CACNA1F

Summary

CACNA1F (calcium voltage-gated channel subunit alpha1 F, HGNC:1393) is a protein-coding gene on chromosome Xp11.23, encoding Voltage-dependent L-type calcium channel subunit alpha-1F (O60840). 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 a multipass transmembrane protein that functions as an alpha-1 subunit of the voltage-dependent calcium channel, which mediates the influx of calcium ions into the cell. The encoded protein forms a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Mutations in this gene can cause X-linked eye disorders, including congenital stationary night blindness type 2A, cone-rod dystropy, and Aland Island eye disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed.

Source: NCBI Gene 778 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CACNA1F-related retinopathy (Definitive, ClinGen) — +5 more curated relationships
• Clinical variants (ClinVar): 1,532 total — 109 pathogenic, 69 likely-pathogenic
• Phenotypes (HPO): 36
• Druggable target: yes — 48 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001256789

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1393
Approved symbol	CACNA1F
Name	calcium voltage-gated channel subunit alpha1 F
Location	Xp11.23
Locus type	gene with protein product
Status	Approved
Aliases	Cav1.4, JM8, JMC8, CSNBX2, CORDX3, CSNB2A, OA2
Ensembl gene	ENSG00000102001
Ensembl biotype	protein_coding
OMIM	300110
Entrez	778

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000323022, ENST00000376251, ENST00000376265, ENST00000480889, ENST00000481035, ENST00000486943

RefSeq mRNA: 3 — MANE Select: NM_001256789 NM_001256789, NM_001256790, NM_005183

CCDS: CCDS35253, CCDS59166, CCDS59167

Canonical transcript exons

ENST00000323022 — 48 exons

Exon	Start	End
ENSE00000000007	49233285	49233340
ENSE00000670125	49230467	49230609
ENSE00000670127	49230220	49230372
ENSE00000670128	49228251	49228447
ENSE00000670133	49226610	49226702
ENSE00000670134	49226409	49226502
ENSE00000670135	49226217	49226243
ENSE00000670136	49225909	49226069
ENSE00000670141	49221035	49221080
ENSE00000670143	49219634	49219790
ENSE00000670145	49219321	49219450
ENSE00000670146	49218882	49218941
ENSE00000670147	49218629	49218735
ENSE00000670148	49218455	49218542
ENSE00000670151	49217755	49217807
ENSE00000670152	49216382	49216528
ENSE00000670153	49215342	49215543
ENSE00000670154	49215086	49215244
ENSE00000867148	49222929	49223136
ENSE00000867150	49220473	49220524
ENSE00001094901	49205616	49205813
ENSE00001094902	49212667	49212795
ENSE00001094907	49213819	49213902
ENSE00001094909	49212974	49212994
ENSE00001094913	49214159	49214269
ENSE00001094915	49209629	49209759
ENSE00001094919	49207005	49207112
ENSE00001094921	49209262	49209393
ENSE00001150141	49206511	49206623
ENSE00001150152	49206728	49206855
ENSE00001244194	49208515	49208684
ENSE00001244250	49224761	49224986
ENSE00001244283	49226970	49227127
ENSE00001244297	49230850	49230989
ENSE00001244303	49231202	49231307
ENSE00001244325	49211898	49211989
ENSE00001469989	49231678	49231927
ENSE00001632730	49212243	49212308
ENSE00001650553	49210590	49210686
ENSE00001701007	49211322	49211481
ENSE00001762981	49217898	49218005
ENSE00001792515	49210965	49211092
ENSE00001799475	49228036	49228139
ENSE00003464525	49222522	49222603
ENSE00003508272	49209941	49210042
ENSE00003566343	49210301	49210403
ENSE00003637910	49222718	49222838
ENSE00003902867	49205063	49205367

Expression profiles

Bgee: expression breadth ubiquitous, 143 present calls, max score 68.67.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3610 / max 130.8790, expressed in 25 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199263	0.3482	25
199262	0.0128	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	68.67	gold quality
granulocyte	CL:0000094	68.43	gold quality
right hemisphere of cerebellum	UBERON:0014890	65.88	gold quality
cerebellar hemisphere	UBERON:0002245	65.77	gold quality
cerebellar cortex	UBERON:0002129	65.65	gold quality
right uterine tube	UBERON:0001302	65.46	gold quality
right lung	UBERON:0002167	65.10	gold quality
cerebellum	UBERON:0002037	64.54	gold quality
small intestine Peyer’s patch	UBERON:0003454	64.27	gold quality
small intestine	UBERON:0002108	62.14	gold quality
prefrontal cortex	UBERON:0000451	61.72	gold quality
mucosa of transverse colon	UBERON:0004991	60.35	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	59.49	gold quality
vena cava	UBERON:0004087	58.83	gold quality
frontal cortex	UBERON:0001870	58.40	gold quality
right frontal lobe	UBERON:0002810	58.22	gold quality
Brodmann (1909) area 9	UBERON:0013540	58.22	gold quality
lymph node	UBERON:0000029	57.82	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	57.68	gold quality
transverse colon	UBERON:0001157	57.52	gold quality
lower esophagus mucosa	UBERON:0035834	57.49	gold quality
spleen	UBERON:0002106	57.28	gold quality
bone marrow cell	CL:0002092	57.19	gold quality
neocortex	UBERON:0001950	57.14	gold quality
upper lobe of left lung	UBERON:0008952	56.73	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	56.68	gold quality
apex of heart	UBERON:0002098	56.56	gold quality
rectum	UBERON:0001052	55.94	gold quality
gall bladder	UBERON:0002110	55.79	gold quality
gingival epithelium	UBERON:0001949	55.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• comprehensive mutation analyses in the 48 CACNA1F exons in 36 families, most of them from Germany (PMID:12111638)
• Novel nonsense mutation detected in exon 7 occurs after the predicted fifth transmembrane domain, deleting part of domain I and all of domains II, III,IV, the EF-hand motif and cytoplasmic C-terminus. (PMID:12552565)
• A novel mutation in the CACNA1F gene adds further support to the contention that CSNB2 represents a genetically distinct retinal disorder of a calcium channel. (PMID:12719097)
• The biophysical and pharmacological properties of human retinal Cav1.4alpha1 using the whole-cell patch-clamp technique after heterologous expression in tsA-201 cells were compared with other L-type alpha1 subunits (PMID:12853422)
• These findings indicate that a mutation of the CACNA1F gene may be associated with retinal and optic disc atrophy with a progressive decline of visual function. (PMID:12860808)
• L-type Ca2+ channel plays a significant role in the Ca2+ influx pathways mediating T lymphocyte activation and proliferation (PMID:12954628)
• Introduction of base pair changes associated with four incomplete X-linked congenital night blindness mutations showed that only the G369D alteration affected channel activation properties. Ca(v)1.4 was found widely expressed outside the retina (PMID:14973233)
• Our data provide unequivocal evidence that congenital stationary night blindness type 2 missense mutations can induce severe changes in Ca(v)1.4 function. (PMID:15634789)
• In a pool of eight diagnosed XLCSNB (X-linked congenital stationary night blindness) patients, five showed a sequence variation in the CACNA1F and two in the NYX gene. (PMID:15761389)
• Molecular analyses, reported separately, identified a novel I745T CACNA1F mutation that was associated in vitro with major alterations in gating and kinetics of the Ca(v)1.4 channel. (PMID:15807819)
• A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation. (PMID:15897456)
• Cav1.4 encodes a calcium channel with low open probability and unitary conductance (PMID:16085774)
• The clinical phenotype of R508Q and L1364H night blindness mutations is unlikely to be explained by changes in channel gating. Instead, these mutations affect the protein expression of Ca(v)1.4 Ca(2+) channels. (PMID:16476079)
• X linked cone-rod dystrophy (CORDX3), is caused by a mutation in CACNA1F. (PMID:16505158)
• The present study clearly indicates that AIED (Aland Island eye disease) is also caused by a novel CACNA1F gene mutation. (PMID:17525176)
• Testing confirms the diagnosis at the molecular level and allows for a more precise prognosis of the possible future clinical evolution (PMID:17651254)
• These findings suggest that the pathology of CSNB-2 in patients with these missense mutations in the Ca(v)1.4 calcium channel is the result in either a gain of function (F742C) or a loss of function (G1007R, R1049W). (PMID:17949918)
• Temperature dependence of Cav1.4 calcium channel gating. (PMID:18206315)
• Congenital stationary night blindness (CSNB2) patients had significantly thinner retinas than myopic controls; and demonstrated qualitatively normal SD OCT and FAF images, and therefore can be differentiated from retinitis pigmentosa patients. (PMID:21920492)
• A novel p.Gly603Arg mutation in CACNA1F causes Aland island eye disease and incomplete congenital stationary night blindness phenotypes in a Canadian family. (PMID:22194652)
• The results expand the mutation spectrum of NYX, CACNA1F and GRM6. They also suggest that NYX mutations are a common cause of congenital stationary night blindness (CSNB). (PMID:22735794)
• This is the first case report describing outer retinal structural anomaly consistent with abnormal bipolar cell synapses in CACNA1F-related disease. (PMID:22744390)
• Complex regulation of voltage-dependent activation and inactivation properties of retinal voltage-gated Cav1.4 L-type Ca2+ channels by Ca2+-binding protein 4 (CaBP4). (PMID:22936811)
• Mutations in Ca(v)1.4 alpha1 are associated with X-linked retinal disorders. (PMID:23219801)
• In 55 male patients with Congenital Stationary Night Blindness 2, we identified 26 pathogenic sequence changes in the CACNA1F gene. Seventeen of these were novel, 14 of these mutations were nonsense or frameshift mutations, and 3 were missense mutations. (PMID:23714322)
• Our data independently confirm CACNA1F as the causative gene for CORDX3-like phenotypes and detailed clinical characterization of the family expands the knowledge about the phenotypic spectrum of deleterious CACNA1F alterations. (PMID:24124559)
• Data on Cav1.4 deficient mice and human female carriers of mutations in CACNA1F are consistent with a phenotype of mosaic congenital stationary night blindness type 2A. (PMID:24163243)
• Mutation in Cav1.4 gene is associated with congenital stationary night blindness type 2. (PMID:24796500)
• analysis of Cav1.4 complexes alpha11.4, beta2, and alpha2delta4 in HEK293T cells and in mouse retina (PMID:25468907)
• Studies indicate a role for L-type calcium channel Cav1.3 and Cav1.4 in cochlear inner hair cells (IHCs) and retinal photoreceptors (PRs). (PMID:25966695)
• novel heterozygous missense mutation (c.1555C>T, p.R519W) in CACNA1F gene, which is probably associated with XLRP. (PMID:26075273)
• a single nucleotide change c.1555C>T in exon 13 of the CACNA1F gene, leading to the substitution of arginine by tryptophan (p.R519W) in a Chinese individual affected by retinitis pigmentosa, is identified. (PMID:26436388)
• exon 47 encodes structural determinants that regulate CDI and voltage-dependent activation of Cav1.4, and is necessary for modulation of channel activation by CaBP4. (PMID:27226626)
• CaV1.4 channels are indeed modulated by PKA phosphorylation within the inhibitor of Ca(2+)-dependent inactivation (ICDI) motif. (PMID:27456671)
• AED, iCSNB, and X-linked cone-rod dystrophy 3 are designations that refer to a broad, continuous spectrum of clinical appearances caused in the majority by a variety of mutations in CACNA1F. (PMID:28002560)
• These two cases demonstrate the clinical overlap between Leber congenital amaurosis and type 2 congenital stationary night blindness in infants and young children. Genetic testing is an essential tool in these cases and provides a more accurate diagnosis and prognosis for patients with inherited retinal degenerative disorders. (PMID:29062221)
• We show that genetic testing may help to differentiate between optic atrophy, Leber’s congenital amaurosis , and CACNA1F-associated retinopathy at a much earlier age, in absence of electrophysiological examination and by widely overlapping phenotypes. (PMID:30260717)
• In Cav1.4Deltaex47, Ca(2+)-dependent inactivation (CDI) requires both the N-terminal and C-terminal (C lobe) lobes of CaM to bind Ca(2+), whereas CDI in K1591X is driven mainly by Ca(2+) binding to the C lobe. (PMID:30355583)
• Data revealed the presence of intronic and synonymous disease-causing variants leading to miss-splicing of CACNA1F-mediated inherited retinal disorders. (PMID:30825406)
• An Ashkenazi Jewish founder mutation in CACNA1F gene is associated with congenital stationary night blindness. (PMID:31651202)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cacna1fb	ENSDARG00000023683
mus_musculus	Cacna1f	ENSMUSG00000031142
rattus_norvegicus	Cacna1f	ENSRNOG00000010348

Paralogs (26): CACNA1G (ENSG00000006283), SCN4A (ENSG00000007314), CACNA1S (ENSG00000081248), CACNA1I (ENSG00000100346), 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 L-type calcium channel subunit alpha-1F — O60840 (reviewed: O60840)

Alternative names: Voltage-gated calcium channel subunit alpha Cav1.4

All UniProt accessions (2): O60840, H7C549

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-1F gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the ‘high-voltage activated’ (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, and by benzothiazepines. Activates at more negative voltages and does not undergo calcium-dependent inactivation (CDI), due to incoming calcium ions, during depolarization. Voltage-dependent L-type calcium channel activates at more hyperpolarized voltages and exhibits a robust calcium-dependent inactivation (CDI), due to incoming calcium ions, during depolarizations. 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. Voltage-dependent L-type calcium channel activates at more hyperpolarized voltages and exhibits a robust calcium-dependent inactivation (CDI), due to incoming calcium ions, during depolarizations.

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 IQ domain) with CABP4; in a calcium independent manner. Interacts with CABP4; suppresses robust calcium-dependent inactivation of channel without enhancing the hyperpolarized voltage-dependent activation.

Subcellular location. Membrane.

Tissue specificity. Expression in skeletal muscle and retina. Isoform 4 is expressed in retina.

Disease relevance. Night blindness, congenital stationary, 2A (CSNB2A) [MIM:300071] A non-progressive retinal disorder characterized by impaired night vision, often associated with nystagmus and myopia. The disease is caused by variants affecting the gene represented in this entry. Cone-rod dystrophy, X-linked 3 (CORDX3) [MIM:300476] An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. The disease is caused by variants affecting the gene represented in this entry. Aaland island eye disease (AIED) [MIM:300600] A retinal disease characterized by a combination of fundus hypopigmentation, decreased visual acuity due to foveal hypoplasia, nystagmus, astigmatism, protan color vision defect, myopia, and defective dark adaptation. Except for progression of axial myopia, the disease can be considered to be a stationary condition. Electroretinography reveals abnormalities in both photopic and scotopic functions. 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. CACNA1F subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
O60840-1	1, Cav1.4FL	yes
O60840-2	2
O60840-4	3
O60840-5	4, Cav1.4Deltaex p45,47
O60840-6	5, Cav1.4Deltaex p45
O60840-7	6, Cav1.4Deltaex 47

RefSeq proteins (3): NP_001243718, NP_001243719, NP_005174 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002077	VDCCAlpha1	Family
IPR005446	VDCC_L_a1su	Family
IPR005821	Ion_trans_dom	Domain
IPR014873	VDCC_a1su_IQ	Domain
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR031649	GPHH_dom	Domain
IPR031688	CAC1F_C	Domain
IPR050599	VDCC_alpha-1_subunit	Family

Pfam: PF00520, PF08763, PF16885, PF16905

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (109 total): topological domain 25, sequence variant 25, transmembrane region 24, region of interest 10, compositionally biased region 10, repeat 4, splice variant 4, binding site 3, sequence conflict 2, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60840-F1	67.46	0.14

Functional residue map

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

Ligand- & substrate-binding residues (3): 330; 711; 1086

Glycosylation sites (1): 295

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 186 (showing top): GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_REGULATION_OF_VOLTAGE_GATED_CALCIUM_CHANNEL_ACTIVITY, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GATA3_01, GOBP_REGULATION_OF_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_CALCIUM_ION_IMPORT, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_RESPONSE_TO_RADIATION, GOBP_DETECTION_OF_LIGHT_STIMULUS, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, AACTTT_UNKNOWN

GO Biological Process (9): visual perception (GO:0007601), detection of light stimulus involved in visual perception (GO:0050908), calcium ion import across plasma membrane (GO:0098703), negative regulation of voltage-gated calcium channel activity (GO:1901386), 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 (6): voltage-gated calcium channel activity (GO:0005245), high voltage-gated calcium channel activity (GO:0008331), metal ion binding (GO:0046872), monoatomic ion channel activity (GO:0005216), calcium channel activity (GO:0005262), protein binding (GO:0005515)

GO Cellular Component (6): photoreceptor outer segment (GO:0001750), voltage-gated calcium channel complex (GO:0005891), membrane (GO:0016020), perikaryon (GO:0043204), monoatomic ion channel complex (GO:0034702), neuronal cell body (GO:0043025)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
voltage-gated calcium channel activity	2
transport	2
sensory perception of light stimulus	1
visual perception	1
detection of light stimulus involved in sensory perception	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
negative regulation of calcium ion transmembrane transporter activity	1
regulation of voltage-gated calcium channel activity	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
calcium channel activity	1
voltage-gated monoatomic cation channel activity	1
cation binding	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
binding	1
photoreceptor cell cilium	1
calcium channel complex	1
plasma membrane protein complex	1
neuronal cell body	1
transmembrane transporter complex	1
somatodendritic compartment	1
cell body	1

Protein interactions and networks

STRING

1610 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CACNA1F	CABP4	P57796	968
CACNA1F	NYX	Q9GZU5	962
CACNA1F	CACNA1S	Q13698	883
CACNA1F	CACNB2	Q08289	848
CACNA1F	RPGR	Q92834	843
CACNA1F	CALM1	P02593	836
CACNA1F	CTBP2	P56545	815
CACNA1F	CACNA1D	Q01668	812
CACNA1F	CACNA2D1	P54289	793
CACNA1F	CACNA1C	Q13936	788
CACNA1F	LRIT3	Q3SXY7	772
CACNA1F	CACNA2D4	Q7Z3S7	746
CACNA1F	A0A590UK56	A0A590UK56	733
CACNA1F	GRM6	O15303	732
CACNA1F	S100G	P29377	699

IntAct

3 interactions, top by confidence:

A	B	Type	Score
CACNA1F	FYN	psi-mi:“MI:0915”(physical association)	0.400
mntH	CACNA1F	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (3): CACNA1F (Reconstituted Complex), CACNA1F (Affinity Capture-MS), CACNA1F (Cross-Linking-MS (XL-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: C9D7C2, O00555, O35505, O42398, O46669, O55017, O57483, O60840, O73700, O73705, O73706, O73707, P07293, P15381, P22002, P22316, P27732, P27884, P35500, P54282, P56698, P56699, P91645, P97445, Q00975, Q01668, Q01815, Q02294, Q02343, Q02485, Q02789, Q05152, Q07652, Q13698, Q13936, Q15878, Q24270, Q25452, Q61290, Q99244

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1532 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	109
Likely pathogenic	69
Uncertain significance	746
Likely benign	458
Benign	60

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012869	NM_001256789.3(CACNA1F):c.396C>G (p.Tyr132Ter)	Pathogenic
1031513	NM_001256789.3(CACNA1F):c.4260+2del	Pathogenic
1074782	NM_001256789.3(CACNA1F):c.2533C>T (p.Gln845Ter)	Pathogenic
11614	NM_001256789.3(CACNA1F):c.1106G>A (p.Gly369Asp)	Pathogenic
11615	NM_001256789.3(CACNA1F):c.2872C>T (p.Arg958Ter)	Pathogenic
11617	NM_001256789.3(CACNA1F):c.2650C>T (p.Arg884Ter)	Pathogenic
11618	NM_001256789.3(CACNA1F):c.4548del (p.Phe1517fs)	Pathogenic
11619	NM_001256789.3(CACNA1F):c.2234T>C (p.Ile745Thr)	Pathogenic
11620	NM_001256789.3(CACNA1F):c.3439-1_3442delinsTGG	Pathogenic
11621	NM_001256789.3(CACNA1F):c.3598-133_3709-76del	Pathogenic
1184528	NM_001256789.3(CACNA1F):c.1877+1G>T	Pathogenic
1213965	NM_001256789.3(CACNA1F):c.1014G>A (p.Trp338Ter)	Pathogenic
1275766	NM_001256789.3(CACNA1F):c.2928+1G>A	Pathogenic
1371623	NM_001256789.3(CACNA1F):c.823del (p.Glu275fs)	Pathogenic
1394042	NM_001256789.3(CACNA1F):c.1407_1408del (p.Glu469fs)	Pathogenic
1395808	NM_001256789.3(CACNA1F):c.1678_1681del (p.Leu560fs)	Pathogenic
1419493	NM_001256789.3(CACNA1F):c.5187del (p.Gln1732fs)	Pathogenic
1422805	NM_001256789.3(CACNA1F):c.3225del (p.Gly1076fs)	Pathogenic
1453333	NM_001256789.3(CACNA1F):c.4800del (p.Ser1601fs)	Pathogenic
1454620	NM_001256789.3(CACNA1F):c.4260+1G>A	Pathogenic
1454940	NM_001256789.3(CACNA1F):c.2616dup (p.Ser873fs)	Pathogenic
1455476	NM_001256789.3(CACNA1F):c.584dup (p.Pro197fs)	Pathogenic
1457082	NM_001256789.3(CACNA1F):c.4486A>T (p.Arg1496Ter)	Pathogenic
1458775	NM_001256789.3(CACNA1F):c.2416G>T (p.Glu806Ter)	Pathogenic
1691797	NM_005183.4(CACNA1F):c.2932C>T (p.Arg978Ter)	Pathogenic
1699126	NM_001256789.3(CACNA1F):c.2504del (p.Pro835fs)	Pathogenic
1699338	NM_001256789.3(CACNA1F):c.1855del (p.Leu619fs)	Pathogenic
1929598	NM_001256789.3(CACNA1F):c.3048C>A (p.Tyr1016Ter)	Pathogenic
195237	NM_001256789.3(CACNA1F):c.244C>T (p.Arg82Ter)	Pathogenic
2007156	NM_001256789.3(CACNA1F):c.4657A>T (p.Lys1553Ter)	Pathogenic

SpliceAI

7005 predictions. Top by Δscore:

Variant	Effect	Δscore
X:49205366:ACC:A	acceptor_loss	1.0000
X:49206981:T:TA	donor_gain	1.0000
X:49206982:C:A	donor_gain	1.0000
X:49207017:T:TA	donor_gain	1.0000
X:49207018:C:A	donor_gain	1.0000
X:49207022:AT:A	donor_gain	1.0000
X:49207023:T:TA	donor_gain	1.0000
X:49209234:T:TA	donor_gain	1.0000
X:49209260:A:AC	donor_gain	1.0000
X:49209261:C:CC	donor_gain	1.0000
X:49209276:AGT:A	donor_gain	1.0000
X:49209278:T:TA	donor_gain	1.0000
X:49209290:T:TA	donor_gain	1.0000
X:49209293:T:TA	donor_gain	1.0000
X:49209302:C:CA	donor_gain	1.0000
X:49209305:T:TA	donor_gain	1.0000
X:49209320:T:TA	donor_gain	1.0000
X:49209326:T:TA	donor_gain	1.0000
X:49209389:CCAGC:C	acceptor_gain	1.0000
X:49209390:CAGCC:C	acceptor_gain	1.0000
X:49209669:AGTAG:A	donor_gain	1.0000
X:49209672:AGC:A	donor_gain	1.0000
X:49209685:T:A	donor_gain	1.0000
X:49209755:CTCCT:C	acceptor_gain	1.0000
X:49209760:C:CC	acceptor_gain	1.0000
X:49209935:GCTCA:G	donor_loss	1.0000
X:49209936:CTCAC:C	donor_loss	1.0000
X:49209938:CACC:C	donor_loss	1.0000
X:49209939:A:AC	donor_gain	1.0000
X:49209940:C:CA	donor_loss	1.0000

AlphaMissense

12923 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:49210990:A:G	W1466R	1.000
X:49210990:A:T	W1466R	1.000
X:49211054:A:C	F1444L	1.000
X:49211054:A:T	F1444L	1.000
X:49211056:A:G	F1444L	1.000
X:49211082:A:G	L1435P	1.000
X:49211084:A:C	N1434K	1.000
X:49211084:A:T	N1434K	1.000
X:49211323:A:G	L1431P	1.000
X:49211346:G:C	S1423R	1.000
X:49211346:G:T	S1423R	1.000
X:49211348:T:G	S1423R	1.000
X:49211460:C:A	W1385C	1.000
X:49211460:C:G	W1385C	1.000
X:49211462:A:G	W1385R	1.000
X:49211462:A:T	W1385R	1.000
X:49213849:G:C	S1265R	1.000
X:49213849:G:T	S1265R	1.000
X:49213851:T:G	S1265R	1.000
X:49215393:G:C	F1140L	1.000
X:49215393:G:T	F1140L	1.000
X:49215395:A:G	F1140L	1.000
X:49215423:G:C	N1130K	1.000
X:49215423:G:T	N1130K	1.000
X:49216387:C:A	W1088C	1.000
X:49216387:C:G	W1088C	1.000
X:49216389:A:G	W1088R	1.000
X:49216389:A:T	W1088R	1.000
X:49218486:A:T	L977H	1.000
X:49218489:G:C	P976R	1.000

dbSNP variants (sampled 300 via entrez): RS1000464385 (X:49218368 C>A,T), RS1001021882 (X:49228575 C>A), RS1001349078 (X:49211704 G>A), RS1001413951 (X:49209754 C>T), RS1002167952 (X:49220635 G>A,T), RS1002467326 (X:49223256 G>A), RS1002498263 (X:49222815 G>A), RS1002726229 (X:49230023 A>G), RS1002911777 (X:49204635 T>A), RS1003070192 (X:49213430 T>C), RS1003136880 (X:49231797 G>A), RS1003302887 (X:49205881 C>T), RS1003429059 (X:49213985 G>A), RS1004141826 (X:49225719 G>A,C,T), RS1004727260 (X:49234382 C>A)

Disease associations

OMIM: gene MIM:300110 | disease phenotypes: MIM:300894, MIM:300896, MIM:300071, MIM:300600, MIM:300476, MIM:310500, MIM:268000, MIM:120970, MIM:160700

GenCC curated gene-disease

Disease	Classification	Inheritance
Aland island eye disease	Definitive	X-linked
congenital stationary night blindness 2A	Strong	X-linked
X-linked cone-rod dystrophy 3	Strong	X-linked
cone-rod dystrophy	Supportive	Autosomal dominant
congenital stationary night blindness	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
CACNA1F-related retinopathy	Definitive	XL

Mondo (14): inherited retinal dystrophy (MONDO:0019118), neurodegeneration with brain iron accumulation 5 (MONDO:0010476), SLC35A2-congenital disorder of glycosylation (MONDO:0010478), congenital stationary night blindness 2A (MONDO:0010241), Aland island eye disease (MONDO:0010371), X-linked cone-rod dystrophy 3 (MONDO:0010335), congenital stationary night blindness (MONDO:0016293), retinitis pigmentosa (MONDO:0019200), retinal disorder (MONDO:0005283), cone-rod dystrophy (MONDO:0015993), optic atrophy (MONDO:0003608), amblyopia (MONDO:0001020), myopia (MONDO:0001384), CACNA1F-related retinopathy (MONDO:0700243)

Orphanet (7): OBSOLETE: Inherited retinal disorder (Orphanet:71862), Beta-propeller protein-associated neurodegeneration (Orphanet:329284), SLC35A2-CDG (Orphanet:356961), Congenital stationary night blindness (Orphanet:215), Åland Islands eye disease (Orphanet:178333), Cone rod dystrophy (Orphanet:1872), Retinitis pigmentosa (Orphanet:791)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000483	Astigmatism
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000529	Progressive visual loss
HP:0000541	Retinal detachment
HP:0000543	Optic disc pallor
HP:0000545	Myopia
HP:0000548	Cone/cone-rod dystrophy
HP:0000551	Color vision defect
HP:0000577	Exotropia
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000662	Nyctalopia
HP:0001105	Retinal atrophy
HP:0001141	Severely reduced visual acuity
HP:0001417	X-linked inheritance
HP:0001419	X-linked recessive inheritance
HP:0005592	Giant melanosomes in melanocytes
HP:0007641	Dyschromatopsia
HP:0007642	Early-onset non-progressive night blindness
HP:0007663	Reduced visual acuity
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007750	Hypoplasia of the fovea
HP:0007843	Attenuation of retinal blood vessels
HP:0007894	Fundus hypopigmentation
HP:0007984	ERG: Reduced dark-adapted b-wave amplitude
HP:0008002	Abnormal macular pigmentation
HP:0008323	Abnormal light- and dark-adapted electroretinogram

GWAS associations

0 associations (top):

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D000550	Amblyopia	C10.228.140.055; C10.597.751.941.073; C11.966.073; C23.888.592.763.941.073
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D009216	Myopia	C11.744.636
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C562664	Aland Island Eye Disease (supp.)
C564507	Cone-Rod Dystrophy, X-Linked, 3 (supp.)
C536122	Night blindness, congenital stationary (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2095229 (PROTEIN FAMILY), CHEMBL2363032 (PROTEIN COMPLEX GROUP)

Molecules with ChEMBL bioactivity

48 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 646,199 (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
CHEMBL1008	BEPRIDIL	4	11,776
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL1107	HALOFANTRINE	4	9,722
CHEMBL1108	DROPERIDOL	4	16,888
CHEMBL114	SAQUINAVIR	4	39,899
CHEMBL1175	DULOXETINE	4	28,527
CHEMBL12	DIAZEPAM	4	92,281
CHEMBL12713	SERTINDOLE	4	8,984
CHEMBL1294	QUINIDINE	4	71,943
CHEMBL141	LAMIVUDINE	4	12,250
CHEMBL1423	PIMOZIDE	4	17,310
CHEMBL16	PHENYTOIN	4	53,375
CHEMBL17157	TERFENADINE	4	25,393
CHEMBL1729	CISAPRIDE	4	14,365
CHEMBL1734	SOLIFENACIN	4	296
CHEMBL193	NIFEDIPINE	4	74,353
CHEMBL23	DILTIAZEM	4	54,676
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL296419	ASTEMIZOLE	4	21,577
CHEMBL363295	TERODILINE	4	5,064
CHEMBL42	CLOZAPINE	4
CHEMBL45816	MIBEFRADIL	4
CHEMBL473	DOFETILIDE	4
CHEMBL479	THIORIDAZINE	4
CHEMBL490	PAROXETINE	4
CHEMBL502	DONEPEZIL	4
CHEMBL533	IBUTILIDE	4
CHEMBL535	SUNITINIB	4
CHEMBL54	HALOPERIDOL	4
CHEMBL5416410	DASATINIB	4

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

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 (6 total), top 6:

Ligand	Action	Affinity	Parameter
(-)-(S)-BayK8644	Activator	7.76	pEC50
nitrendipine	Antagonist	6.0	pIC50
nifedipine	Antagonist	6.0	pIC50
nimodipine	Antagonist	6.0	pIC50
L-(cis)-diltiazem	Gating inhibitor	4.1	pIC50
diltiazem	Channel blocker	4.0	pIC50

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL514508	IC50	11000 nM

ChEMBL bioactivities

196 potent at pChembl≥5 of 244 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL286157
10.89	IC50	0.013	nM	CHEMBL317044
10.82	IC50	0.015	nM	CHEMBL441428
10.77	IC50	0.017	nM	CHEMBL286598
10.66	IC50	0.022	nM	CHEMBL37402
10.57	IC50	0.027	nM	CHEMBL103806
10.52	IC50	0.03	nM	CHEMBL37899
10.48	IC50	0.033	nM	CHEMBL204616
10.35	IC50	0.045	nM	CHEMBL35368
10.34	IC50	0.046	nM	CHEMBL1099207
10.30	IC50	0.05	nM	CHEMBL285868
9.85	IC50	0.14	nM	CHEMBL321999
9.82	IC50	0.15	nM	NITRENDIPINE
9.60	IC50	0.25	nM	CHEMBL105444
9.46	IC50	0.35	nM	NITRENDIPINE
9.41	IC50	0.39	nM	CHEMBL35123
9.00	IC50	1	nM	NITRENDIPINE
8.82	IC50	1.5	nM	CHEMBL329897
8.82	IC50	1.5	nM	CHEMBL3891844
8.82	IC50	1.5	nM	CHEMBL319033
8.77	IC50	1.7	nM	CHEMBL89260
8.72	IC50	1.9	nM	CHEMBL3890624
8.70	IC50	2	nM	CHEMBL2092901
8.64	IC50	2.3	nM	CHEMBL102498
8.62	IC50	2.4	nM	CHEMBL3973392
8.59	IC50	2.6	nM	CHEMBL89049
8.57	IC50	2.7	nM	CHEMBL84906
8.57	IC50	2.7	nM	CHEMBL3891844
8.55	IC50	2.8	nM	CHEMBL318521
8.52	IC50	3	nM	CHEMBL3919024
8.51	IC50	3.1	nM	CHEMBL86415
8.51	IC50	3.1	nM	CHEMBL3919898
8.44	IC50	3.6	nM	CHEMBL89904
8.40	IC50	4	nM	CHEMBL3392282
8.35	IC50	4.5	nM	CHEMBL3965812
8.28	IC50	5.2	nM	CHEMBL89175
8.27	Ki	5.4	nM	GALLOPAMIL
8.23	IC50	5.9	nM	CHEMBL3906126
8.22	IC50	6	nM	CHEMBL3890916
8.15	IC50	7	nM	CHEMBL3940577
8.14	IC50	7.2	nM	CHEMBL3969562
8.12	IC50	7.6	nM	CHEMBL3937280
8.12	IC50	7.6	nM	CHEMBL3965812
8.10	IC50	8	nM	CHEMBL3983323
8.05	IC50	9	nM	CHEMBL3942512
8.03	IC50	9.4	nM	CHEMBL3922498
8.01	IC50	9.7	nM	CHEMBL3897303
8.00	IC50	10	nM	NIFEDIPINE
7.96	IC50	11	nM	CHEMBL315125
7.96	IC50	11	nM	GALLOPAMIL

PubChem BioAssay actives

144 with measured affinity, of 800 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
3-O-methyl 5-O-(2-methylpropyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45613: Inhibition of [3H]nitrendipine binding to guinea pig ileal longitudinal smooth muscle	ic50	<0.0001	uM
5-O-[6-[5-ethoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carbonyl]oxyhexyl] 3-O-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45611: Inhibition of [3H]nitrendipine binding to L-type calcium channel of guinea pig ileal longitudinal smooth muscle	ic50	<0.0001	uM
5-O-[10-[5-ethoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carbonyl]oxydecyl] 3-O-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45611: Inhibition of [3H]nitrendipine binding to L-type calcium channel of guinea pig ileal longitudinal smooth muscle	ic50	<0.0001	uM
5-O-[8-[5-ethoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carbonyl]oxyoctyl] 3-O-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45611: Inhibition of [3H]nitrendipine binding to L-type calcium channel of guinea pig ileal longitudinal smooth muscle	ic50	<0.0001	uM
3-O-ethyl 5-O-octyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45611: Inhibition of [3H]nitrendipine binding to L-type calcium channel of guinea pig ileal longitudinal smooth muscle	ic50	<0.0001	uM
diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45611: Inhibition of [3H]nitrendipine binding to L-type calcium channel of guinea pig ileal longitudinal smooth muscle	ic50	<0.0001	uM
5-O-[2-[2,6-dimethyl-4-(3-nitrophenyl)-5-propan-2-yloxycarbonyl-1,4-dihydropyridine-3-carbonyl]oxyethyl] 3-O-ethyl 2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45611: Inhibition of [3H]nitrendipine binding to L-type calcium channel of guinea pig ileal longitudinal smooth muscle	ic50	<0.0001	uM
5-O-[4-[5-ethoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carbonyl]oxybutyl] 3-O-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45611: Inhibition of [3H]nitrendipine binding to L-type calcium channel of guinea pig ileal longitudinal smooth muscle	ic50	<0.0001	uM
3-O-methyl 5-O-(2-methylpropyl) 4-(3-cyanophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate	45613: Inhibition of [3H]nitrendipine binding to guinea pig ileal longitudinal smooth muscle	ic50	<0.0001	uM
3-O-methyl 5-O-(2-methylpropyl) 2,6-dimethyl-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3,5-dicarboxylate	45613: Inhibition of [3H]nitrendipine binding to guinea pig ileal longitudinal smooth muscle	ic50	<0.0001	uM
Nisoldipine	45613: Inhibition of [3H]nitrendipine binding to guinea pig ileal longitudinal smooth muscle	ic50	<0.0001	uM
5-O-[12-[5-ethoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carbonyl]oxydodecyl] 3-O-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45611: Inhibition of [3H]nitrendipine binding to L-type calcium channel of guinea pig ileal longitudinal smooth muscle	ic50	0.0001	uM
3-O-methyl 5-O-(2-methylpropyl) 2,6-dimethyl-4-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3,5-dicarboxylate	45613: Inhibition of [3H]nitrendipine binding to guinea pig ileal longitudinal smooth muscle	ic50	0.0001	uM
5-O-ethyl 3-O-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45611: Inhibition of [3H]nitrendipine binding to L-type calcium channel of guinea pig ileal longitudinal smooth muscle	ic50	0.0001	uM
3-O-methyl 5-O-(2-methylpropyl) 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate	45613: Inhibition of [3H]nitrendipine binding to guinea pig ileal longitudinal smooth muscle	ic50	0.0003	uM
5-O-[2-[5-ethoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carbonyl]oxyethyl] 3-O-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45611: Inhibition of [3H]nitrendipine binding to L-type calcium channel of guinea pig ileal longitudinal smooth muscle	ic50	0.0004	uM
diethyl 4-(2,3-dichlorophenyl)-6-methyl-2-sulfanylidene-1,4-dihydropyrimidine-3,5-dicarboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0015	uM
3-O-methyl 5-O-(2-methylpropyl) 4-(4-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate	45613: Inhibition of [3H]nitrendipine binding to guinea pig ileal longitudinal smooth muscle	ic50	0.0015	uM
3-O-ethyl 5-O-propan-2-yl 6-methyl-4-(3-nitrophenyl)-2-sulfanylidene-1,4-dihydropyrimidine-3,5-dicarboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0017	uM
3-O-ethyl 5-O-propan-2-yl (4R)-6-methyl-4-(3-nitrophenyl)-2-sulfanylidene-1,4-dihydropyrimidine-3,5-dicarboxylate	45769: In vitro vasorelaxant activity (calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0020	uM
3-O-methyl 5-O-(2-methylpropyl) 4-(3-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate	45613: Inhibition of [3H]nitrendipine binding to guinea pig ileal longitudinal smooth muscle	ic50	0.0023	uM
3-O-ethyl 5-O-propan-2-yl 6-methyl-4-(3-nitrophenyl)-2-oxo-1,4-dihydropyrimidine-3,5-dicarboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0026	uM
diethyl 4-(2-chloro-3-nitrophenyl)-6-methyl-2-sulfanylidene-1,4-dihydropyrimidine-3,5-dicarboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0027	uM
3-O-methyl 5-O-(2-methylpropyl) 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate	45613: Inhibition of [3H]nitrendipine binding to guinea pig ileal longitudinal smooth muscle	ic50	0.0028	uM
diethyl 6-methyl-4-(2-nitrophenyl)-2-sulfanylidene-1,4-dihydropyrimidine-3,5-dicarboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0031	uM
5-O-ethyl 3-O-methyl 6-methyl-4-(3-nitrophenyl)-2-sulfanylidene-1,4-dihydropyrimidine-3,5-dicarboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0036	uM
diethyl 2-ethylsulfanyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45769: In vitro vasorelaxant activity (calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0040	uM
ethyl 3-(benzenesulfonyl)-6-methyl-4-(3-nitrophenyl)-2-sulfanylidene-1,4-dihydropyrimidine-5-carboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0052	uM
5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-yl-2-(3,4,5-trimethoxyphenyl)pentanenitrile	751841: Binding affinity to L-Ca2+ channel verapamil site (unknown origin) by radioligand displacement assay	ki	0.0054	uM
Nifedipine	1207754: Inhibition of Cav1.2 current measured using QPatch automatic path clamp system in CHO cells expressing Cav1.2, beta-2 and alpha-2/delta-1 subunits	ic50	0.0100	uM
ethyl 3-(4-methoxybenzoyl)-6-methyl-4-(3-nitrophenyl)-2-sulfanylidene-1,4-dihydropyrimidine-5-carboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0110	uM
5-O-ethyl 3-O-propan-2-yl 6-methyl-4-(3-nitrophenyl)-2-sulfanylidene-1,4-dihydropyrimidine-3,5-dicarboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0140	uM
diethyl 6-methyl-4-(3-nitrophenyl)-2-sulfanylidene-1,4-dihydropyrimidine-3,5-dicarboxylate	45769: In vitro vasorelaxant activity (calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0170	uM
diethyl 4-(2-chlorophenyl)-6-methyl-2-sulfanylidene-1,4-dihydropyrimidine-3,5-dicarboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0170	uM
diethyl 2,6-dimethyl-4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate	45622: Inhibition of [3H]PN-200110 binding to Calcium channel in guinea pig ileum membrane	ki	0.0217	uM
diethyl 6-methyl-2-sulfanylidene-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyrimidine-3,5-dicarboxylate	45769: In vitro vasorelaxant activity (calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0260	uM
diethyl 2-ethoxy-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate	45769: In vitro vasorelaxant activity (calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0260	uM
diethyl 4-deuterio-4-(3,5-dimethyl-1,2-oxazol-4-yl)-2,6-dimethyl-1H-pyridine-3,5-dicarboxylate	45623: Inhibition of [3H]PN-200110 binding to Calcium channel in guinea pig ileum membrane.	ki	0.0299	uM
diethyl 4-(3,5-dimethyl-1,2-oxazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate	45622: Inhibition of [3H]PN-200110 binding to Calcium channel in guinea pig ileum membrane	ki	0.0328	uM
diethyl 4-[3-(4-bromophenyl)-5-methyl-1,2-oxazol-4-yl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate	1466481: Displacement of [3H]PN-200110 from voltage-dependent L-type calcium channel (unknown origin) by scintillation counting method	ic50	0.0360	uM
ethyl 6-methyl-4-(3-nitrophenyl)-3-propyl-2-sulfanylidene-1,4-dihydropyrimidine-5-carboxylate	45769: In vitro vasorelaxant activity (calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0500	uM
diethyl 4-(5-ethyl-3-methyl-1,2-oxazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate	45622: Inhibition of [3H]PN-200110 binding to Calcium channel in guinea pig ileum membrane	ki	0.0625	uM
diethyl 2,6-dimethyl-4-(5-pentyl-3-phenyl-1,2-oxazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate	45622: Inhibition of [3H]PN-200110 binding to Calcium channel in guinea pig ileum membrane	ki	0.0784	uM
diethyl 4-(3-chlorophenyl)-6-methyl-2-sulfanylidene-1,4-dihydropyrimidine-3,5-dicarboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.0880	uM
3-O-ethyl 5-O-methyl 6-methyl-4-(3-nitrophenyl)-2-sulfanylidene-1,4-dihydropyrimidine-3,5-dicarboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.1000	uM
3-O-ethyl 5-O-[[1-(2-phenylethyl)triazol-4-yl]methyl] 4-[3-(4-bromophenyl)-5-methyl-1,2-oxazol-4-yl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate	1466481: Displacement of [3H]PN-200110 from voltage-dependent L-type calcium channel (unknown origin) by scintillation counting method	ic50	0.1270	uM
(3R)-1,1-dibutyl-3-(5-phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydropyrido[3,4-b]indole	676783: Binding affinity to L-type calcium channel	ic50	0.1280	uM
ethyl 6-methyl-2-methylsulfanyl-4-(3-nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate	45769: In vitro vasorelaxant activity (calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.1300	uM
diethyl 6-methyl-4-(3-nitrophenyl)-2-oxo-1,4-dihydropyrimidine-3,5-dicarboxylate	217468: In vitro vasorelaxant activity (voltage-gated calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta	ic50	0.1400	uM
N-[4,6-dimethoxy-2-(3-morpholin-4-ylpropylamino)pyrimidin-5-yl]-5-[(3,3,6-trimethyl-1,2-dihydroinden-5-yl)oxy]furan-2-carboxamide	265813: Binding affinity to L type calcium channel	ki	0.1450	uM

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sotorasib	affects cotreatment, decreases expression	1
bisphenol A	increases methylation	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
ethyl-p-hydroxybenzoate	decreases expression	1
perfluorooctanoic acid	affects cotreatment, increases expression	1
perfluorooctane sulfonic acid	affects cotreatment, increases expression	1
perfluorohexanesulfonic acid	increases expression, affects cotreatment	1
trametinib	decreases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Menthol	increases expression	1
Valproic Acid	increases methylation	1
Vanadium	increases expression	1
Aflatoxin B1	increases methylation	1
Coal Ash	increases expression	1

ChEMBL screening assays

221 unique, capped per target: 135 binding, 79 functional, 5 toxicity, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003715	Functional	Antagonist activity at voltage-dependent L-type calcium channel in human SH-SY5Y cells assessed as inhibition of KCl-induced increase in cytosolic calcium concentration at 0.3 uM pretreated for 10 mins before KCl challenge relative to contr	Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer’s disease. — J Med Chem
CHEMBL1059038	Binding	Inhibition of human L-type calcium channel at 100 uM	Spirocyclic delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4’-piperidine]-4-yl) benzamide (ADL5747). — J Med Chem
CHEMBL4236597	ADMET	Inhibition of L-type calcium channel (unknown origin) by patch clamp assay	Discovery of TRPM8 Antagonist ( S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration