CACNG4

Summary

CACNG4 (calcium voltage-gated channel auxiliary subunit gamma 4, HGNC:1408) is a protein-coding gene on chromosome 17q24.2, encoding Voltage-dependent calcium channel gamma-4 subunit (Q9UBN1). Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit.

The protein encoded by this gene is a type I transmembrane AMPA receptor regulatory protein (TARP). TARPs regulate both trafficking and channel gating of the AMPA receptors. This gene is part of a functionally diverse eight-member protein subfamily of the PMP-22/EMP/MP20 family and is located in a cluster with two family members, a type II TARP and a calcium channel gamma subunit.

Source: NCBI Gene 27092 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 46 total
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈4% of expected missense variation)
• GTEx eGene: eQTL in 17 tissues, sQTL in 0 (q < 0.05)
• ChEMBL bioactivity: 2 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.86 (intermediate), LOEUF 0.59 (moderately constrained)
• MANE Select transcript: NM_014405

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1408
Approved symbol	CACNG4
Name	calcium voltage-gated channel auxiliary subunit gamma 4
Location	17q24.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC11138, MGC24983
Ensembl gene	ENSG00000075461
Ensembl biotype	protein_coding
OMIM	606404
Entrez	27092

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

MANE Select: ENST00000262138

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000262138, ENST00000921465, ENST00001140212

RefSeq mRNA: 1 — MANE Select: NM_014405 NM_014405

CCDS: CCDS11667

Canonical transcript exons

ENST00000262138 — 4 exons

Exon	Start	End
ENSE00000547770	67018189	67018272
ENSE00000742723	67024860	67025000
ENSE00001149242	66964707	66965131
ENSE00001268756	67030466	67033398

Expression profiles

Bgee: expression breadth ubiquitous, 146 present calls, max score 96.90.

FANTOM5 (CAGE): breadth broad, TPM avg 19.9795 / max 407.8816, expressed in 627 samples.

Highest expression (Bgee): cortical plate, ventricular zone, ganglionic eminence, type B pancreatic cell, nucleus accumbens.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CACNG4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 17 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

17 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Lung	eqtl	3.8e-45	-0.56	17:66952169:A:G
Esophagus Muscularis	eqtl	3.4e-37	-0.59	17:66952169:A:G
Muscle Skeletal	eqtl	3.2e-32	+1.22	17:67044307:T:A
Esophagus Mucosa	eqtl	1.5e-18	-0.57	17:66952169:A:G
Esophagus Gastroesophageal Junction	eqtl	2.5e-13	-0.51	17:66952169:A:G
Adipose Visceral Omentum	eqtl	2.4e-10	-0.28	17:66952169:A:G
Colon Sigmoid	eqtl	2.7e-09	-0.43	17:66952169:A:G
Thyroid	eqtl	7.2e-09	-0.37	17:66952169:A:G
Nerve Tibial	eqtl	4.9e-06	+0.25	17:66973188:T:G
Vagina	eqtl	6.9e-06	-0.69	17:66952169:A:G
Pituitary	eqtl	7.2e-04	+1.06	17:66960848:C:T
Minor Salivary Gland	eqtl	7.3e-04	-0.38	17:66952169:A:G
Skin Not Sun Exposed Suprapubic	eqtl	1.6e-02	-0.17	17:66938733:C:G
Uterus	eqtl	2.4e-02	-0.46	17:66952169:A:G
Artery Coronary	eqtl	3.0e-02	-0.55	17:67957232:G:A
Brain Spinal cord cervical c-1	eqtl	4.1e-02	-0.51	17:65994075:T:A
Brain Nucleus accumbens basal ganglia	eqtl	4.7e-02	-0.48	17:67306200:C:T

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
162320	12.5119	569
162319	3.9116	481
162321	3.3594	385
162322	0.1827	93
208354	0.0139	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	96.90	gold quality
ventricular zone	UBERON:0003053	95.42	gold quality
ganglionic eminence	UBERON:0004023	95.19	gold quality
type B pancreatic cell	CL:0000169	94.96	gold quality
nucleus accumbens	UBERON:0001882	93.75	gold quality
olfactory bulb	UBERON:0002264	93.21	gold quality
embryo	UBERON:0000922	93.04	gold quality
pancreatic ductal cell	CL:0002079	92.73	silver quality
putamen	UBERON:0001874	92.71	gold quality
caudate nucleus	UBERON:0001873	92.48	gold quality
amygdala	UBERON:0001876	90.63	gold quality
temporal lobe	UBERON:0001871	89.78	gold quality
vena cava	UBERON:0004087	89.72	gold quality
CA1 field of hippocampus	UBERON:0003881	89.65	gold quality
hypothalamus	UBERON:0001898	89.08	gold quality
entorhinal cortex	UBERON:0002728	88.98	silver quality
endothelial cell	CL:0000115	88.60	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	88.50	gold quality
body of tongue	UBERON:0011876	88.04	gold quality
inferior olivary complex	UBERON:0002127	88.01	silver quality
triceps brachii	UBERON:0001509	87.73	silver quality
Brodmann (1909) area 46	UBERON:0006483	87.57	silver quality
mammary duct	UBERON:0001765	87.51	gold quality
lateral nuclear group of thalamus	UBERON:0002736	87.44	silver quality
medulla oblongata	UBERON:0001896	87.43	silver quality
gluteal muscle	UBERON:0002000	87.26	silver quality
lateral globus pallidus	UBERON:0002476	87.22	silver quality
diaphragm	UBERON:0001103	87.19	gold quality
pons	UBERON:0000988	86.66	silver quality
superficial temporal artery	UBERON:0001614	86.53	gold quality
tongue	UBERON:0001723	86.42	gold quality
pericardium	UBERON:0002407	86.34	gold quality
germinal epithelium of ovary	UBERON:0001304	86.12	gold quality
pharyngeal mucosa	UBERON:0000355	86.11	gold quality
telencephalon	UBERON:0001893	86.00	gold quality
epithelium of mammary gland	UBERON:0003244	86.00	gold quality
pylorus	UBERON:0001166	85.95	gold quality
Ammon’s horn	UBERON:0001954	85.84	gold quality
superior surface of tongue	UBERON:0007371	85.78	gold quality
cerebellar vermis	UBERON:0004720	85.62	gold quality
quadriceps femoris	UBERON:0001377	85.48	gold quality
tibialis anterior	UBERON:0001385	85.45	silver quality
trachea	UBERON:0003126	85.41	gold quality
vastus lateralis	UBERON:0001379	85.32	gold quality
saphenous vein	UBERON:0007318	85.27	gold quality
nipple	UBERON:0002030	85.04	gold quality
midbrain	UBERON:0001891	84.83	gold quality
superior frontal gyrus	UBERON:0002661	84.70	gold quality
cingulate cortex	UBERON:0003027	84.42	gold quality
substantia nigra	UBERON:0002038	84.41	gold quality
anterior cingulate cortex	UBERON:0009835	84.37	gold quality
thymus	UBERON:0002370	84.31	gold quality
trigeminal ganglion	UBERON:0001675	83.96	gold quality
buccal mucosa cell	CL:0002336	83.63	silver quality
renal medulla	UBERON:0000362	83.55	gold quality
cerebral cortex	UBERON:0000956	83.24	gold quality
deltoid	UBERON:0001476	83.21	gold quality
pigmented layer of retina	UBERON:0001782	83.15	silver quality
epithelial cell of pancreas	CL:0000083	82.91	gold quality
secondary oocyte	CL:0000655	82.77	gold quality
bronchus	UBERON:0002185	82.68	silver quality
neocortex	UBERON:0001950	82.67	gold quality
parotid gland	UBERON:0001831	82.58	silver quality
epithelium of bronchus	UBERON:0002031	82.55	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	82.54	gold quality
forebrain	UBERON:0001890	82.53	gold quality
occipital lobe	UBERON:0002021	82.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.22	gold quality
frontal cortex	UBERON:0001870	81.79	gold quality
prefrontal cortex	UBERON:0000451	81.73	gold quality
brain	UBERON:0000955	81.71	gold quality
periodontal ligament	UBERON:0008266	81.60	gold quality
synovial joint	UBERON:0002217	81.46	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	81.40	gold quality
bronchial epithelial cell	CL:0002328	81.26	silver quality
epithelium of nasopharynx	UBERON:0001951	81.00	gold quality
left ventricle myocardium	UBERON:0006566	81.00	gold quality
ileal mucosa	UBERON:0000331	80.87	silver quality
mucosa of paranasal sinus	UBERON:0005030	80.81	gold quality
primary visual cortex	UBERON:0002436	80.71	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	80.69	gold quality
hair follicle	UBERON:0002073	80.50	gold quality
adult organism	UBERON:0007023	80.25	silver quality
right frontal lobe	UBERON:0002810	80.03	gold quality
cardiac muscle of right atrium	UBERON:0003379	79.58	gold quality
spinal cord	UBERON:0002240	79.31	gold quality
biceps brachii	UBERON:0001507	79.27	gold quality
penis	UBERON:0000989	79.22	gold quality
mucosa of sigmoid colon	UBERON:0004993	79.17	silver quality
mucosa of urinary bladder	UBERON:0001259	78.97	gold quality
cranial nerve II	UBERON:0000941	78.62	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	78.40	gold quality
cartilage tissue	UBERON:0002418	78.28	silver quality
urethra	UBERON:0000057	78.22	gold quality
Brodmann (1909) area 9	UBERON:0013540	77.76	gold quality
gingival epithelium	UBERON:0001949	77.46	gold quality
male germ cell	CL:0000015	76.99	gold quality
visceral pleura	UBERON:0002401	76.88	gold quality
jejunum	UBERON:0002115	76.87	gold quality
pleura	UBERON:0000977	76.86	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	22.24
E-ANND-3	no	1.45

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 62 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Basal ganglia	tissue	155.8	not detected
Putamen	tissue	141.4
Ventral forebrain	tissue	88.5
Nucleus accumbens	tissue	68.4
Caudate putamen	tissue	67.9
Septum	tissue	61.3
Thalamus	tissue	42.9
Amygdala	tissue	36.2
Cerebral cortex	tissue	33.6	low
Insular cortex	tissue	33.6
Prefrontal cortex	tissue	32.8
Motor cortex	tissue	32.3
Hypothalamus	tissue	27.9
Midbrain	tissue	27.5
Locus coeruleus	tissue	26.9
Temporal cortex	tissue	26.6
Hippocampal formation	tissue	26.2
Entorhinal cortex	tissue	26.2
Retrosplenial and cingulate cortex	tissue	25.1
Pons	tissue	24.9
Retrosplenial cortex	tissue	24.2
Superior colliculi	tissue	23.3
Substantia nigra	tissue	22.0
Hippocampus	tissue	22.0	not detected
Olfactory bulb	tissue	20.4
Occipital cortex	tissue	20.1
Somatosensory cortex	tissue	19.7
Medulla oblongata	tissue	19.1
Frontal cortex	tissue	18.1
Spinal cord	tissue	17.1
Corpus callosum	tissue	16.7
Cerebellum	tissue	16.4	not detected
Periaqueductal gray	tissue	16.4
Prostate	tissue	11.0	not detected
Postcentral gyrus	tissue	9.6
Lung	tissue	5.4	not detected
Breast	tissue	5.0	not detected
Fallopian tube	tissue	3.9	not detected
Choroid plexus	tissue	3.4
Seminal vesicle	tissue	1.2	not detected
Parathyroid gland	tissue	1.1	low
Smooth muscle	tissue	1.0	not detected
Stomach 1	tissue	0.8	not detected
Adrenal gland	tissue	0.8	not detected
Retina	tissue	0.7
Vagina	tissue	0.6	not detected
Placenta	tissue	0.6	not detected
Gallbladder	tissue	0.4	not detected
Cervix	tissue	0.3	not detected
Urinary bladder	tissue	0.3	not detected
Pancreas	tissue	0.3	not detected
Endometrium 1	tissue	0.3	not detected
Pituitary gland	tissue	0.2
Duodenum	tissue	0.2	not detected
Skin 1	tissue	0.1	not detected
Testis	tissue	0.1	not detected
Salivary gland	tissue	0.1	not detected
Rectum	tissue	0.1	not detected
Skeletal muscle	tissue	0.1	not detected
Colon	tissue	0.1	not detected

Brain sub-regions (HPA Brain Atlas): detected in 188; highest nTPM — Caudate nucleus (62.2), Habenula (57.8), Nucleus basalis of Meynert (52.0), Basal amygdala (50.6), Corticomedial amygdala (45.4).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting CACNG4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 81 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6127	100.00	66.76	2188
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785

Functional genomics

gnomAD constraint: pLI 0.862, LOEUF 0.59, missense Z 1.61 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000262138 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈4% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
17:66,964,912–67,024,884	114 / 161.6	0.71	no
17:67,024,885–67,024,927	3 / 16.3	0.18	yes (p 9.8e-04)
17:67,024,928–67,031,001	240 / 277.6	0.86	no

Literature-anchored findings (GeneRIF, showing 2)

• examined distribution of the stargazin-like proteins gamma2, gamma3, and gamma4 in human CNS: gamma2 is expressed in cerebellum, cerebral cortex, hippocampus and thalamus, whereas gamma3 abounds in cerebral cortex & amygdala and gamma4 in basal ganglia (PMID:14505496)
• These results indicate that CACNG4, CACNG5, CACNG6 and CACNG8 may contribute to the risk of SCZ. The statistical epistasis identified between CACNG5 and CACNG6 suggests that there may be an underlying biological interaction between the two genes. (PMID:27102562)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cacng4b	ENSDARG00000074669
danio_rerio	cacng4a	ENSDARG00000115540
mus_musculus	Cacng4	ENSMUSG00000020723
rattus_norvegicus	Cacng4	ENSRNOG00000003262
drosophila_melanogaster	stg1	FBGN0288700

Paralogs (5): CACNG3 (ENSG00000006116), CACNG5 (ENSG00000075429), CACNG7 (ENSG00000105605), CACNG8 (ENSG00000142408), CACNG2 (ENSG00000166862)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1859167) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal miniature excitatory postsynaptic currents	1
decreased miniature excitatory postsynaptic current amplitude	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	Q4R589	100.0%	Diamond
Pongo abelii	Q5R5X2	100.0%	Diamond
Bos taurus	Q0VD05	99.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CACNG5	protein-coding	27091
PRKCA	protein-coding	5578
MIR634	ncRNA	693219
CACNG1	protein-coding	786
HELZ-AS1	ncRNA	101928021
HELZ	protein-coding	9931

Protein

Protein identifiers

Voltage-dependent calcium channel gamma-4 subunit — Q9UBN1 (reviewed: Q9UBN1)

Alternative names: Neuronal voltage-gated calcium channel gamma-4 subunit, Transmembrane AMPAR regulatory protein gamma-4

All UniProt accessions (1): Q9UBN1

UniProt curated annotations — full annotation on UniProt →

Function. Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit. Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs), including GRIA1 and GRIA4. Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization and by mediating their resensitization.

Subunit / interactions. Interacts with CACNA1C. Identified in a complex with the L-type calcium channel subunits CACNA1C, CACNA2D1 and either CACNB1 or CACNB2. Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs). Interacts with GRIA1.

Subcellular location. Cell membrane.

Tissue specificity. Detected in heart left ventricle.

Similarity. Belongs to the PMP-22/EMP/MP20 family. CACNG subfamily.

RefSeq proteins (1): NP_055220* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004031	PMP22/EMP/MP20/Claudin	Family
IPR005423	VDCC_g4su	Family
IPR008368	VDCC_gsu	Family
IPR051072	CACNG_subunit	Family

Pfam: PF00822

UniProt features (15 total): topological domain 5, transmembrane region 4, glycosylation site 2, chain 1, region of interest 1, compositionally biased region 1, modified residue 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBN1-F1	65.80	0.17

Human Protein Atlas

Protein class: Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, FDA approved drug targets, Small molecule drugs

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IH enhanced · IF approved

Functional residue map

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

Post-translational modifications (1)

Type	Positions
Phosphoserine	259

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	42, 45

Function

Pathways and Gene Ontology

Reactome pathways

5 curated (TAS) of 12; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

12 pathways:

ID	Pathway	Evidence
R-HSA-5682910	LGI-ADAM interactions	curated
R-HSA-5576892	Phase 0 - rapid depolarisation	curated
R-HSA-5576893	Phase 2 - plateau phase	curated
R-HSA-112308	Presynaptic depolarization and calcium channel opening	curated
R-HSA-399719	Trafficking of AMPA receptors	curated
R-HSA-5576891	Cardiac conduction	—
R-HSA-1266738	Developmental Biology	—
R-HSA-399721	Glutamate binding, activation of AMPA receptors and synaptic plasticity	—
R-HSA-397014	Muscle contraction	—
R-HSA-112316	Neuronal System	—
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission	—
R-HSA-112315	Transmission across Chemical Synapses	—

MSigDB gene sets: 193 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_COCAINE, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, KEGG_MAPK_SIGNALING_PATHWAY, GOZGIT_ESR1_TARGETS_DN, GOCC_CELL_SURFACE, MODULE_313, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, GOBP_RESPONSE_TO_ALKALOID, MODULE_205, SMID_BREAST_CANCER_LUMINAL_B_UP

GO Biological Process (10): transmission of nerve impulse (GO:0019226), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), response to cocaine (GO:0042220), positive regulation of synaptic transmission, glutamatergic (GO:0051968), postsynaptic neurotransmitter receptor diffusion trapping (GO:0098970), regulation of AMPA receptor activity (GO:2000311), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (6): voltage-gated calcium channel activity (GO:0005245), calcium channel regulator activity (GO:0005246), channel regulator activity (GO:0016247), ionotropic glutamate receptor binding (GO:0035255), calcium channel activity (GO:0005262), protein binding (GO:0005515)

GO Cellular Component (12): plasma membrane (GO:0005886), cell surface (GO:0009986), endocytic vesicle membrane (GO:0030666), AMPA glutamate receptor complex (GO:0032281), somatodendritic compartment (GO:0036477), cell body (GO:0044297), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), L-type voltage-gated calcium channel complex (GO:1990454), voltage-gated calcium channel complex (GO:0005891), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

7 top-level categories:

Category	Pathways
Transmission across Chemical Synapses	2
Cardiac conduction	2
Glutamate binding, activation of AMPA receptors and synaptic plasticity	1
Developmental Biology	1
Neuronal System	1
Neurotransmitter receptors and postsynaptic signal transmission	1
Muscle contraction	1

GO top-level categories

49 GO namespaces:

Category	Terms
cellular anatomical structure	4
postsynaptic membrane	2
postsynaptic specialization membrane	2
calcium channel activity	2
action potential	1
cell communication	1
chemical synaptic transmission	1
nervous system process	1
positive regulation of insulin secretion	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
response to alkaloid	1
response to oxygen-containing compound	1
synaptic transmission, glutamatergic	1
positive regulation of synaptic transmission	1
regulation of synaptic transmission, glutamatergic	1
receptor localization to synapse	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
neurotransmitter receptor diffusion trapping	1
AMPA glutamate receptor activity	1
regulation of transmembrane transporter activity	1
regulation of neurotransmitter receptor activity	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
voltage-gated monoatomic cation channel activity	1
ion channel regulator activity	1
channel activity	1
transporter regulator activity	1
glutamate receptor binding	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
binding	1
membrane	1
cell periphery	1
endocytic vesicle	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
ionotropic glutamate receptor complex	1
postsynaptic density	1
synapse	1
voltage-gated calcium channel complex	1
T-tubule	1
calcium channel complex	1
plasma membrane protein complex	1
transmembrane transporter complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 28 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
regulation of AMPA receptor activity	BP	direct assay
L-type voltage-gated calcium channel complex	CC	direct assay
calcium channel regulator activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 860 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CACNG4	CACNG1	Q06432	922
CACNG4	CACNB1	Q02641	772
CACNG4	CACNA1D	Q01668	716
CACNG4	CACNA2D1	P54289	701
CACNG4	CACNB3	P54284	451
CACNG4	PRKCA	P17252	449
CACNG4	SERTM1	A2A2V5	438
CACNG4	CACNB4	O00305	404
CACNG4	PDCL2	Q8N4E4	399
CACNG4	KCNB2	Q92953	399
CACNG4	CACNA2D4	Q7Z3S7	384
CACNG4	CACNA1B	Q00975	375
CACNG4	CACNA1E	Q15878	370
CACNG4	CNBD2	Q96M20	367
CACNG4	VSIG1	Q86XK7	365

IntAct

Human interaction partners of CACNG4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 82 partners by confidence:

Partner	Interaction type	MIscore	Records
PATJ	direct interaction	0.440	9
GRIP1	direct interaction	0.440	5
GRIP2	direct interaction	0.440	5
MAGI2	direct interaction	0.440	4
DLG1	direct interaction	0.440	3
DLG4	direct interaction	0.440	3
IL16	direct interaction	0.440	3
MPDZ	direct interaction	0.440	3
NHERF4	direct interaction	0.440	3
WHRN	direct interaction	0.440	3
APBA2	direct interaction	0.440	2
DLG2	direct interaction	0.440	2
DLG3	direct interaction	0.440	2
GRID2IP	direct interaction	0.440	2
LNX1	direct interaction	0.440	2
LNX2	direct interaction	0.440	2
MAGI1	direct interaction	0.440	2
PDZK1	direct interaction	0.440	2
TJP1	direct interaction	0.440	2
AHNAK	direct interaction	0.440	1
APBA1	direct interaction	0.440	1
APBA3	direct interaction	0.440	1
ARHGAP21	direct interaction	0.440	1
CARD11	direct interaction	0.440	1
CASK	direct interaction	0.440	1
DLG5	direct interaction	0.440	1
DVL3	direct interaction	0.440	1
FRMPD1	direct interaction	0.440	1
FRMPD2	direct interaction	0.440	1
FRMPD3	direct interaction	0.440	1

BioGRID (71 interactions; top human partners by supporting records): ARL10 (Affinity Capture-MS; 3 records), DPY19L3 (Affinity Capture-MS; 3 records), MTX1 (Affinity Capture-MS; 3 records), MTX3 (Affinity Capture-MS; 3 records), RMND1 (Affinity Capture-MS; 3 records), COQ5 (Affinity Capture-MS; 2 records), MRS2 (Affinity Capture-MS; 2 records), RSPRY1 (Affinity Capture-MS; 2 records), ACSL1 (Affinity Capture-MS), ACVR2A (Affinity Capture-MS), ALDH3B1 (Affinity Capture-MS), ALG5 (Affinity Capture-MS), ANAPC7 (Affinity Capture-MS), ATP1A3 (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS)

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 82 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
Ras activation upon Ca2+ influx through NMDA receptor	5	53.9×	1e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	51.3×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	51.3×	1e-06
Assembly and cell surface presentation of NMDA receptors	10	47.9×	5e-13
Dopamine Neurotransmitter Release Cycle	5	46.8×	2e-06
Long-term potentiation	5	44.9×	2e-06
Neurexins and neuroligins	11	40.9×	3e-13
Protein-protein interactions at synapses	7	35.1×	6e-08

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	72.6×	3e-14
protein localization to synapse	6	57.5×	1e-07
receptor clustering	7	54.6×	9e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	6	37.2×	1e-06
protein-containing complex assembly	9	12.8×	2e-06
cell-cell adhesion	10	12.7×	6e-07
chemical synaptic transmission	7	6.8×	2e-03
protein transport	9	4.9×	2e-03

Disease & clinical

Genetic variants

Variant evidence for CACNG4: 46 ClinVar records (0 pathogenic / likely pathogenic); 5 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	0
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 465):

Position(s)	Effect	Δscore	Sites
17:67018187–67018188	acceptor_loss	1.0000	6
17:67018273–67018274	donor_loss	1.0000	4
17:67024847	acceptor_gain	1.0000
17:67018177	acceptor_gain	0.9900
17:67018273	donor_loss	0.9900
17:67024853–67024854	acceptor_gain	0.9900	2
17:67025001–67025002	donor_loss	0.9900	5
17:66965132–66965133	donor_loss	0.9800	5
17:67020750	donor_gain	0.9800
17:67021709	donor_gain	0.9800

AlphaMissense

846 missense substitutions predicted likely pathogenic (of 2,145 scored), across 198 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M24	9	0.898	0.995
F192	8	0.995	1.000
F185	8	0.994	0.999
D31	8	0.990	0.999
F110	8	0.988	0.997
H63	8	0.962	0.998
F145	8	0.958	0.991
S114	8	0.951	1.000
F86	8	0.941	0.997
N152	8	0.931	0.999
D95	8	0.828	0.937
D93	8	0.795	0.900
C80	7	0.998	0.999
C70	7	0.997	0.999
C41	7	0.996	0.998
W33	7	0.995	0.999
C71	7	0.995	0.998
W67	7	0.994	1.000
W183	7	0.980	0.999
E196	7	0.969	0.998

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Breast Invasive Carcinoma, Glioblastoma Multiforme)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.000875

Disease associations

OMIM: gene MIM:606404 | disease phenotypes:

GWAS associations

5 associations:

Study	Trait	p-value
GCST009724_104	Vertical cup-disc ratio (multi-trait analysis)	7e-9
GCST012256_10	SAPHO syndrome	7e-8
GCST009723_92	Vertical cup-disc ratio (adjusted for vertical disc diameter)	1e-7
GCST005024_63	Pursuit maintenance gain	2e-6
GCST011528_6	Response to antidepressants (symptom improvement)	4e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0008433	pursuit maintenance gain measurement
EFO:0006939	cup-to-disc ratio measurement
EFO:0007006	depressive symptom measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

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

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 68,316 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

2 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1428	NIMODIPINE	4	32,766
CHEMBL95	TACRINE	4	35,550

PharmGKB: 1 entry (CPIC guideline: no)

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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Calcitriol	affects cotreatment, increases expression	2
Estradiol	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	increases expression, affects cotreatment, decreases expression	2
propionaldehyde	decreases expression	1
bisphenol A	decreases methylation	1
ethyl-p-hydroxybenzoate	increases expression	1
beta-lapachone	decreases expression	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
abrine	decreases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	increases mutagenesis	1
Diazinon	increases methylation	1
Diethylhexyl Phthalate	increases expression	1
Endosulfan	decreases expression	1
Formaldehyde	increases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Sarin	decreases expression, increases 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

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7LE	Ubigene A-549 CACNG4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CACNG4 across ~30M SureChEMBL compounds — explore on Sugi Predict.