CACNA2D4

Summary

CACNA2D4 (calcium voltage-gated channel auxiliary subunit alpha2delta 4, HGNC:20202) is a protein-coding gene on chromosome 12p13.33, encoding Voltage-dependent calcium channel subunit alpha-2/delta-4 (Q7Z3S7). The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.

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

Source: NCBI Gene 93589 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CACNA2D4-related retinopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 1,444 total — 10 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_172364

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20202
Approved symbol	CACNA2D4
Name	calcium voltage-gated channel auxiliary subunit alpha2delta 4
Location	12p13.33
Locus type	gene with protein product
Status	Approved
Aliases	alpha2delta-4
Ensembl gene	ENSG00000151062
Ensembl biotype	protein_coding
OMIM	608171
Entrez	93589

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 11 retained_intron, 9 protein_coding, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000280663, ENST00000382722, ENST00000444595, ENST00000536818, ENST00000536846, ENST00000537784, ENST00000537923, ENST00000538027, ENST00000538450, ENST00000539048, ENST00000540728, ENST00000541331, ENST00000541444, ENST00000541616, ENST00000542340, ENST00000543405, ENST00000545595, ENST00000585385, ENST00000585708, ENST00000585732, ENST00000586184, ENST00000587995, ENST00000588077, ENST00000588896, ENST00000589502, ENST00000590880

RefSeq mRNA: 1 — MANE Select: NM_172364 NM_172364

CCDS: CCDS44785

Canonical transcript exons

ENST00000382722 — 38 exons

Exon	Start	End
ENSE00002314938	1918247	1918652
ENSE00002841109	1791963	1793759
ENSE00003465086	1860145	1860206
ENSE00003467256	1811662	1811723
ENSE00003472738	1884768	1884881
ENSE00003479055	1801043	1801118
ENSE00003484591	1909906	1909965
ENSE00003493720	1856184	1856229
ENSE00003500560	1882867	1883000
ENSE00003500718	1795668	1795780
ENSE00003510184	1795299	1795381
ENSE00003512105	1840739	1840819
ENSE00003534107	1878956	1879036
ENSE00003540556	1884243	1884321
ENSE00003551063	1886223	1886373
ENSE00003563943	1913023	1913139
ENSE00003578664	1885965	1886039
ENSE00003592980	1799675	1799695
ENSE00003615079	1853951	1854044
ENSE00003617397	1874604	1874675
ENSE00003621018	1801574	1801644
ENSE00003624187	1846594	1846689
ENSE00003629899	1884987	1885076
ENSE00003635816	1810543	1810587
ENSE00003637029	1914854	1914935
ENSE00003638222	1887009	1887069
ENSE00003649816	1878315	1878389
ENSE00003650380	1875251	1875337
ENSE00003666177	1844402	1844529
ENSE00003668021	1907875	1908037
ENSE00003669230	1858577	1858644
ENSE00003672113	1800386	1800438
ENSE00003672347	1907440	1907571
ENSE00003674794	1810278	1810340
ENSE00003678184	1797418	1797535
ENSE00003683542	1879804	1879881
ENSE00003693315	1800000	1800052
ENSE00003693641	1856012	1856109

Expression profiles

Bgee: expression breadth ubiquitous, 136 present calls, max score 90.16.

FANTOM5 (CAGE): breadth broad, TPM avg 3.9985 / max 425.5581, expressed in 496 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128943	2.5280	384
128949	0.8569	67
128945	0.1997	93
128944	0.1686	95
128950	0.1568	23
128948	0.0568	23
128942	0.0317	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	90.16	gold quality
leukocyte	CL:0000738	89.77	gold quality
granulocyte	CL:0000094	89.56	gold quality
blood	UBERON:0000178	86.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.27	gold quality
right testis	UBERON:0004534	81.81	gold quality
vermiform appendix	UBERON:0001154	81.65	gold quality
left testis	UBERON:0004533	81.13	gold quality
testis	UBERON:0000473	80.68	gold quality
tibial nerve	UBERON:0001323	80.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.66	gold quality
subcutaneous adipose tissue	UBERON:0002190	78.93	gold quality
spleen	UBERON:0002106	78.68	gold quality
small intestine Peyer’s patch	UBERON:0003454	78.19	gold quality
duodenum	UBERON:0002114	78.09	gold quality
adipose tissue	UBERON:0001013	78.07	gold quality
small intestine	UBERON:0002108	77.11	gold quality
omental fat pad	UBERON:0010414	77.10	gold quality
right coronary artery	UBERON:0001625	77.09	gold quality
mucosa of transverse colon	UBERON:0004991	77.06	gold quality
transverse colon	UBERON:0001157	76.33	gold quality
left coronary artery	UBERON:0001626	75.96	gold quality
descending thoracic aorta	UBERON:0002345	75.64	gold quality
lymph node	UBERON:0000029	75.45	gold quality
sural nerve	UBERON:0015488	75.33	gold quality
bone element	UBERON:0001474	74.89	gold quality
placenta	UBERON:0001987	74.89	gold quality
bone marrow	UBERON:0002371	74.89	gold quality
gall bladder	UBERON:0002110	74.78	gold quality
upper lobe of left lung	UBERON:0008952	74.36	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.23

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

74 targeting CACNA2D4, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4534	99.99	66.58	1907
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-3119	99.92	71.34	2390
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-532-3P	99.34	65.76	1195

Literature-anchored findings (GeneRIF, showing 5)

• Calcium channel alpha(2)delta-4 subunit has limited distribution in special cell types of the pituitary, adrenal gland, colon, and fetal liver. (PMID:12181424)
• A rare, partial deletion of 35.7 kb in CACNA2D4 in two unrelated late onset bipolar I patients and in one control individual, were identified. (PMID:22488967)
• This report describes a distinctive ERG phenotype, predominantly involving the cone pathways, in 2 unrelated patients from different ethnic backgrounds with homozygous mutations in CACNA2D4 and normal retinal imaging (PMID:26560832)
• We have confirmed the TRPM1 36,445 bp deletion is a founder mutation in the Ashkenazi-Jewish (AJ) population with a carrier rate of 1 in 50. We have also confirmed the 35,741 bp deletion in the CACNA2D4 gene is a founder mutation in the AJ population with a carrier rate of 1 in 56. (PMID:28726569)
• We find that increasing the expression of Cav at the synaptic membrane is an evolutionarily conserved function of Cacna2d4b. Yet, since both paralogs participate in cone synaptic transmission, we propose partial subfunctionalization in zebrafish. Similar to human patients, our double KO zebrafish model shows mild cone dysfunction, which was not associated with signs of retinal degeneration. (PMID:31834350)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cacna2d4b	ENSDARG00000023886
danio_rerio	CACNA2D4	ENSDARG00000026855
danio_rerio	cacna2d4a	ENSDARG00000103810
mus_musculus	Cacna2d4	ENSMUSG00000041460
rattus_norvegicus	Cacna2d4	ENSRNOG00000008031
drosophila_melanogaster	stj	FBGN0261041
caenorhabditis_elegans		WBGENE00006772

Paralogs (4): CACNA2D2 (ENSG00000007402), CACNA2D1 (ENSG00000153956), CACNA2D3 (ENSG00000157445), CACHD1 (ENSG00000158966)

Protein

Protein identifiers

Voltage-dependent calcium channel subunit alpha-2/delta-4 — Q7Z3S7 (reviewed: Q7Z3S7)

Alternative names: Voltage-gated calcium channel subunit alpha-2/delta-4

All UniProt accessions (9): Q7Z3S7, B4DVU4, E7EUE0, K7EIY9, K7EJY1, K7ER25, K7ER98, X6RLU5, X6RLY7

UniProt curated annotations — full annotation on UniProt →

Function. The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.

Subunit / interactions. Dimer formed of alpha-2-2 and delta-2 chains; disulfide-linked. Voltage-dependent calcium channels are multisubunit complexes, consisting of alpha-1 (CACNA1), alpha-2 (CACNA2D), beta (CACNB) and delta (CACNA2D) subunits in a 1:1:1:1 ratio. Interacts with CACNA1C and CACNB3.

Subcellular location. Membrane.

Tissue specificity. Predominantly expressed in certain types of endocrine cells. Present in the Paneth cells of the small intestine. Also present in the erythroblasts in the fetal liver, in the cells of the zona reticularis of the adrenal gland and in the basophils of the pituitary. Present at low level in some brain regions such as the cerebellum (at protein level).

Post-translational modifications. May be proteolytically processed into subunits alpha-2-4 and delta-4 that are disulfide-linked. It is however unclear whether such cleavage really takes place in vivo and has a functional role.

Disease relevance. Retinal cone dystrophy 4 (RCD4) [MIM:610478] Characterized by minimal symptoms except for slowly progressive reduction in visual acuity. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The MIDAS-like motif in the VWFA domain binds divalent metal cations and is required to promote trafficking of the alpha-1 (CACNA1) subunit to the plasma membrane by an integrin-like switch.

Miscellaneous. In contrast to CACNA2D1 and CACNA2D2, it does not bind gabapentin, an antiepileptic drug. May be due to an intron retention. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

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

Isoforms (6)

UniProt ID	Names	Canonical?
Q7Z3S7-1	1, Alpha2delta-4a	yes
Q7Z3S7-2	2
Q7Z3S7-4	4, Alpha2delta-4b
Q7Z3S7-5	5, Alpha2delta-4c
Q7Z3S7-6	6, Alpha2delta-4d
Q7Z3S7-7	7

RefSeq proteins (1): NP_758952* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002035	VWF_A	Domain
IPR013608	VWA_N	Domain
IPR013680	VDCC_a2/dsu	Domain
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR051173	Ca_channel_alpha-2/delta	Family

Pfam: PF08399, PF08473, PF13768

UniProt features (31 total): splice variant 7, sequence conflict 5, chain 3, binding site 3, sequence variant 3, glycosylation site 2, topological domain 2, domain 2, signal peptide 1, disulfide bond 1, transmembrane region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z3S7-F1	81.69	0.42

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): 297; 299; 301

Disulfide bonds (1): 447–1097

Glycosylation sites (2): 201, 664

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 181 (showing top): KEGG_MAPK_SIGNALING_PATHWAY, ACTGCAG_MIR173P, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_MUSCLE_CONTRACTION, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, CCTGTGA_MIR513, GOBP_RESPONSE_TO_RADIATION, GOBP_DETECTION_OF_LIGHT_STIMULUS, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOBP_DETECTION_OF_ABIOTIC_STIMULUS, GOBP_DETECTION_OF_STIMULUS, GOBP_SENSORY_PERCEPTION

GO Biological Process (5): detection of light stimulus involved in visual perception (GO:0050908), calcium ion transmembrane transport (GO:0070588), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (3): voltage-gated calcium channel activity (GO:0005245), metal ion binding (GO:0046872), calcium channel activity (GO:0005262)

GO Cellular Component (3): voltage-gated calcium channel complex (GO:0005891), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
visual perception	1
detection of light stimulus involved in sensory perception	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
calcium channel activity	1
voltage-gated monoatomic cation channel activity	1
cation binding	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
calcium channel complex	1
plasma membrane protein complex	1
cellular anatomical structure	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

932 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CACNA2D4	CACNB3	P54284	866
CACNA2D4	CACNA1A	P78510	805
CACNA2D4	CACNB1	Q02641	795
CACNA2D4	CACNA1C	Q13936	789
CACNA2D4	CACNB2	Q08289	750
CACNA2D4	CACNA1F	O60840	746
CACNA2D4	CACNG1	Q06432	699
CACNA2D4	CABP4	P57796	693
CACNA2D4	CACNA1D	Q01668	616
CACNA2D4	LRIT3	Q3SXY7	593
CACNA2D4	NYX	Q9GZU5	586
CACNA2D4	LRTM2	Q8N967	582
CACNA2D4	KCNV2	Q8TDN2	556
CACNA2D4	TRPM1	Q7Z4N2	533
CACNA2D4	GNAT1	P11488	519

IntAct

2 interactions, top by confidence:

A	B	Type	Score
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A0G2K1Q8, A0AAQ4VMX2, A2VE29, A6X935, O00534, O02668, O09126, O97827, P01029, P09172, P14046, P19823, P19827, P28665, P28666, P48831, P59509, P70505, P79263, P97278, P97279, Q00193, Q03626, Q0VCM5, Q14624, Q29052, Q3T052, Q3UV74, Q5RER0, Q60813, Q61702, Q61703, Q64237, Q68CI2, Q6IE52, Q75WE7, Q7Z3S7, Q86UX2, Q8BG22, Q8BJD1

Diamond homologs: Q5RJF7, Q7Z3S7, Q88KP1, Q8CFG5, Q8IZS8, Q9Z1L5, G3XD24, A5F389, A5W2C8, B0R461, C0SP89, G3XDA3, O32239, P02941, P02942, P07017, P07018, P0C6D8, P15492, P21822, P21823, P35841, P39209, P39216, P39217, P42257, P42258, P42259, P50466, Q02929, Q0VTI9, Q2W8M7, Q5V5V4, Q6HNQ4, Q882Z2, Q88D09, Q88E10, Q88IY8, Q88JK6, Q88N45

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1444 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	3
Uncertain significance	835
Likely benign	457
Benign	64

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
3234715	NM_172364.5(CACNA2D4):c.3177_3178dup (p.Asp1060fs)	Pathogenic
3248889	NM_172364.5:c.(1719+1_1720-1)_(2551+1_2552-1)del	Pathogenic
3250232	NM_172364.5(CACNA2D4):c.2854C>T (p.Gln952Ter)	Pathogenic
375308	NM_172364.4(CACNA2D4):c.1720-74_2551+1189delinsTG	Pathogenic
685389	GRCh37/hg19 12p13.33(chr12:1950037-1986237)x1	Pathogenic
685775	GRCh37/hg19 12p13.33(chr12:1949889-1986237)x1	Pathogenic
686267	GRCh37/hg19 12p13.33(chr12:1949889-1986237)x1	Pathogenic
686567	GRCh37/hg19 12p13.33(chr12:1949889-1986237)x1	Pathogenic
687142	GRCh37/hg19 12p13.33(chr12:1950037-1985170)x1	Pathogenic
812253	NC_000012.12:g.1839550_1875411del	Pathogenic
3767350	NM_172364.5(CACNA2D4):c.1644+1G>A	Likely pathogenic
438233	Single allele	Likely pathogenic
596323	NM_172364.5(CACNA2D4):c.165G>A (p.Trp55Ter)	Likely pathogenic

SpliceAI

7954 predictions. Top by Δscore:

Variant	Effect	Δscore
12:1797416:A:AC	donor_gain	1.0000
12:1797417:C:CC	donor_gain	1.0000
12:1797417:CTT:C	donor_gain	1.0000
12:1797419:T:TA	donor_gain	1.0000
12:1797536:C:CC	acceptor_gain	1.0000
12:1810273:CTCA:C	donor_loss	1.0000
12:1810274:TCAC:T	donor_loss	1.0000
12:1810275:CA:C	donor_loss	1.0000
12:1810276:A:AC	donor_gain	1.0000
12:1810277:C:CT	donor_gain	1.0000
12:1810277:CCT:C	donor_gain	1.0000
12:1810277:CCTCT:C	donor_gain	1.0000
12:1810339:TC:T	acceptor_gain	1.0000
12:1810339:TCC:T	acceptor_loss	1.0000
12:1810340:CC:C	acceptor_gain	1.0000
12:1810341:C:CA	acceptor_loss	1.0000
12:1810341:C:CC	acceptor_gain	1.0000
12:1810342:T:A	acceptor_loss	1.0000
12:1811720:GCGG:G	acceptor_gain	1.0000
12:1811721:CGG:C	acceptor_gain	1.0000
12:1811721:CGGC:C	acceptor_gain	1.0000
12:1811722:GGCTA:G	acceptor_loss	1.0000
12:1811723:GC:G	acceptor_loss	1.0000
12:1811724:C:CC	acceptor_gain	1.0000
12:1811724:C:CG	acceptor_loss	1.0000
12:1811725:T:G	acceptor_loss	1.0000
12:1830915:C:A	acceptor_gain	1.0000
12:1830919:T:A	acceptor_gain	1.0000
12:1830931:CAA:C	acceptor_loss	1.0000
12:1830932:AAG:A	acceptor_gain	1.0000

AlphaMissense

7510 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:1887010:A:G	W281R	0.999
12:1887010:A:T	W281R	0.999
12:1907909:G:C	S205R	0.999
12:1907909:G:T	S205R	0.999
12:1907911:T:G	S205R	0.999
12:1879015:C:G	G529R	0.998
12:1882893:A:G	W487R	0.998
12:1882893:A:T	W487R	0.998
12:1887021:C:G	R277P	0.998
12:1907542:A:G	S227P	0.998
12:1879826:A:T	V514D	0.997
12:1882930:G:C	S474R	0.997
12:1882930:G:T	S474R	0.997
12:1882932:T:G	S474R	0.997
12:1884310:G:C	F428L	0.997
12:1884310:G:T	F428L	0.997
12:1884312:A:G	F428L	0.997
12:1886287:G:T	A310D	0.997
12:1886288:C:G	A310P	0.997
12:1907485:A:G	W246R	0.997
12:1907485:A:T	W246R	0.997
12:1907541:G:A	S227F	0.997
12:1795363:C:G	C1082S	0.996
12:1795364:A:T	C1082S	0.996
12:1879014:C:T	G529D	0.996
12:1879836:C:G	A511P	0.996
12:1884257:G:T	A446E	0.996
12:1884306:A:C	Y430D	0.996
12:1886242:T:A	D325V	0.996
12:1886243:C:G	D325H	0.996

dbSNP variants (sampled 300 via entrez): RS1000041204 (12:1848760 G>A), RS1000055119 (12:1801204 C>A,T), RS1000056956 (12:1843098 A>C), RS1000084831 (12:1888174 T>G), RS1000113271 (12:1838195 C>T), RS1000117153 (12:1881970 A>G), RS1000117244 (12:1806797 T>C), RS1000145962 (12:1837911 G>C), RS1000147736 (12:1843408 A>G), RS1000160572 (12:1893325 G>A), RS1000190343 (12:1796846 T>TCCGCGCGG), RS1000191642 (12:1864714 T>C,G), RS1000198033 (12:1820719 C>A,T), RS1000217201 (12:1815998 C>G), RS1000234980 (12:1828777 C>T)

Disease associations

OMIM: gene MIM:608171 | disease phenotypes: MIM:610478, MIM:602093, MIM:120970, MIM:268000, MIM:601777

GenCC curated gene-disease

Disease	Classification	Inheritance
retinal cone dystrophy 4	Strong	Autosomal recessive
cone-rod dystrophy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
CACNA2D4-related retinopathy	Definitive	AR

Mondo (10): retinal cone dystrophy 4 (MONDO:0012507), inherited retinal dystrophy (MONDO:0019118), retinal disorder (MONDO:0005283), optic atrophy (MONDO:0003608), CACNA2D4-related retinopathy (MONDO:0700244), cone dystrophy 3 (MONDO:0011193), cone dystrophy (MONDO:0000455), cone-rod dystrophy (MONDO:0015993), retinitis pigmentosa (MONDO:0019200), cone-rod dystrophy 6 (MONDO:0011143)

Orphanet (4): Cone rod dystrophy (Orphanet:1872), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Progressive cone dystrophy (Orphanet:1871), Retinitis pigmentosa (Orphanet:791)

HPO phenotypes

21 total (22 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0000529	Progressive visual loss
HP:0000543	Optic disc pallor
HP:0000548	Cone/cone-rod dystrophy
HP:0000551	Color vision defect
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000662	Nyctalopia
HP:0001105	Retinal atrophy
HP:0001133	Constriction of peripheral visual field
HP:0007641	Dyschromatopsia
HP:0007663	Reduced visual acuity
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007814	Retinal pigment epithelial mottling
HP:0007843	Attenuation of retinal blood vessels
HP:0007984	ERG: Reduced dark-adapted b-wave amplitude
HP:0012508	Metamorphopsia
HP:0030466	Abnormal full-field electroretinogram
HP:0000556	Retinal dystrophy

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002587_18	Blood pressure (smoking interaction)	2.000000e-07
GCST002830_34	Urate levels in lean individuals	5.000000e-06
GCST009391_1201	Metabolite levels	6.000000e-06
GCST009391_1220	Metabolite levels	2.000000e-06
GCST009391_1462	Metabolite levels	2.000000e-06
GCST009391_1507	Metabolite levels	2.000000e-06
GCST009391_1834	Metabolite levels	6.000000e-06
GCST009391_1859	Metabolite levels	4.000000e-06
GCST009391_1871	Metabolite levels	1.000000e-06
GCST009391_253	Metabolite levels	1.000000e-06
GCST009391_289	Metabolite levels	1.000000e-06
GCST009391_369	Metabolite levels	7.000000e-06
GCST009391_69	Metabolite levels	3.000000e-06

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006526	pack-years measurement
EFO:0004531	urate measurement
EFO:0010418	triacylglycerol 52:6 measurement
EFO:0010421	triacylglycerol 54:3 measurement
EFO:0010406	triacylglycerol 48:3 measurement
EFO:0010417	triacylglycerol 52:5 measurement
EFO:0010412	triacylglycerol 50:5 measurement
EFO:0010410	triacylglycerol 50:3 measurement
EFO:0010411	triacylglycerol 50:4 measurement
EFO:0010426	triacylglycerol 54:8 measurement
EFO:0010425	triacylglycerol 54:7 measurement
EFO:0010435	triacylglycerol 56:8 measurement
EFO:0010353	diacylglycerol 34:2 measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D000077765	Cone Dystrophy	C11.270.151; C11.768.216
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
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
C566470	Retinal Cone Dystrophy 4 (supp.)
C538363	Retinal cone dystrophy 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

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

Molecules with ChEMBL bioactivity

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

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

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

ChEMBL bioactivities

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

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

PubChem BioAssay actives

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

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases expression, affects methylation	5
Valproic Acid	increases methylation, affects cotreatment, decreases expression	4
trichostatin A	affects cotreatment, decreases expression	3
bisphenol A	affects cotreatment, decreases methylation, increases expression	2
Aflatoxin B1	increases expression, affects methylation	2
triphenyl phosphate	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	increases methylation	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	affects methylation	1
Calcium	affects binding, increases transport, affects cotreatment, increases reaction	1
Cisplatin	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	affects expression	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Methapyrilene	decreases methylation	1
Tobacco Smoke Pollution	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Cyclosporine	increases expression	1
Sodium Selenite	decreases expression	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

13 unique, capped per target: 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3737861	Binding	Inhibition of voltage-gated calcium channel (unknown origin)	Discovery and Pharmacology of a Novel Class of Diacylglycerol Acyltransferase 2 Inhibitors. — J Med Chem

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_1536	NCI-H2171	Cancer cell line	Male
CVCL_YA24	IDG-HEK293T-CACNA2D4-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
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]
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
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