CACNG2

Summary

CACNG2 (calcium voltage-gated channel auxiliary subunit gamma 2, HGNC:1406) is a protein-coding gene on chromosome 22q12.3, encoding Voltage-dependent calcium channel gamma-2 subunit (Q9Y698). Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs).

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. The AMPA subtype of ionotropic glutamate receptors are ligand gated ion channels that are typically activated by glutamate released from presynaptic neuron terminals and mediate fast neurotransmission in excitatory synapses. TARPs thus play an important role in synaptic plasticity, learning and memory. Mutations in this gene cause an autosomal dominant form of cognitive disability.

Source: NCBI Gene 10369 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant non-syndromic intellectual disability (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 77 total
• Phenotypes (HPO): 5
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_006078

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1406
Approved symbol	CACNG2
Name	calcium voltage-gated channel auxiliary subunit gamma 2
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Aliases	stargazin, MGC138502, MGC138504
Ensembl gene	ENSG00000166862
Ensembl biotype	protein_coding
OMIM	602911
Entrez	10369

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000300105, ENST00000480002

RefSeq mRNA: 2 — MANE Select: NM_006078 NM_001379051, NM_006078

CCDS: CCDS13931

Canonical transcript exons

ENST00000300105 — 4 exons

Exon	Start	End
ENSE00001107275	36560857	36564886
ENSE00001107278	36587465	36587548
ENSE00001107287	36566353	36566493
ENSE00001276309	36702366	36703752

Expression profiles

Bgee: expression breadth broad, 70 present calls, max score 79.00.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7653 / max 80.2800, expressed in 116 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193968	0.7112	115
193966	0.0327	5
193963	0.0213	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	79.00	gold quality
cerebellar cortex	UBERON:0002129	78.93	gold quality
cerebellar hemisphere	UBERON:0002245	78.90	gold quality
cerebellum	UBERON:0002037	78.55	gold quality
buccal mucosa cell	CL:0002336	78.53	gold quality
postcentral gyrus	UBERON:0002581	77.57	gold quality
Brodmann (1909) area 46	UBERON:0006483	77.56	gold quality
parietal lobe	UBERON:0001872	76.28	gold quality
superior frontal gyrus	UBERON:0002661	75.92	gold quality
prefrontal cortex	UBERON:0000451	75.25	gold quality
frontal cortex	UBERON:0001870	74.78	gold quality
right frontal lobe	UBERON:0002810	74.02	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	73.75	gold quality
neocortex	UBERON:0001950	73.60	gold quality
entorhinal cortex	UBERON:0002728	72.44	gold quality
cerebral cortex	UBERON:0000956	71.46	gold quality
Brodmann (1909) area 9	UBERON:0013540	71.41	gold quality
anterior cingulate cortex	UBERON:0009835	71.31	gold quality
cingulate cortex	UBERON:0003027	71.28	gold quality
primary visual cortex	UBERON:0002436	70.75	gold quality
lateral nuclear group of thalamus	UBERON:0002736	70.64	gold quality
cortical plate	UBERON:0005343	70.40	gold quality
triceps brachii	UBERON:0001509	70.10	gold quality
gluteal muscle	UBERON:0002000	69.98	gold quality
occipital lobe	UBERON:0002021	69.41	gold quality
telencephalon	UBERON:0001893	68.46	gold quality
brain	UBERON:0000955	68.02	gold quality
orbitofrontal cortex	UBERON:0004167	67.45	silver quality
temporal lobe	UBERON:0001871	67.35	gold quality
forebrain	UBERON:0001890	66.96	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.30

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 20)

• 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 suggest that stargazin (gamma-2) not only promotes AMPA receptor surface expression but also directly modulates AMPA receptor activity. (PMID:15567474)
• AMPA receptors complexed with stargazin are significantly more responsive to synaptically released glutamate compared with AMPA receptors lacking stargazin. (PMID:15758178)
• Stargazin enhances trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors GluR1 and GluR2 by blocking endoplasmic reticulum retention. (PMID:16793768)
• the Q/R site modulates the interaction of stargazin with the transmembrane domains of AMPA receptors via an allosteric mechanism and that this modulation leads to the observed differences in the electrophysiological properties of the receptor (PMID:17483093)
• Stargazin polymorphisms may play a role in the response to lithium treatment. (PMID:18408563)
• The genes CACNG2 might be vulnerability genes for neuropsychologically defined subgroups of schizophrenic patients. (PMID:18571626)
• findings show stargazin demonstrates differential control of AMPA receptor subunit stability (PMID:19543281)
• Data show that S-nitrosylation of stargazin increases binding to the AMPAR subunit GluR1, causing increased surface expression of the AMPAR. (PMID:19805317)
• Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2 (PMID:20688780)
• Autoinactivation is a subunit and splice form dependent property of AMPA receptor-stargazin complexes, which involves structural rearrangements within the complex rather than any physical dissociation. (PMID:23166629)
• The additional cleft closure and/or stabilization of the more closed-cleft states of the LBD is expected to translate to higher agonist efficacy and could contribute to the structural mechanism for stargazin modulation of AMPAR function. (PMID:25422502)
• A transient positive feedback mechanism between AMPAR and stargazin has implications for information processing in the brain, because it should allow activity-dependent facilitation of excitatory synaptic transmission through a postsynaptic mechanism. (PMID:26744192)
• In addition to changes in MEK3 gene regulation, our study demonstrated upregulation of CACNG2 and GADD45G at the mRNA level in CMM patients. (PMID:27418173)
• Our nanopositioning data place stargazin below the AMPA receptor ligand-binding domain, where it is well poised to act as a scaffold to facilitate the long-range conformational selection observations seen in single-molecule experiments. These data support a model of stargazin acting to stabilize or select conformational states that favor activation. (PMID:27705782)
• TARP gamma-2 reduces the ability of low glutamate concentrations to cause AMPAR desensitization and enhances channel gating at low glutamate occupancy. (PMID:28768197)
• The results of this study conclude that the A-C-C haplotype at the 3 single-nucleotide polymorphisms (rs4820242, rs2284015, and rs2284017) in the CACNG2 gene is associated with increased risk of developing Chronic postmastectomy pain. (PMID:30371558)
• Lithium response in Bipolar Disorder was significantly associated with single nucleotide polymorphism in CACNG2 in both the prospective and retrospective cohorts. (PMID:30738251)
• Association between CACNG2 polymorphisms (rs4820242, rs2284015 and rs2284017) and chronic peripheral neuropathic pain risk in a Mexican population. (PMID:35776036)
• TARPgamma2 Is Required for Normal AMPA Receptor Expression and Function in Direction-Selective Circuits of the Mammalian Retina. (PMID:37491367)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cacng2a	ENSDARG00000032565
		ENSDARG00000102376
mus_musculus	Cacng2	ENSMUSG00000019146
rattus_norvegicus	Cacng2	ENSRNOG00000065511
caenorhabditis_elegans		WBGENE00017400

Paralogs (5): CACNG3 (ENSG00000006116), CACNG5 (ENSG00000075429), CACNG4 (ENSG00000075461), CACNG7 (ENSG00000105605), CACNG8 (ENSG00000142408)

Protein

Protein identifiers

Voltage-dependent calcium channel gamma-2 subunit — Q9Y698 (reviewed: Q9Y698)

Alternative names: Neuronal voltage-gated calcium channel gamma-2 subunit, Transmembrane AMPAR regulatory protein gamma-2

All UniProt accessions (1): Q9Y698

UniProt curated annotations — full annotation on UniProt →

Function. Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits. Thought to stabilize the calcium channel in an inactivated (closed) state.

Subunit / interactions. The L-type calcium channel is composed of five subunits: alpha-1, alpha-2/delta, beta and gamma. Interacts with the PDZ domains of DLG4/PSD-95 and DLG1/SAP97. May interact with GOPC. Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CNIH2, CNIH3, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with GRIA1 and GRIA2. Interacts with MPP2.

Subcellular location. Membrane. Synapse. Synaptosome.

Tissue specificity. Brain.

Post-translational modifications. Phosphorylation of Thr-321 impairs interaction with DLG1 and DLG4.

Disease relevance. Intellectual developmental disorder, autosomal dominant 10 (MRD10) [MIM:614256] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (2): NP_001365980, NP_006069* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004031	PMP22/EMP/MP20/Claudin	Family
IPR005422	VDCC_g2su	Family
IPR008368	VDCC_gsu	Family
IPR051072	CACNG_subunit	Family

Pfam: PF00822

UniProt features (12 total): transmembrane region 4, modified residue 3, chain 1, sequence variant 1, strand 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6TNO	X-RAY DIFFRACTION	1.9
6DLZ	ELECTRON MICROSCOPY	3.9
6DM1	ELECTRON MICROSCOPY	4.2
6DM0	ELECTRON MICROSCOPY	4.4
6O9G	ELECTRON MICROSCOPY	4.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y698-F1	66.26	0.18

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 (3): 253, 271, 321

Glycosylation sites (1): 48

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-112308	Presynaptic depolarization and calcium channel opening
R-HSA-399719	Trafficking of AMPA receptors
R-HSA-5682910	LGI-ADAM interactions
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1266738	Developmental Biology
R-HSA-399721	Glutamate binding, activation of AMPA receptors and synaptic plasticity

MSigDB gene sets: 247 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_MEMBRANE_DEPOLARIZATION, WWTAAGGC_UNKNOWN, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, KEGG_MAPK_SIGNALING_PATHWAY, CMYB_01, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_PROTEIN_TARGETING, GOCC_CELL_SURFACE, FOXO4_01, AP2_Q3, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GOBP_REFLEX

GO Biological Process (19): protein targeting to membrane (GO:0006612), neuromuscular junction development (GO:0007528), transmission of nerve impulse (GO:0019226), response to calcium ion (GO:0051592), membrane depolarization (GO:0051899), positive regulation of synaptic transmission, glutamatergic (GO:0051968), membrane hyperpolarization (GO:0060081), eye blink reflex (GO:0060082), postsynaptic neurotransmitter receptor diffusion trapping (GO:0098970), neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645), positive regulation of protein localization to basolateral plasma membrane (GO:1904510), regulation of AMPA receptor activity (GO:2000311), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), regulation of membrane potential (GO:0042391), nervous system process (GO:0050877), calcium ion transmembrane transport (GO:0070588), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072)

GO Molecular Function (5): voltage-gated calcium channel activity (GO:0005245), channel regulator activity (GO:0016247), ionotropic glutamate receptor binding (GO:0035255), calcium channel activity (GO:0005262), protein binding (GO:0005515)

GO Cellular Component (16): plasma membrane (GO:0005886), voltage-gated calcium channel complex (GO:0005891), cell surface (GO:0009986), endocytic vesicle membrane (GO:0030666), AMPA glutamate receptor complex (GO:0032281), somatodendritic compartment (GO:0036477), cerebellar mossy fiber (GO:0044300), Schaffer collateral - CA1 synapse (GO:0098685), hippocampal mossy fiber to CA3 synapse (GO:0098686), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702), neuron projection (GO:0043005), organelle (GO:0043226), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-5 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of membrane potential	2
postsynaptic membrane	2
receptor localization to synapse	2
regulation of postsynaptic membrane neurotransmitter receptor levels	2
postsynaptic specialization membrane	2
regulation of biological quality	2
synapse	2
protein targeting	1
establishment of protein localization to membrane	1
synapse organization	1
action potential	1
cell communication	1
chemical synaptic transmission	1
nervous system process	1
response to metal ion	1
synaptic transmission, glutamatergic	1
positive regulation of synaptic transmission	1
regulation of synaptic transmission, glutamatergic	1
reflex	1
neurotransmitter receptor diffusion trapping	1
protein-containing complex localization	1
protein localization to postsynaptic specialization membrane	1
protein localization to basolateral plasma membrane	1
positive regulation of protein localization to cell periphery	1
regulation of protein localization to basolateral plasma membrane	1
positive regulation of protein localization to membrane	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
monoatomic ion transmembrane transport	1
system process	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
calcium channel activity	1
voltage-gated monoatomic cation channel activity	1

Protein interactions and networks

STRING

1200 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CACNG2	DLG4	P78352	998
CACNG2	GRIA1	P42261	990
CACNG2	MAGI2	Q86UL8	912
CACNG2	SHISA9	B4DS77	906
CACNG2	GRIA2	P42262	886
CACNG2	ADAM22	Q9P0K1	874
CACNG2	DLG1	Q12959	873
CACNG2	CACNG1	Q06432	871
CACNG2	DLG3	Q92796	850
CACNG2	GRIA4	P48058	818
CACNG2	LGI1	O95970	810
CACNG2	CLRN1	P58418	804
CACNG2	DLG2	Q15700	772
CACNG2	ATP6V1C2	Q8NEY4	762
CACNG2	CACNB4	O00305	754

IntAct

129 interactions, top by confidence:

A	B	Type	Score
CACNG2	GOPC	psi-mi:“MI:0407”(direct interaction)	0.590
WIPF1	CACNG2	psi-mi:“MI:0915”(physical association)	0.560
CACNG2	CCNT1	psi-mi:“MI:0914”(association)	0.530
SRPK2	CACNG2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CACNG2	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
SYNJ2BP	CACNG2	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
DLG4	CACNG2	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	PDZRN3	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	TAMALIN	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
CACNG2	NOS1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (51): ITPR2 (Affinity Capture-MS), HBS1L (Affinity Capture-MS), GOPC (Affinity Capture-MS), MTCH2 (Affinity Capture-MS), CSNK1E (Affinity Capture-MS), CSNK1D (Affinity Capture-MS), CCNT1 (Affinity Capture-MS), STAT3 (Affinity Capture-MS), ATF1 (Affinity Capture-MS), EPHA7 (Affinity Capture-MS), HBS1L (Affinity Capture-MS), CSNK1E (Affinity Capture-MS), GOPC (Affinity Capture-MS), STAT3 (Affinity Capture-MS), CCNT1 (Affinity Capture-MS)

ESM2 similar proteins: A8MUP6, O00168, O08589, O35464, O42581, O42582, O54851, O60359, O70610, O88602, P49190, P56749, Q0IIL2, Q0VD05, Q148L1, Q2KHT4, Q32LT7, Q3SZT1, Q3TH73, Q4R589, Q4V922, Q569C0, Q5R5X2, Q5R9K1, Q5VW38, Q66IQ1, Q6AYL2, Q6DFT4, Q6GPA5, Q6NUZ2, Q6P1U2, Q6P6V6, Q71RJ2, Q7ZWN9, Q866T7, Q8BGN8, Q8BXN9, Q8R1W2, Q8TBG9, Q8VHW9

Diamond homologs: O60359, O88602, Q0VD05, Q4R589, Q5R5X2, Q71RJ2, Q8VHW2, Q8VHW4, Q8VHW5, Q8VHW8, Q8VHW9, Q8VHX0, Q8WXS5, Q9JJV4, Q9JJV5, Q9UBN1, Q9UF02, Q9Y698, P62955, P62956, P62957

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKACA	“down-regulates activity”	CACNG2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 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	51.0×	2e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	48.5×	2e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	48.5×	2e-06
Assembly and cell surface presentation of NMDA receptors	10	45.3×	1e-12
Dopamine Neurotransmitter Release Cycle	5	44.3×	3e-06
Long-term potentiation	5	42.5×	3e-06
Neurexins and neuroligins	11	38.7×	7e-13
Protein-protein interactions at synapses	7	33.2×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	78.0×	3e-16
protein localization to synapse	6	56.0×	1e-07
receptor clustering	7	53.3×	1e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	42.3×	4e-08
protein-containing complex assembly	10	13.9×	2e-07
cell-cell adhesion	9	11.1×	7e-06
chemical synaptic transmission	7	6.6×	3e-03
protein transport	8	4.3×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	11
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1389 predictions. Top by Δscore:

Variant	Effect	Δscore
22:36566349:TTA:T	donor_loss	1.0000
22:36566351:A:AG	donor_loss	1.0000
22:36566352:C:A	donor_loss	1.0000
22:36566437:CCA:C	acceptor_gain	1.0000
22:36566494:C:CC	acceptor_gain	1.0000
22:36587463:A:AC	donor_gain	1.0000
22:36587464:C:CC	donor_gain	1.0000
22:36587464:CGG:C	donor_gain	1.0000
22:36587464:CGGA:C	donor_gain	1.0000
22:36587544:ATTCC:A	acceptor_gain	1.0000
22:36587545:TTCC:T	acceptor_gain	1.0000
22:36587546:TCC:T	acceptor_gain	1.0000
22:36587547:CC:C	acceptor_gain	1.0000
22:36587547:CCC:C	acceptor_gain	1.0000
22:36587547:CCCT:C	acceptor_loss	1.0000
22:36587548:CC:C	acceptor_gain	1.0000
22:36587548:CCTG:C	acceptor_loss	1.0000
22:36587549:C:A	acceptor_loss	1.0000
22:36587549:C:CC	acceptor_gain	1.0000
22:36587550:T:C	acceptor_loss	1.0000
22:36683702:C:A	donor_gain	1.0000
22:36564882:CAGAC:C	acceptor_gain	0.9900
22:36564884:GAC:G	acceptor_gain	0.9900
22:36564884:GACC:G	acceptor_loss	0.9900
22:36564885:ACCT:A	acceptor_loss	0.9900
22:36564886:CCTGC:C	acceptor_loss	0.9900
22:36564887:C:A	acceptor_loss	0.9900
22:36564887:C:CC	acceptor_gain	0.9900
22:36564888:T:G	acceptor_loss	0.9900
22:36564905:CGGGG:C	acceptor_gain	0.9900

AlphaMissense

2132 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:36564742:C:T	G194E	1.000
22:36564743:C:A	G194W	1.000
22:36564743:C:G	G194R	1.000
22:36564743:C:T	G194R	1.000
22:36564762:G:C	F187L	1.000
22:36564762:G:T	F187L	1.000
22:36564763:A:G	F187S	1.000
22:36564764:A:G	F187L	1.000
22:36564766:G:A	S186F	1.000
22:36564766:G:T	S186Y	1.000
22:36564772:G:T	A184D	1.000
22:36564775:C:T	G183E	1.000
22:36564776:C:A	G183W	1.000
22:36564776:C:G	G183R	1.000
22:36564776:C:T	G183R	1.000
22:36564783:G:C	F180L	1.000
22:36564783:G:T	F180L	1.000
22:36564784:A:G	F180S	1.000
22:36564785:A:G	F180L	1.000
22:36564787:G:A	S179F	1.000
22:36564791:A:G	W178R	1.000
22:36564791:A:T	W178R	1.000
22:36564793:C:A	G177V	1.000
22:36564793:C:T	G177D	1.000
22:36564794:C:A	G177C	1.000
22:36564794:C:G	G177R	1.000
22:36564853:A:T	I157K	1.000
22:36564862:A:C	I154R	1.000
22:36564862:A:T	I154K	1.000
22:36564868:C:A	G152V	1.000

dbSNP variants (sampled 300 via entrez): RS1000058142 (22:36685204 G>A), RS1000065289 (22:36583015 C>T), RS1000067598 (22:36567950 A>C), RS1000187961 (22:36632053 G>A,C), RS1000188485 (22:36682415 T>A,C,G), RS1000196547 (22:36606986 T>A,G), RS1000219722 (22:36682716 A>G), RS1000245616 (22:36598415 C>G,T), RS1000246946 (22:36614443 C>T), RS1000257387 (22:36673960 C>T), RS1000259430 (22:36647186 T>C), RS1000274261 (22:36562173 G>A), RS1000275034 (22:36566667 G>A), RS1000286719 (22:36674145 G>A), RS1000297723 (22:36598189 T>C)

Disease associations

OMIM: gene MIM:602911 | disease phenotypes: MIM:614256

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant
intellectual disability, autosomal dominant 10	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	AD

Mondo (5): intellectual disability, autosomal dominant 10 (MONDO:0013657), neurodevelopmental disorder (MONDO:0700092), complex neurodevelopmental disorder (MONDO:0100038), ependymoma (MONDO:0016698), autosomal dominant non-syndromic intellectual disability (MONDO:0015802)

Orphanet (2): Non-specific syndromic intellectual disability (Orphanet:528084), Ependymoma (Orphanet:251636)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001250	Seizure
HP:0002342	Moderate intellectual disability
HP:0011463	Childhood onset
HP:0410263	Brain imaging abnormality

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002724_2	Airway responsiveness in chronic obstructive pulmonary disease	2.000000e-06
GCST011494_106	Daytime nap	9.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006897	airway responsiveness measurement
EFO:0007828	daytime rest measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D004806	Ependymoma	C04.557.465.625.600.380.290; C04.557.470.670.380.290; C04.557.580.625.600.380.290
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363032 (PROTEIN COMPLEX GROUP), CHEMBL4296111 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

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

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

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2284017	Efficacy	3	lithium	Bipolar Disorder
rs2284018	Efficacy	3	lithium	Bipolar Disorder

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2284017	CACNG2	3	2.00	1	lithium
rs2284018	CACNG2	3	2.00	1	lithium

Binding affinities (BindingDB)

127 measured of 127 human assays (127 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
8-(7-chloro-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-5-yl)-7-(4-fluorophenyl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.01 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
2-cyclopentyl-7-(4-fluorophenyl)-8-(7-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.016 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
2-cyclobutyl-3-(7-methyl-1H-indazol-5-yl)-5-(trifluoromethyl)pyrazolo[4,3-b]pyridine	IC50	0.02 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
3-(7-chloro-1H-indazol-5-yl)-2-cyclobutyl-5-(trifluoromethyl)pyrazolo[4,3-b]pyridine	IC50	0.02 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
2-cyclobutyl-7-(4-fluorophenyl)-8-(7-methyl-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.025 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2-propan-2-yl-7-(trifluoromethyl)imidazo[1,2-a]pyridine	IC50	0.025 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
7-chloro-5-[2-cyclobutyl-5-(trifluoromethyl)pyrazolo[4,3-b]pyridin-3-yl]-1,3-dihydroindol-2-one	IC50	0.032 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
7-(4-fluorophenyl)-8-(7-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.032 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
2-(difluoromethyl)-7-(4-fluorophenyl)-8-(7-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.032 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
8-(7-methyl-1H-indazol-5-yl)-7-propan-2-yl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.032 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
5-[2-cyclobutyl-5-(trifluoromethyl)pyrazolo[4,3-b]pyridin-3-yl]-7-methyl-1,3-dihydroindol-2-one	IC50	0.05 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2,7-bis(trifluoromethyl)imidazo[1,2-a]pyridine	IC50	0.05 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
3-(7-chloro-1H-indazol-5-yl)-2-propan-2-yl-5-(trifluoromethyl)pyrazolo[4,3-b]pyridine	IC50	0.063 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
7-cyclopentyl-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.079 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
2-cyclopropyl-7-(4-fluorophenyl)-8-(7-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.079 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
5-(difluoromethyl)-3-(7-methyl-1H-indazol-5-yl)-2-propan-2-ylpyrazolo[4,3-b]pyridine	IC50	0.1 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2-propan-2-yl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine	IC50	0.1 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
8-(7-methyl-1H-indazol-5-yl)-2-propan-2-yl-7-(trifluoromethyl)imidazo[1,2-a]pyridine	IC50	0.1 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
2-cyclopentyl-3-(7-methyl-1H-indazol-5-yl)-5-(trifluoromethyl)pyrazolo[4,3-b]pyridine	IC50	0.126 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2-propan-2-yl-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.126 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2-cyclopropyl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine	IC50	0.126 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
3-chloro-8-(7-chloro-1H-indazol-5-yl)-2-cyclopropyl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine	IC50	0.126 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
5,7-bis(difluoromethyl)-3-(7-methyl-1H-indazol-5-yl)-2-propan-2-ylpyrazolo[4,3-b]pyridine	IC50	0.158 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2-cyclopropyl-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.158 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-7-propan-2-yl-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine	IC50	0.158 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
5-[2,7-bis(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]-7-chloro-1,3-dihydroindol-2-one	IC50	0.158 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
2-cyclopropyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.2 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
7-chloro-5-[2-propan-2-yl-5-(trifluoromethyl)pyrazolo[4,3-b]pyridin-3-yl]-1,3-dihydroindol-2-one	IC50	0.251 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
3-(7-methyl-1H-indazol-5-yl)-2-propan-2-yl-5-(trifluoromethyl)pyrazolo[4,3-b]pyridine	IC50	0.251 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
6-[7-(4-fluorophenyl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-3H-1,3-benzothiazol-2-one	IC50	0.251 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2,7-bis(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.251 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
2-cyclopropyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine	IC50	0.251 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
2-cyclopropyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine	IC50	0.251 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
3-(7-chloro-1H-indazol-5-yl)-2-methyl-5-(trifluoromethyl)pyrazolo[4,3-b]pyridine	IC50	0.316 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2-(difluoromethyl)-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.316 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
7-(azetidin-1-yl)-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.316 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2,7-bis(trifluoromethyl)-[1,2,4]triazolo[1,5-c]pyrimidine	IC50	0.316 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
5-[2,7-bis(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-7-chloro-1,3-dihydroindol-2-one	IC50	0.316 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
8-(7-methyl-1H-indazol-5-yl)-2,7-bis(trifluoromethyl)imidazo[1,2-a]pyridine	IC50	0.316 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
7-chloro-5-[2-cyclopropyl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-8-yl]-1,3-dihydroindol-2-one	IC50	0.316 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2-(difluoromethyl)-7-propan-2-ylimidazo[1,2-c]pyrimidine	IC50	0.316 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2-cyclopropyl-3-fluoro-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine	IC50	0.316 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
3-(7-chloro-1H-indazol-5-yl)-2-ethyl-5-(trifluoromethyl)pyrazolo[4,3-b]pyridine	IC50	0.398 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
7-methyl-5-[2-propan-2-yl-5-(trifluoromethyl)pyrazolo[4,3-b]pyridin-3-yl]-1,3-dihydroindol-2-one	IC50	0.398 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
7-chloro-5-[5-(difluoromethyl)-2-propan-2-ylpyrazolo[4,3-b]pyridin-3-yl]-1,3-dihydroindol-2-one	IC50	0.398 nM	US-10100045: 3-aryl-2H-pyrazolo[4,3-b]pyridine compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2-(difluoromethyl)-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-c]pyrimidine	IC50	0.398 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-7-(difluoromethyl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.398 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
8-(7-chloro-1H-indazol-5-yl)-2-ethyl-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine	IC50	0.398 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
5-[2,7-bis(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]-7-methyl-1,3-dihydroindol-2-one	IC50	0.398 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators
2-ethyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine	IC50	0.398 nM	US-10155769: Fused azaheterocyclic compounds and their use as AMPA receptor modulators

ChEMBL bioactivities

76 potent at pChembl≥5 of 93 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL4522808
9.70	IC50	0.1995	nM	CHEMBL4436028
9.60	IC50	0.2512	nM	CHEMBL4581775
9.40	IC50	0.3981	nM	CHEMBL4522625
9.40	IC50	0.3981	nM	CHEMBL4466359
9.30	IC50	0.5012	nM	CHEMBL4454257
9.30	IC50	0.5012	nM	CHEMBL4535626
9.30	IC50	0.5012	nM	CHEMBL4443161
9.20	IC50	0.631	nM	CHEMBL4439877
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
8.30	IC50	5.012	nM	CHEMBL4465598
8.30	IC50	5.012	nM	CHEMBL4582925
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	CHEMBL4474333
7.96	IC50	11	nM	CHEMBL3948329
7.92	IC50	12	nM	CHEMBL3898359
7.90	IC50	12.59	nM	CHEMBL4518912
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

PubChem BioAssay actives

31 with measured affinity, of 136 total; 30 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
5-[2-(4-fluorophenyl)-8-(4-fluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-3-yl]-1,3-dihydroindol-2-one	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0001	uM
5-[2-(4-fluorophenyl)-7-(4-hydroxypiperidin-1-yl)pyrazolo[1,5-c]pyrimidin-3-yl]-1,3-dihydroindol-2-one	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0002	uM
5-[7-(4-acetylpiperazin-1-yl)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-1,3-dihydroindol-2-one	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0003	uM
5-[2-(4-fluorophenyl)-8-(4-hydroxypiperidin-1-yl)imidazo[1,2-a]pyrazin-3-yl]-1,3-dihydroindol-2-one	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0004	uM
5-[8-(4-acetylpiperazin-1-yl)-2-(4-fluorophenyl)imidazo[1,2-a]pyrazin-3-yl]-1,3-dihydroindol-2-one	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0004	uM
5-[2-(4-fluorophenyl)-7-morpholin-4-ylpyrazolo[1,5-c]pyrimidin-3-yl]-1,3-dihydroindol-2-one	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0005	uM
5-[2-(4-fluorophenyl)-8-morpholin-4-ylimidazo[1,2-a]pyrazin-3-yl]-1,3-dihydroindol-2-one	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0005	uM
5-[2-(4-fluorophenyl)-8-(3-oxopiperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl]-1,3-dihydroindol-2-one	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0005	uM
4-[2-(4-fluorophenyl)-3-(1H-indazol-5-yl)imidazo[1,2-a]pyrazin-8-yl]morpholine	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0006	uM
5-[2-(4-fluorophenyl)-7-(4-fluoropiperidin-1-yl)pyrazolo[1,5-c]pyrimidin-3-yl]-1,3-dihydroindol-2-one	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0050	uM
5-[2-(4-fluorophenyl)-7-(3-oxopiperazin-1-yl)pyrazolo[1,5-c]pyrimidin-3-yl]-1,3-dihydroindol-2-one	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0050	uM
4-[2-(4-chlorophenyl)-8-morpholin-4-ylimidazo[1,2-a]pyrazin-3-yl]phenol	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0100	uM
4-[2-(4-fluorophenyl)-8-morpholin-4-ylimidazo[1,2-a]pyrazin-3-yl]phenol	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0126	uM
4-[2-(4-fluorophenyl)-8-morpholin-4-ylimidazo[1,2-a]pyrazin-3-yl]aniline	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.0631	uM
4-[2-(4-fluorophenyl)-3-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-8-yl]morpholine	1542530: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux at 100 uM by calcium 5/6 dye based FLIPR assay	ic50	0.5012	uM
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
4-[2-(4-fluorophenyl)benzimidazol-1-yl]phenol	1542529: Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux by calcium 5/6 dye based FLIPR assay	ic50	1.2589	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
5-[2-chloro-6-(trifluoromethoxy)phenyl]-7-methyl-1,3-dihydroindol-2-one	1385855: Modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293F cells assessed as blockade of glutamate-induced calcium flux by calcium 5/6 dye based FLIPR assay	ic50	10.0000	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

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases methylation, increases methylation	2
bisphenol A	affects cotreatment, increases methylation	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	affects methylation	1
vanadyl sulfate	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Barium	affects transport	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression	1
Endosulfan	decreases expression	1
Folic Acid	decreases expression	1
Lead	affects expression	1
Methapyrilene	affects methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Coal Ash	increases expression	1

ChEMBL screening assays

17 unique, capped per target: 15 binding, 2 admet

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
CHEMBL4339687	ADMET	Negative allosteric modulation of recombinant human GluA1 flop isoform/TARPgamma2 expressed in HEK293 cells assessed as inhibition of glutamate-induced calcium flux by calcium 5/6 dye based FLIPR assay	Discovery of Imidazo[1,2-a]pyrazines and Pyrazolo[1,5-c]pyrimidines as TARP γ-8 Selective AMPAR Negative Modulators. — ACS Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00517959	PHASE3	UNKNOWN	SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors
NCT01096368	PHASE3	COMPLETED	Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Ependymoma
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00003479	PHASE2	TERMINATED	Antineoplaston Therapy in Treating Patients With Ependymoma
NCT00520936	PHASE2	COMPLETED	A Study of Pemetrexed in Children With Recurrent Cancer
NCT00840047	PHASE2	ACTIVE_NOT_RECRUITING	Methionine PET/CT Studies In Patients With Cancer
NCT01088035	PHASE2	TERMINATED	Carboplatin as a Radiosensitizer in Treating Childhood Ependymoma
NCT01247922	PHASE2	TERMINATED	Single-agent Erlotinib in Patients Previously Treated With Oral Etoposide in Protocol OSI-774-205
NCT01288235	PHASE2	COMPLETED	Proton Radiotherapy for Pediatric Brain Tumors Requiring Partial Brain Irradiation
NCT01295944	PHASE2	COMPLETED	Carboplatin and Bevacizumab for Recurrent Ependymoma
NCT01356290	PHASE2	RECRUITING	Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors
NCT01836549	PHASE2	TERMINATED	Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors
NCT02125786	PHASE2	ACTIVE_NOT_RECRUITING	A Trial of Surgery and Fractionated Re-Irradiation for Recurrent Ependymoma
NCT02689336	PHASE2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors
NCT03095248	PHASE2	TERMINATED	Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03173950	PHASE2	COMPLETED	Immune Checkpoint Inhibitor Nivolumab in People With Recurrent Select Rare CNS Cancers
NCT03194906	PHASE2	COMPLETED	Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Localized Brain Tumors
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03220035	PHASE2	COMPLETED	Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)
NCT03233204	PHASE2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03526250	PHASE2	COMPLETED	Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)
NCT03698994	PHASE2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT03727841	PHASE2	TERMINATED	Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma
NCT04049669	PHASE2	ACTIVE_NOT_RECRUITING	Pediatric Trial of Indoximod With Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPG
NCT04195555	PHASE2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04284774	PHASE2	ACTIVE_NOT_RECRUITING	Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04320888	PHASE2	ACTIVE_NOT_RECRUITING	Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial