activity	1
voltage-gated monoatomic cation channel activity	1
voltage-gated calcium channel activity	1
SNARE binding	1
cation binding	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
calcium channel complex	1
plasma membrane protein complex	1
somatodendritic compartment	1
cell body	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

227 interactions, top by confidence:

A	B	Type	Score
CACNA1A	ABI1	psi-mi:“MI:0915”(physical association)	0.510
AMIGO2	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
CACNA1A	ARHGAP22	psi-mi:“MI:0915”(physical association)	0.510
TSPOAP1	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
CACNA1A	CSNK2B	psi-mi:“MI:0915”(physical association)	0.510
CACNA1A	DNAJB5	psi-mi:“MI:0915”(physical association)	0.510
GRN	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
CACNA1A	HIVEP1	psi-mi:“MI:0915”(physical association)	0.510
CACNA1A	ADGRL1	psi-mi:“MI:0915”(physical association)	0.510
LTBP4	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
MATN2	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
MEGF6	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
CACNA1A	MEGF8	psi-mi:“MI:0915”(physical association)	0.510
RBM12B	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
PUF60	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
TUBB2B	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
UQCRC2	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
YLPM1	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
CACNA1A	AMIGO2	psi-mi:“MI:0915”(physical association)	0.510
CACNA1A	TSPOAP1	psi-mi:“MI:0915”(physical association)	0.510
DNAJB5	CACNA1A	psi-mi:“MI:0915”(physical association)	0.510
CACNA1A	LTBP4	psi-mi:“MI:0915”(physical association)	0.510
CACNA1A	MATN2	psi-mi:“MI:0915”(physical association)	0.510

BioGRID (119): CACNA1A (Synthetic Growth Defect), CACNA1A (Proximity Label-MS), CACNA1A (Proximity Label-MS), UBE2L3 (Affinity Capture-Western), MAP1B (Affinity Capture-Western), Rnf138 (Two-hybrid), Rnf138 (Reconstituted Complex), CACNA1A (Affinity Capture-Western), CACNA1A (Affinity Capture-Western), CACNB4 (Reconstituted Complex), CACNA1A (Reconstituted Complex), CACNA1A (Two-hybrid), CACNA1A (Reconstituted Complex), CACNA1A (Affinity Capture-MS), CACNA1A (PCA)

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, 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

6 interactions.

A	Effect	B	Mechanism
CACNA1A	“up-regulates quantity”	calcium(2+)	relocalization
CACNA1A	up-regulates	Excitatory_synaptic_transmission
EPAS1	“up-regulates quantity by expression”	CACNA1A	“transcriptional regulation”
DCC	“up-regulates activity”	CACNA1A
ANK2	“up-regulates quantity”	CACNA1A	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 145 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Trafficking of GluR2-containing AMPA receptors	5	34.3×	5e-05
Ras activation upon Ca2+ influx through NMDA receptor	5	29.1×	7e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	27.8×	7e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	27.8×	7e-05
Long-term potentiation	5	24.3×	1e-04
Assembly and cell surface presentation of NMDA receptors	8	20.7×	2e-06
Molecules associated with elastic fibres	6	18.9×	7e-05
Neurexins and neuroligins	8	16.1×	9e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein localization to synapse	6	34.0×	8e-06
establishment or maintenance of epithelial cell apical/basal polarity	7	30.1×	2e-06
receptor clustering	6	27.7×	2e-05
regulation of postsynaptic membrane neurotransmitter receptor levels	6	22.0×	5e-05
embryo implantation	5	13.0×	4e-03
protein-containing complex assembly	9	7.6×	5e-04
nervous system development	12	4.1×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

4515 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	324
Likely pathogenic	211
Uncertain significance	1859
Likely benign	1366
Benign	202

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1011068	NM_001127222.2(CACNA1A):c.4324T>G (p.Tyr1442Asp)	Pathogenic
1012935	NM_001127222.2(CACNA1A):c.4828_4829del (p.Leu1610fs)	Pathogenic
1012936	NM_001127222.2(CACNA1A):c.4250+1G>C	Pathogenic
1027685	NM_001127222.2(CACNA1A):c.3039C>G (p.Tyr1013Ter)	Pathogenic
1027687	NM_001127222.2(CACNA1A):c.826G>T (p.Glu276Ter)	Pathogenic
1033712	NM_001127222.2(CACNA1A):c.2482C>T (p.Gln828Ter)	Pathogenic
1068487	NM_001127222.2(CACNA1A):c.4514T>C (p.Phe1505Ser)	Pathogenic
1070324	NM_001127222.2(CACNA1A):c.3563del (p.Asn1188fs)	Pathogenic
1070484	NC_000019.9:g.(?13338225)(13342694_?)del	Pathogenic
1072305	NM_001127222.2(CACNA1A):c.6397_6403del (p.Arg2133fs)	Pathogenic
1074371	NM_001127222.2(CACNA1A):c.4085del (p.Leu1362fs)	Pathogenic
1074784	NM_001127222.2(CACNA1A):c.2401G>T (p.Glu801Ter)	Pathogenic
1075147	NM_001127222.2(CACNA1A):c.6371C>A (p.Ser2124Ter)	Pathogenic
1075289	NM_001127222.2(CACNA1A):c.4795del (p.Val1599fs)	Pathogenic
1075959	NM_001127222.2(CACNA1A):c.3006_3007delinsCT (p.Arg1002_Arg1003delinsSerTer)	Pathogenic
1076899	NM_001127221.2(CACNA1A):c.5588_5589del (p.Leu1863fs)	Pathogenic
1202591	NM_001127222.2(CACNA1A):c.655A>G (p.Ile219Val)	Pathogenic
1204133	NM_001127222.2(CACNA1A):c.4403C>T (p.Ser1468Leu)	Pathogenic
1253847	NM_001127222.2(CACNA1A):c.6097C>T (p.Gln2033Ter)	Pathogenic
1298310	NM_001127222.2(CACNA1A):c.3414del (p.Thr1139fs)	Pathogenic
1300496	NM_001127222.2(CACNA1A):c.6147_6163del (p.Gln2049fs)	Pathogenic
1328102	GRCh37/hg19 19p13.2(chr19:13374979-13388396)x1	Pathogenic
1334375	NM_001127222.2(CACNA1A):c.526del (p.Val176fs)	Pathogenic
1335330	NM_001127222.2(CACNA1A):c.4765del (p.Ala1589fs)	Pathogenic
1338921	NM_001127222.2(CACNA1A):c.5335C>T (p.Arg1779Ter)	Pathogenic
1342943	NM_001127222.2(CACNA1A):c.2752G>T (p.Gly918Cys)	Pathogenic
1366064	NC_000019.9:g.(?13427906)(13617038_?)del	Pathogenic
1373236	NM_001127222.2(CACNA1A):c.2840del (p.Pro947fs)	Pathogenic
1374639	NM_001127222.2(CACNA1A):c.507G>A (p.Trp169Ter)	Pathogenic
1376008	NM_001127222.2(CACNA1A):c.876dup (p.Gly293fs)	Pathogenic

SpliceAI

9514 predictions. Top by Δscore:

Variant	Effect	Δscore
19:13208413:T:TC	acceptor_gain	1.0000
19:13209306:GCCCA:G	donor_loss	1.0000
19:13209307:CCCA:C	donor_loss	1.0000
19:13209308:CCA:C	donor_loss	1.0000
19:13209309:CA:C	donor_loss	1.0000
19:13209310:A:AT	donor_loss	1.0000
19:13209311:CCTG:C	donor_loss	1.0000
19:13209494:ATGGT:A	acceptor_gain	1.0000
19:13209495:TGGT:T	acceptor_gain	1.0000
19:13209496:GGT:G	acceptor_gain	1.0000
19:13209497:GT:G	acceptor_gain	1.0000
19:13209499:C:CC	acceptor_gain	1.0000
19:13209499:CT:C	acceptor_loss	1.0000
19:13209500:T:G	acceptor_loss	1.0000
19:13212097:CCTCA:C	donor_loss	1.0000
19:13212098:CTCAC:C	donor_loss	1.0000
19:13212099:TCA:T	donor_loss	1.0000
19:13212100:CAC:C	donor_loss	1.0000
19:13212101:A:AG	donor_loss	1.0000
19:13212102:C:CA	donor_loss	1.0000
19:13212213:CGGA:C	acceptor_gain	1.0000
19:13212217:C:CC	acceptor_gain	1.0000
19:13212518:CCATC:C	acceptor_gain	1.0000
19:13212519:CATCC:C	acceptor_gain	1.0000
19:13212521:TC:T	acceptor_gain	1.0000
19:13212522:CC:C	acceptor_gain	1.0000
19:13212629:A:AC	donor_gain	1.0000
19:13212630:C:CC	donor_gain	1.0000
19:13212630:CAGGG:C	donor_gain	1.0000
19:13212639:T:TA	donor_gain	1.0000

AlphaMissense

16542 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:13214291:A:T	I1961N	1.000
19:13214300:G:T	A1958D	1.000
19:13214316:C:G	G1953R	1.000
19:13214316:C:T	G1953R	1.000
19:13214552:A:G	W1930R	1.000
19:13214552:A:T	W1930R	1.000
19:13214575:A:G	L1922P	1.000
19:13224687:A:G	L1904P	1.000
19:13224696:C:G	R1901P	1.000
19:13224702:A:G	L1899P	1.000
19:13224711:A:G	L1896P	1.000
19:13224729:A:T	V1890D	1.000
19:13224753:A:G	L1882P	1.000
19:13224768:A:G	L1877P	1.000
19:13227452:A:C	C1868W	1.000
19:13227454:A:G	C1868R	1.000
19:13230107:A:G	W1835R	1.000
19:13230107:A:T	W1835R	1.000
19:13230163:A:G	L1816P	1.000
19:13230174:G:C	N1812K	1.000
19:13230174:G:T	N1812K	1.000
19:13230178:T:A	D1811V	1.000
19:13230178:T:G	D1811A	1.000
19:13230179:C:G	D1811H	1.000
19:13230199:A:G	L1804P	1.000
19:13230201:A:C	N1803K	1.000
19:13230201:A:T	N1803K	1.000
19:13231769:A:G	C1781R	1.000
19:13231800:A:C	C1770W	1.000
19:13231801:C:T	C1770Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000002960 (19:13346216 T>C), RS1000005423 (19:13274693 A>C,G), RS1000024000 (19:13432271 C>T), RS1000027455 (19:13221470 T>C), RS1000029600 (19:13392693 A>G), RS1000042310 (19:13424363 C>G), RS1000049892 (19:13477015 G>A), RS1000055796 (19:13348656 T>C,G), RS1000069412 (19:13354395 G>T), RS1000075405 (19:13236893 C>G), RS1000097136 (19:13352816 A>G), RS1000098052 (19:13334655 G>A), RS1000105992 (19:13210105 A>G), RS1000109122 (19:13392132 G>T), RS1000116696 (19:13432452 A>T)

Disease associations

OMIM: gene MIM:601011 | disease phenotypes: MIM:108500, MIM:183086, MIM:617106, MIM:141500, MIM:617350, MIM:160120, MIM:224500, MIM:602535, MIM:614753, MIM:609129, MIM:606369, MIM:620029, MIM:104290, MIM:308350, MIM:108600, MIM:300672

GenCC curated gene-disease

Disease	Classification	Inheritance
episodic ataxia type 2	Definitive	Autosomal dominant
undetermined early-onset epileptic encephalopathy	Definitive	Autosomal dominant
migraine, familial hemiplegic, 1	Strong	Autosomal dominant
spinocerebellar ataxia type 6	Strong	Autosomal dominant
developmental and epileptic encephalopathy, 42	Strong	Autosomal dominant
torsion dystonia 2	Strong	Autosomal recessive
Lennox-Gastaut syndrome	Supportive	Autosomal dominant
familial or sporadic hemiplegic migraine	Supportive	Autosomal dominant
benign paroxysmal torticollis of infancy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex movement disorder with or without neurodevelopmental features	Definitive	AR

Mondo (41): episodic ataxia type 2 (MONDO:0007163), spinocerebellar ataxia type 6 (MONDO:0008457), developmental and epileptic encephalopathy, 42 (MONDO:0014917), migraine, familial hemiplegic, 1 (MONDO:0020756), developmental and epileptic encephalopathy, 52 (MONDO:0033361), cerebellar ataxia (MONDO:0000437), cerebral palsy (MONDO:0006497), disorder of sexual differentiation (MONDO:0002145), hereditary episodic ataxia (MONDO:0016227), CACNA1A-related complex neurodevelopmental disorder (MONDO:0100254), autism spectrum disorder (MONDO:0005258), torsion dystonia 2 (MONDO:0009141), intellectual disability (MONDO:0001071), migraine disorder (MONDO:0005277), Marshall-Smith syndrome (MONDO:0011244)

Orphanet (24): Familial or sporadic hemiplegic migraine (Orphanet:569), Familial paroxysmal ataxia (Orphanet:97), Spinocerebellar ataxia type 6 (Orphanet:98758), Rare ataxia (Orphanet:102002), Difference of sex development (Orphanet:90771), Hereditary episodic ataxia (Orphanet:211062), Primary dystonia, DYT2 type (Orphanet:99657), Malan overgrowth syndrome (Orphanet:420179), Marshall-Smith syndrome (Orphanet:561), Lennox-Gastaut syndrome (Orphanet:2382), Alternating hemiplegia of childhood (Orphanet:2131), Subependymal giant cell astrocytoma (Orphanet:251618), Benign hereditary chorea (Orphanet:1429), Amyotrophic lateral sclerosis (Orphanet:803), Hereditary ataxia (Orphanet:183518)

HPO phenotypes

221 total (30 of 221 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000297	Facial hypotonia
HP:0000348	High forehead
HP:0000360	Tinnitus
HP:0000365	Hearing impairment
HP:0000473	Torticollis
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000565	Esotropia
HP:0000575	Scotoma
HP:0000577	Exotropia
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000643	Blepharospasm
HP:0000648	Optic atrophy
HP:0000651	Diplopia
HP:0000657	Oculomotor apraxia
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000712	Emotional lability
HP:0000713	Agitation
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002787_1	Exfoliation syndrome	7.000000e-06
GCST002787_4	Exfoliation syndrome	3.000000e-11
GCST003141_6	Proteinuria and chronic kidney disease	3.000000e-06
GCST011494_3	Daytime nap	2.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement

MeSH disease descriptors (21)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D002547	Cerebral Palsy	C10.228.140.140.254
D002819	Chorea	C10.228.662.262.249; C10.597.350.250; C23.888.592.350.250
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
D004828	Epilepsies, Partial	C10.228.140.490.360
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065768	Lennox Gastaut Syndrome	C10.228.140.490.493.750; C16.320.495
D008881	Migraine Disorders	C10.228.140.546.399.750
D065886	Neurodevelopmental Disorders	F03.625
D013285	Strabismus	C10.292.562.887; C11.590.810
C538268	Auditory neuropathy (supp.)
C564064	CDKL5 deficiency disorder (supp.)
C538006	Dystonia musculorum deformans type 2 (supp.)
C535506	Episodic Ataxia, Type 2 (supp.)
C536890	Hemiplegic migraine, familial type 1 (supp.)
C531684	Hereditary spinal ataxia (supp.)
C536026	Marshall-Smith syndrome (supp.)
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2363032 (PROTEIN COMPLEX GROUP), CHEMBL3988640 (PROTEIN COMPLEX), CHEMBL4266 (SINGLE PROTEIN)

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
rs2112460	Efficacy	3	antidepressants	Major Depressive Disorder

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs16030	CACNA1A		0.00	0
rs2074880	CACNA1A		0.00	0
rs2112460	CACNA1A	3	0.00	1	antidepressants
rs2248069	CACNA1A		0.00	0
rs7254351	CACNA1A		0.00	0
rs10416717	CACNA1A		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 (18 total), top 18:

Ligand	Action	Affinity	Parameter
ω-agatoxin IIIA	Antagonist	9.3	pKd
ω-conotoxin MVIIC	Antagonist	9.2	pIC50
ω-phonetoxin-IIA	Channel blocker	9.2	pKd
ω-conotoxin MVIID	Channel blocker	9.0	pIC50
ω-agatoxin IVA	Antagonist	8.7	pIC50
ω-agatoxin IVB	Antagonist	8.5	pKd
DW13.3	Channel blocker	8.4	pEC50
ω-conotoxin CVIB	Antagonist	8.0	pIC50
kurtoxin	Antagonist	7.8	pEC50
ω-conotoxin CVIC	Antagonist	7.5	pIC50
ω-grammotoxin SIA	Antagonist	7.1	pIC50
PnTx-3-6	Channel blocker	6.6	pIC50
mibefradil	Antagonist	6.5	pIC50
Cd2+	Channel blocker	6.3	pIC50
ziconotide	Antagonist	6.3	pIC50
ω-conotoxin CVIA	Antagonist	6.1	pIC50
ω-conotoxin GVIA	Antagonist	6.0	pIC50
ω-conotoxin CVID	Antagonist	4.2	pIC50

ChEMBL bioactivities

66 potent at pChembl≥5 of 83 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
6.01	IC50	966	nM	CHEMBL597585
5.90	IC50	1260	nM	CHEMBL2017291
5.75	IC50	1800	nM	CHEMBL4228929
5.66	IC50	2200	nM	CHEMBL4226021

PubChem BioAssay actives

14 with measured affinity, of 105 total; 14 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
(2R)-2-[[6-[(5-methylthiophen-2-yl)methylamino]-9-propylpurin-2-yl]amino]butan-1-ol	712276: Agonist activity at P/Q-type Cav2.1 expressed in tsA201 cell assessed as calcium current by whole-cell patch clamp method	ec50	8.8000	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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression	4
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation, increases mutagenesis	3
TL8-506	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	increases abundance, affects methylation	1
cypermethrin	decreases expression	1
coumarin	increases phosphorylation	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
NSC 689534	affects binding, increases expression	1
Temozolomide	decreases expression	1
Vorinostat	affects cotreatment, increases expression	1
Vehicle Emissions	decreases expression	1
Cannabinoids	affects methylation, increases abundance	1
Carbamazepine	affects expression	1
Copper	affects binding, increases expression	1
Succimer	affects cotreatment, increases expression	1
Methotrexate	increases expression	1
Pesticides	increases methylation	1
Phenylmercuric Acetate	affects cotreatment, decreases expression	1
Phthalic Acids	increases methylation	1
Rotenone	decreases expression	1
Testosterone	decreases expression	1

ChEMBL screening assays

19 unique, capped per target: 18 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3737861	Binding	Inhibition of voltage-gated calcium channel (unknown origin)	Discovery and Pharmacology of a Novel Class of Diacylglycerol Acyltransferase 2 Inhibitors. — J Med Chem
CHEMBL2212931	Functional	Agonist activity at P/Q-type Cav2.1 expressed in tsA201 cell assessed as calcium current by whole-cell patch clamp method	Synthesis and biological evaluation of a selective N- and p/q-type calcium channel agonist. — ACS Med Chem Lett

Cellosaurus cell lines

39 cell lines: 29 induced pluripotent stem cell, 7 transformed cell line, 2 finite cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0IV	UCSFi001-A-60	Induced pluripotent stem cell	Male
CVCL_C0IW	UCSFi001-A-61	Induced pluripotent stem cell	Male
CVCL_C0IX	UCSFi001-A-62	Induced pluripotent stem cell	Male
CVCL_C0LR	GM28364	Transformed cell line	Female
CVCL_C0M8	GM28544	Transformed cell line	Male
CVCL_C0M9	GM28545	Transformed cell line	Female
CVCL_C1WX	STBCi028-A-1	Induced pluripotent stem cell	Female
CVCL_C7MH	GM28378	Transformed cell line	Female
CVCL_C9H1	BIONi010-C-56	Induced pluripotent stem cell	Male
CVCL_C9H2	BIONi010-C-57	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01370486	PHASE4	WITHDRAWN	Melatonin Versus Placebo in the Lennox-Gastaut Syndrome: Neurophysiological and Neuropsychological Effects
NCT02731300	PHASE4	COMPLETED	Transcranial Direct Current Stimulation, Treatment of Childhood Drug-Resistant Lennox-Gastaut Syndrome, A Pilot Study
NCT04133480	PHASE4	WITHDRAWN	Investigation of Cognitive Outcomes With Cannabidiol Oral Solution
NCT05044819	PHASE4	ACTIVE_NOT_RECRUITING	Assessment of Potential for Chronic Liver Injury in Participants Treated With Epidiolex (Cannabidiol) Oral Solution
NCT06924827	PHASE4	NOT_YET_RECRUITING	A Study to Investigate the Transition of Children From ‘Artisanal Cannabidiol (CBD) to Epidiolex
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT07221292	PHASE3	NOT_YET_RECRUITING	Pivotal Study of N-acetyl-L-leucine for CACNA1A
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT00004776	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Oral Topiramate for Lennox-Gastaut Syndrome
NCT01146951	PHASE3	COMPLETED	A Placebo-Controlled, Double-Blind Comparative Study of E2080 in Lennox-Gastaut Syndrome Patients (Study E2080-J081-304)
NCT01151540	PHASE3	COMPLETED	A Long Term Extension Study of E2080 in Lennox-Gastaut Patients
NCT01160770	PHASE3	COMPLETED	Safety and Effectiveness of Open-Label Clobazam in Subjects With Lennox-Gastaut Syndrome
NCT01405053	PHASE3	COMPLETED	Study of Rufinamide in Pediatric Subjects 1 to Less Than 4 Years of Age With Lennox-Gastaut Syndrome Inadequately Controlled With Other Anti-epileptic Drugs
NCT02224560	PHASE3	COMPLETED	Efficacy and Safety of GWP42003-P for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults
NCT02224573	PHASE3	COMPLETED	An Open Label Extension Study of Cannabidiol (GWP42003-P) in Children and Adults With Dravet or Lennox-Gastaut Syndromes
NCT02224690	PHASE3	COMPLETED	A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P; CBD) as Adjunctive Treatment for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults
NCT02318537	PHASE3	WITHDRAWN	Cannabidiol Oral Solution as an Adjunctive Therapy for Treatment of Participants With Inadequately Controlled Lennox-Gastaut Syndrome
NCT02834793	PHASE3	TERMINATED	Study of Perampanel as Adjunctive Treatment for Inadequately Controlled Seizures Associated With Lennox-Gastaut Syndrome
NCT03355209	PHASE3	COMPLETED	A Study to Investigate the Efficacy and Safety of ZX008 (Fenfluramine Hydrochloride) as an Adjunctive Therapy in Children and Adults With Lennox-Gastaut Syndrome
NCT03936777	PHASE3	COMPLETED	A Study to Investigate the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution in Children and Adults With Epileptic Encephalopathy Including Dravet Syndrome and Lennox-Gastaut Syndrome
NCT04611438	PHASE3	UNKNOWN	Research on Cognitive Effect of Cannabidiol on Dravet Syndrome and Lennox-Gastaut SyndromeGastaut Syndrome
NCT04938427	PHASE3	COMPLETED	A Study of Soticlestat as an Add-on Therapy in Children, Teenagers, and Adults With Lennox-Gastaut Syndrome