RGS7

Summary

RGS7 (regulator of G protein signaling 7, HGNC:10003) is a protein-coding gene on chromosome 1q43, encoding Regulator of G-protein signaling 7 (P49802). GTPase activator component of the RGS7-GNB5 complex that regulates G protein-coupled receptor signaling cascades.

Enables G-protein alpha-subunit binding activity; G-protein beta-subunit binding activity; and GTPase activator activity. Involved in G protein-coupled receptor signaling pathway; negative regulation of G protein-coupled receptor signaling pathway; and positive regulation of GTPase activity. Located in cytosol. Is active in plasma membrane.

Source: NCBI Gene 6000 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 55 total
• Cancer driver (intOGen): activating (oncogene-like) across 4 cancer types
• MANE Select transcript: NM_001364886

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10003
Approved symbol	RGS7
Name	regulator of G protein signaling 7
Location	1q43
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000182901
Ensembl biotype	protein_coding
OMIM	602517
Entrez	6000

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 24 protein_coding, 15 protein_coding_CDS_not_defined, 11 retained_intron, 5 nonsense_mediated_decay

ENST00000348120, ENST00000366563, ENST00000366564, ENST00000366565, ENST00000440928, ENST00000685354, ENST00000685936, ENST00000686049, ENST00000686241, ENST00000686277, ENST00000686340, ENST00000686423, ENST00000686465, ENST00000686645, ENST00000686908, ENST00000687018, ENST00000687040, ENST00000687111, ENST00000687448, ENST00000687793, ENST00000687918, ENST00000687977, ENST00000688028, ENST00000688216, ENST00000688438, ENST00000688545, ENST00000688633, ENST00000688703, ENST00000688737, ENST00000688738, ENST00000688863, ENST00000689115, ENST00000689223, ENST00000689595, ENST00000689602, ENST00000689639, ENST00000689640, ENST00000690019, ENST00000690224, ENST00000690236, ENST00000690356, ENST00000690539, ENST00000690614, ENST00000691271, ENST00000691285, ENST00000691399, ENST00000691485, ENST00000691597, ENST00000691979, ENST00000691989, ENST00000692317, ENST00000692410, ENST00000692860, ENST00000693043, ENST00000693448

RefSeq mRNA: 20 — MANE Select: NM_001364886 NM_001282773, NM_001282775, NM_001282778, NM_001350113, NM_001350114, NM_001350115, NM_001350116, NM_001364886, NM_001374806, NM_001374807, NM_001374808, NM_001374809, NM_001374810, NM_001374811, NM_001374812, NM_001374813, NM_001374814, NM_001374815, NM_001374816, NM_002924

CCDS: CCDS31071, CCDS60457, CCDS60458, CCDS60459, CCDS91176, CCDS91177, CCDS91178, CCDS91179, CCDS91180, CCDS91181

Canonical transcript exons

ENST00000440928 — 19 exons

Exon	Start	End
ENSE00001294812	240868587	240868668
ENSE00001297373	240816317	240816415
ENSE00001298506	240802904	240802993
ENSE00001299196	240800641	240800721
ENSE00001300869	240814716	240814777
ENSE00001302592	240806140	240806326
ENSE00001312706	240811918	240812043
ENSE00001316483	240827098	240827172
ENSE00001318821	240813618	240813728
ENSE00001389586	240801455	240801508
ENSE00001442036	241355699	241355826
ENSE00001596620	240930717	240930768
ENSE00001605069	240868776	240868852
ENSE00001621492	240870055	240870119
ENSE00003582563	240936600	240936706
ENSE00003591673	240983079	240983129
ENSE00003622381	241098666	241098762
ENSE00003901365	240775514	240776213
ENSE00003901819	241356899	241357205

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 98.59.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1129 / max 137.9278, expressed in 380 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
18281	1.4559	287
18280	0.3641	98
18282	0.1474	77
18264	0.0719	29
18270	0.0283	10
18265	0.0261	10
18266	0.0128	4
202023	0.0065	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.59	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.55	gold quality
middle temporal gyrus	UBERON:0002771	96.25	gold quality
frontal pole	UBERON:0002795	96.19	gold quality
CA1 field of hippocampus	UBERON:0003881	96.17	gold quality
orbitofrontal cortex	UBERON:0004167	95.92	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.22	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.13	gold quality
primary visual cortex	UBERON:0002436	95.01	gold quality
paraflocculus	UBERON:0005351	94.79	gold quality
superior frontal gyrus	UBERON:0002661	94.54	gold quality
cerebellar vermis	UBERON:0004720	94.22	gold quality
occipital lobe	UBERON:0002021	93.60	gold quality
postcentral gyrus	UBERON:0002581	93.38	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.32	gold quality
prefrontal cortex	UBERON:0000451	93.23	gold quality
parietal lobe	UBERON:0001872	92.80	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.80	gold quality
frontal cortex	UBERON:0001870	92.44	gold quality
neocortex	UBERON:0001950	91.97	gold quality
entorhinal cortex	UBERON:0002728	91.83	gold quality
cerebral cortex	UBERON:0000956	91.66	gold quality
cortical plate	UBERON:0005343	91.45	gold quality
nucleus accumbens	UBERON:0001882	91.41	gold quality
cerebellum	UBERON:0002037	91.14	gold quality
cerebellar cortex	UBERON:0002129	91.02	gold quality
cerebellar hemisphere	UBERON:0002245	90.94	gold quality
cingulate cortex	UBERON:0003027	90.52	gold quality
telencephalon	UBERON:0001893	90.50	gold quality
anterior cingulate cortex	UBERON:0009835	90.45	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	4253.17
E-HCAD-25	yes	2431.68
E-MTAB-7316	yes	1164.76
E-GEOD-81547	yes	20.75
E-GEOD-137537	yes	6.86
E-HCAD-10	yes	4.71
E-ANND-3	no	4.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT3

miRNA regulators (miRDB)

62 targeting RGS7, 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-8485	100.00	77.57	4731
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-5003-5P	99.61	69.13	1624

Literature-anchored findings (GeneRIF, showing 20)

• tumor necrosis factor-alpha regulates the interaction of RGS7 with 14-3-3 (PMID:12077120)
• could play a role in synaptic vesicle exocytosis through its interaction with snapin (PMID:12659861)
• Galpha-regulated plasma membrane localization and palmitoylation of RGS7. (PMID:15496508)
• cytoplasmic RGS7*Gbeta5*R7BP heterotrimers and RGS7*Gbeta5 heterodimers are equivalently inefficient regulators of G protein-coupled receptor signaling relative to plasma membrane-bound heterotrimers bearing palmitoylated R7BP. (PMID:16867977)
• The DEP domain of RGS7 can directly bind to the third intracellular loop of the M3R and attenuate receptor-induced Ca2+ mobilization in a M3 subtype-selective manner. (PMID:19182865)
• cytosolic chaperonin complex-dependent mechanism exists for Gbeta5-RGS7 assembly that utilizes the co-chaperone activity of PhLP1 in a unique way (PMID:19376773)
• common variation within the RGS7 locus may be involved in multiple sclerosis susceptibility. (PMID:19626040)
• Gi/o signaling and the palmitoyltransferase DHHC2 regulate palmitate cycling and shuttling of RGS7 family-binding protein. (PMID:21343290)
• New single nucleotide polymorphisms associated with differences in platelets reactivity in patients with type 2 diabetes treated with acetylsalicylic acid: genome-wide association approach and pooled DNA strategy. (PMID:23054467)
• the GAP activity of RGS9-2 showed a strong receptor preference for D2R over MOR. Finally, RGS7 displayed an four times greater GAP activity relative to RGS9-2. (PMID:23857581)
• Fine mapping of the uterine leiomyoma locus on 1q43 close to a lncRNA in the RGS7-FH interval (PMID:26113603)
• R7-binding protein had a strong inhibitory effect on homo-oligomerization of RGS7. (PMID:26895961)
• Data (including data from studies using transgenic mice) suggest that R7BP-RGS7 heterotrimers interact with Galpha13 to augment signaling pathways in neurons that regulate neurite morphogenesis. (R7BP = RGS7 family binding protein; RGS7 = regulator of G-protein signaling 7 protein; Galpha13 = GTP-binding protein alpha subunit 13) (PMID:28432124)
• Results found that RGS7 was mutated in 11% of melanomas with three recurrent mutations (p.R44C, p.E383K and p.R416Q). p.R44C was shown to destabilize the protein due to the loss of an H-bond and salt bridge. RGS7 p.R44C has weaker catalytic activity for its substrate Galphao, thus providing a dual mechanism for its loss of function resulting in increase anchorage-independent growth, migration and invasion of melanoma c… (PMID:29330521)
• Data mapped differences in deuterium exchange between the regulator of G protein signaling 7 (RGS7)-Gbeta5 protein(Gbeta5)-RGS7 family binding protein (R7BP) trimer and the RGS7-Gbeta5 dimer. (PMID:30540250)
• Cryo-EM structure of human GPR158 receptor coupled to the RGS7-Gbeta5 signaling complex. (PMID:34793198)
• Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gbeta5. (PMID:34815401)
• A RGS7-CaMKII complex drives myocyte-intrinsic and myocyte-extrinsic mechanisms of chemotherapy-induced cardiotoxicity. (PMID:36574707)
• RGS7 silence protects palmitic acid-induced pancreatic beta-cell injury by inactivating the chemokine signaling pathway. (PMID:36999276)
• RGS7 balances acetylation/de-acetylation of p65 to control chemotherapy-dependent cardiac inflammation. (PMID:37589751)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rgs7a	ENSDARG00000016584
danio_rerio	rgs7b	ENSDARG00000096687
mus_musculus	Rgs7	ENSMUSG00000026527
rattus_norvegicus	Rgs7	ENSRNOG00000021984

Paralogs (23): RGS11 (ENSG00000076344), RGS1 (ENSG00000090104), RGS17 (ENSG00000091844), AXIN1 (ENSG00000103126), RGS9 (ENSG00000108370), RGS2 (ENSG00000116741), RGS4 (ENSG00000117152), RGSL1 (ENSG00000121446), RGS13 (ENSG00000127074), RGS22 (ENSG00000132554), RGS8 (ENSG00000135824), RGS3 (ENSG00000138835), RGS5 (ENSG00000143248), RGS16 (ENSG00000143333), RGS20 (ENSG00000147509), RGS10 (ENSG00000148908), RGS18 (ENSG00000150681), RGS12 (ENSG00000159788), AXIN2 (ENSG00000168646), RGS14 (ENSG00000169220), RGS19 (ENSG00000171700), RGS6 (ENSG00000182732), RGS21 (ENSG00000253148)

Protein

Protein identifiers

Regulator of G-protein signaling 7 — P49802 (reviewed: P49802)

All UniProt accessions (19): A0A8I5KR27, A0A8I5KRH6, A0A8I5KRS1, A0A8I5KUA7, A0A8I5KV90, A0A8I5KVW2, A0A8I5KXV8, A0A8I5KXW5, A0A8I5KY39, A0A8I5KY47, A0A8I5KZ23, A0A8I5KZ50, A0A8I5QJ89, A0A8I5QJE1, A0A8I5QJU0, A0A8I5QKX5, B7Z257, P49802, Q5T3H5

UniProt curated annotations — full annotation on UniProt →

Function. GTPase activator component of the RGS7-GNB5 complex that regulates G protein-coupled receptor signaling cascades. The RGS7-GNB5 complex acts as an inhibitor signal transduction by promoting the GTPase activity of G protein alpha subunits, such as GNAO1, thereby driving them into their inactive GDP-bound form. May play a role in synaptic vesicle exocytosis. Glycine-dependent regulation of the RGS7-GNB5 complex by GPR158 affects mood and cognition via its ability to regulate neuronal excitability in L2/L3 pyramidal neurons of the prefrontal cortex. Modulates the activity of potassium channels that are activated by GNAO1 in response to muscarinic acetylcholine receptor M2/CHRM2 signaling.

Subunit / interactions. Interacts with GNB5, forming the RGS7-GNB5 complex. Interacts with GPR158; promotes the GTPase activator activity of the RGS7-GNB5 complex in absence of glycine, in contrast GTPase activator activity of the RGS7-GNB5 complex is inhibited in presence of glycine. Interacts with GPR179. Interacts with PKD1; this prevents rapid proteasomal degradation. Interacts with RGS7BP, leading to regulate the subcellular location of the heterodimer formed with GNB5. Interacts (phosphorylated form) with 14-3-3 protein YWHAQ. Interacts with SNAPIN. Interacts with GNAI1. Interacts with GNAO1, GNAI3 and GNAZ.

Subcellular location. Cytoplasm. Cytosol. Cell membrane. Membrane.

Post-translational modifications. Palmitoylated. Ubiquitinated, leading to rapid proteasomal degradation. Phosphorylation and subsequent interaction with 14-3-3 proteins inhibits GAP activity.

Isoforms (5)

UniProt ID	Names	Canonical?
P49802-1	1, A	yes
P49802-2	2, B
P49802-3	3
P49802-4	4
P49802-5	5

RefSeq proteins (20): NP_001269702, NP_001269704, NP_001269707, NP_001337042, NP_001337043, NP_001337044, NP_001337045, NP_001351815, NP_001361735, NP_001361736, NP_001361737, NP_001361738, NP_001361739, NP_001361740, NP_001361741, NP_001361742, NP_001361743, NP_001361744, NP_001361745, NP_002915 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000591	DEP_dom	Domain
IPR015898	G-protein_gamma-like_dom	Domain
IPR016137	RGS	Domain
IPR036284	GGL_sf	Homologous_superfamily
IPR036305	RGS_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR040759	RGS_DHEX	Domain
IPR044926	RGS_subdomain_2	Homologous_superfamily
IPR047016	RGS6/7/9/11	Family
IPR047017	RGS6/7/9/11_DHEX_sf	Homologous_superfamily

Pfam: PF00610, PF00615, PF00631, PF18148

UniProt features (54 total): helix 25, strand 7, splice variant 4, turn 4, modified residue 4, domain 3, sequence variant 2, sequence conflict 2, chain 1, mutagenesis site 1, region of interest 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2A72	X-RAY DIFFRACTION	2
7SHF	ELECTRON MICROSCOPY	3.4
7EWP	ELECTRON MICROSCOPY	4.3
7EWR	ELECTRON MICROSCOPY	4.7
2D9J	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49802-F1	86.50	0.77

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 (4): 229, 241, 243, 434

Mutagenesis-validated functional residues (1):

Position	Phenotype
306	diminishes interaction with gnb5.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-418594	G alpha (i) signalling events
R-HSA-6814122	Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding

MSigDB gene sets: 180 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GNF2_RTN1, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, FISCHER_G1_S_CELL_CYCLE, GOBP_REGULATION_OF_GTPASE_ACTIVITY, AP4_Q6, TGACCTY_ERR1_Q2, CAGCTG_AP4_Q5, MORF_RAD51L3, MODULE_66, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, SETLUR_PROSTATE_CANCER_TMPRSS2_ERG_FUSION_DN, GOBP_REGULATION_OF_POSTSYNAPTIC_MEMBRANE_POTENTIAL

GO Biological Process (7): G protein-coupled receptor signaling pathway (GO:0007186), intracellular signal transduction (GO:0035556), positive regulation of GTPase activity (GO:0043547), negative regulation of G protein-coupled receptor signaling pathway (GO:0045744), regulation of postsynaptic membrane potential (GO:0060078), regulation of G protein-coupled receptor signaling pathway (GO:0008277), negative regulation of signal transduction (GO:0009968)

GO Molecular Function (4): G-protein alpha-subunit binding (GO:0001965), GTPase activity (GO:0003924), GTPase activator activity (GO:0005096), G-protein beta-subunit binding (GO:0031681)

GO Cellular Component (13): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), presynaptic membrane (GO:0042734), neuron projection (GO:0043005), dendrite terminus (GO:0044292), postsynaptic membrane (GO:0045211), cell tip (GO:0051286), glutamatergic synapse (GO:0098978), membrane (GO:0016020), dendrite (GO:0030425), presynapse (GO:0098793)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
GPCR downstream signalling	1
Chaperonin-mediated protein folding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
signal transduction	3
intracellular anatomical structure	2
GTPase activity	2
G protein-coupled receptor signaling pathway	2
regulation of signal transduction	2
protein binding	2
synaptic membrane	2
synapse	2
G protein-coupled receptor activity	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
regulation of G protein-coupled receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of membrane potential	1
negative regulation of cell communication	1
negative regulation of signaling	1
negative regulation of response to stimulus	1
ribonucleoside triphosphate phosphatase activity	1
enzyme activator activity	1
GTPase regulator activity	1
intracellular membrane-bounded organelle	1
cytoplasm	1
membrane	1
cell periphery	1
presynapse	1
plasma membrane bounded cell projection	1
dendrite	1
postsynapse	1
cell pole	1
neuron projection	1
dendritic tree	1

Protein interactions and networks

STRING

2190 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RGS7	GNB5	O14775	999
RGS7	RGS7BP	Q6MZT1	988
RGS7	GNAO1	P09471	970
RGS7	SUCLG2	Q96I99	891
RGS7	GPR158	Q5T848	886
RGS7	RGS9BP	Q6ZS82	870
RGS7	GGT5	P36269	862
RGS7	SUCLG1	P53597	792
RGS7	GNAQ	P50148	785
RGS7	GRK2	P25098	770
RGS7	ARHGEF1	Q92888	769
RGS7	ARHGEF11	O15085	756
RGS7	RGSL1	A5PLK6	742
RGS7	PLEK	P08567	727
RGS7	PLEK2	Q9NYT0	706

IntAct

12 interactions, top by confidence:

A	B	Type	Score
RGS7		psi-mi:“MI:0915”(physical association)	0.490
Gnao1	RGS7	psi-mi:“MI:0407”(direct interaction)	0.440
CRK	RGS7	psi-mi:“MI:0915”(physical association)	0.400
RGS7	PLCG1	psi-mi:“MI:0915”(physical association)	0.400
RGS7	H1-2	psi-mi:“MI:0915”(physical association)	0.400
RGS7	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
GNB5	CCT3	psi-mi:“MI:0914”(association)	0.350
MCM7		psi-mi:“MI:0914”(association)	0.350
pipB2	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
FOS	RGS7	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): RGS7 (Affinity Capture-MS), RGS7 (Two-hybrid), RGS7 (Affinity Capture-MS), GNAQ (FRET), RGS7 (Two-hybrid), RGS7 (Affinity Capture-Western), SNAPIN (Affinity Capture-Western), RGS7 (Reconstituted Complex), RGS7 (Synthetic Lethality), RGS7 (Reconstituted Complex), RGS7 (Reconstituted Complex), RGS7 (Reconstituted Complex), RGS7 (Reconstituted Complex), RGS7 (Reconstituted Complex), RGS7 (Proximity Label-MS)

ESM2 similar proteins: A0A571BF63, A0A5F8MPE6, A1A535, A8QHQ0, B0W730, O23463, O46470, O54829, O64851, O82645, P49758, P49802, P49803, P49809, Q058N0, Q0VA04, Q14D04, Q28IH8, Q4R6I5, Q4R7Z7, Q502W7, Q569B9, Q5PQS3, Q5SPP5, Q5XG48, Q5XIR8, Q641A2, Q6ZQ18, Q7T0S7, Q86VD1, Q8BG67, Q8BMD7, Q8CDN8, Q8H1E8, Q8IGJ0, Q8N957, Q8NCR3, Q8NHS4, Q96L03, Q96LI9

Diamond homologs: A1A643, F1S668, O08773, O08774, O08849, O08850, O08899, O14921, O14924, O15169, O15492, O15539, O35625, O42400, O43566, O43665, O46469, O46470, O46471, O54828, O54829, O70239, O70240, O70521, O75916, O76081, O88566, O94810, P34295, P41220, P49758, P49795, P49796, P49797, P49798, P49799, P49800, P49802, P49803, P49804

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKCA	“down-regulates activity”	RGS7	phosphorylation

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 4 cancer types — BRCA, LUAD, LUSC, MEL.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	7
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

5039 predictions. Top by Δscore:

Variant	Effect	Δscore
1:240813729:C:CC	acceptor_gain	1.0000
1:240816394:CATTT:C	acceptor_gain	1.0000
1:240816412:CAGA:C	acceptor_gain	1.0000
1:240816413:AGA:A	acceptor_gain	1.0000
1:240816414:GA:G	acceptor_gain	1.0000
1:240816416:C:CC	acceptor_gain	1.0000
1:240816417:T:C	acceptor_loss	1.0000
1:240816421:T:TC	acceptor_gain	1.0000
1:240827100:T:TA	donor_gain	1.0000
1:240838535:C:CT	acceptor_gain	1.0000
1:240838535:C:T	acceptor_gain	1.0000
1:240838536:A:T	acceptor_gain	1.0000
1:240868664:CCACT:C	acceptor_gain	1.0000
1:240868665:CACT:C	acceptor_gain	1.0000
1:240868665:CACTC:C	acceptor_gain	1.0000
1:240868666:ACT:A	acceptor_gain	1.0000
1:240868667:CT:C	acceptor_gain	1.0000
1:240868667:CTC:C	acceptor_gain	1.0000
1:240868668:TC:T	acceptor_loss	1.0000
1:240868668:TCT:T	acceptor_gain	1.0000
1:240868669:C:CC	acceptor_gain	1.0000
1:240868669:CTGTC:C	acceptor_loss	1.0000
1:240868674:A:T	acceptor_gain	1.0000
1:240868676:C:CT	acceptor_gain	1.0000
1:240868678:C:CT	acceptor_gain	1.0000
1:240868679:A:T	acceptor_gain	1.0000
1:240868680:G:C	acceptor_gain	1.0000
1:240868680:G:GC	acceptor_gain	1.0000
1:240868774:A:AC	donor_gain	1.0000
1:240868775:C:CC	donor_gain	1.0000

AlphaMissense

2161 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001505 (1:240955307 C>T), RS1000001889 (1:241069591 C>A,T), RS1000005383 (1:241317335 T>C), RS1000007228 (1:241277746 A>G), RS1000012391 (1:241357534 G>A), RS1000014822 (1:240799567 A>G), RS1000018249 (1:241105653 C>T), RS1000027861 (1:241147551 C>G), RS1000028374 (1:240953009 A>T), RS1000031497 (1:241066709 G>T), RS1000032476 (1:241256910 A>T), RS1000035670 (1:241336371 A>T), RS1000049865 (1:240899865 A>G), RS1000053399 (1:240946609 A>G), RS1000053837 (1:241011841 A>G)

Disease associations

OMIM: gene MIM:602517 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (1): neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001762_860	Obesity-related traits	9.000000e-06
GCST002599_3	Longevity (90 years and older)	2.000000e-06
GCST003262_599	Post bronchodilator FEV1	5.000000e-06
GCST004640_2	Western dietary pattern	3.000000e-07
GCST005169_2	Diastolic blood pressure	1.000000e-06
GCST006041_42	Major depressive disorder	3.000000e-06
GCST007576_235	Chronotype	1.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004620	vitamin B12 measurement
EFO:0004314	forced expiratory volume
EFO:0008111	diet measurement
EFO:0006336	diastolic blood pressure
EFO:0008328	chronotype measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — R7 family

Binding affinities (BindingDB)

56 measured of 180 human assays (192 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
(2E)-3-(2-chloroanilino)-2-(3,3-dimethyl-2,4-dihydroisoquinolin-1-ylidene)-3-keto-propionic acid ethyl ester	EC50	10 nM
(3R)-2-(4-fluorophenyl)sulfonyl-3,4-dihydro-1H-isoquinoline-3-carboxylic acid	EC50	10 nM
2,4-dimethyl-6-[2-oxidanylidene-2-(4-phenylpiperazin-1-yl)ethyl]-1,6-naphthyridin-5-one	EC50	18 nM
MLS000093573	IC50	23 nM
1-(1-adamantyl)-3-(1,3-benzodioxol-5-ylmethyl)urea	EC50	60 nM
2,5-bis(chloranyl)-3-(4-methylpiperazin-1-yl)-6-(2-piperidin-1-yl-1,3-thiazol-5-yl)cyclohexa-2,5-diene-1,4-dione	EC50	160 nM
2,5-bis(chloranyl)-3-[2-(dimethylamino)-1,3-thiazol-5-yl]-6-pyrrolidin-1-yl-cyclohexa-2,5-diene-1,4-dione	EC50	210 nM
MLS000114722	EC50	820 nM
MLS000689390	EC50	880 nM
3-chloranyl-N-(3-morpholin-4-ylpropyl)-6-nitro-1-benzothiophene-2-carboxamide	EC50	950 nM
3,4,5-trihydroxybenzoic acid [(3R,4S,5S,6S)-3,4,5,6-tetragalloyloxytetrahydropyran-2-yl]methyl ester	EC50	951 nM
2-[2-oxidanylidene-2-[2-[(Z)-(3-oxidanyl-4-oxidanylidene-cyclohexa-2,5-dien-1-ylidene)methyl]hydrazinyl]ethoxy]-N’’-[(Z)-(3-oxidanyl-4-oxidanylidene-cyclohexa-2,5-dien-1-ylidene)methyl]benzohydrazide	IC50	1070 nM
1,6,6-triphenyl-3-(p-tolyl)-3-azabicyclo[3.1.0]hexane-2,4-quinone	EC50	1160 nM
2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)sulfanyl]-1-oxidopyridin-1-ium	EC50	1320 nM
cid_25227363	EC50	1430 nM
Chebulinic acid	IC50	1520 nM
MLS000697664	IC50	1560 nM
4-chloranyl-6-(4,6-dimethylpyrimidin-2-yl)sulfanyl-N-methyl-1,3,5-triazin-2-amine	EC50	1630 nM
2-(4,6-dimethyl-3-oxidanylidene-[1,2]thiazolo[5,4-b]pyridin-2-yl)-N-(3-fluorophenyl)ethanamide	EC50	1720 nM
2-(3-keto-4,6-dimethyl-isothiazolo[5,4-b]pyridin-2-yl)-N-propyl-acetamide	EC50	1750 nM
MLS000689393	EC50	1750 nM
DEFEROXAMINE	EC50	1850 nM
1,12,23-trihydroxy-1,6,12,17,23,28-hexazacyclotritriacontane-2,5,13,16,24,27-hexone	EC50	2240 nM
2,5-bis(chloranyl)-3-piperidin-1-yl-6-(2-piperidin-1-yl-1,3-thiazol-5-yl)cyclohexa-2,5-diene-1,4-dione	EC50	2320 nM
3-chloranyl-N-(3,3-dimethylbutan-2-yl)-6-nitro-1-benzothiophene-2-carboxamide	EC50	2470 nM
MLS000544577	IC50	2630 nM
(4E)-2,3-dihydroxy-4-[[(4-methyl-2-methylimino-1,3-thiazol-3-yl)amino]methylidene]cyclohexa-2,5-dien-1-one	IC50	2720 nM
MLS000759648	IC50	3520 nM
5-acetyl-2-[[5-(4-ketocyclohexa-2,5-dien-1-ylidene)-3-isoxazoline-3-carbonyl]amino]-4-methyl-thiophene-3-carboxylic acid ethyl ester	IC50	3690 nM
MLS000757112	IC50	4290 nM
(1R,19R,21S,22R,23R)-6,7,8,11,12,13,22,23-octahydroxy-3,16-dioxo-2,17,20-trioxatetracyclo[17.3.1.0^{4,9}.0^{10,15}]tricosa-4(9),5,7,10,12,14-hexaen-21-yl 3,4,5-trihydroxybenzoate	IC50	4480 nM
3-[[[(E)-(2,3-dihydroxy-4-keto-cyclohexa-2,5-dien-1-ylidene)methyl]amino]carbamoyl]-N,N-diethyl-benzenesulfonamide	EC50	5130 nM
MLS000390238	EC50	5260 nM
2-(4-Methoxy-phenyl)-[1,4]benzoquinone	IC50	5430 nM
3,4,5-trihydroxy-N’-[(1Z)-1-(4-nitrophenyl)ethylidene]benzohydrazide	EC50	5960 nM
4-[(3-carbamoyl-4,5-dimethyl-2-thienyl)amino]-4-keto-butyric acid methyl ester	EC50	6560 nM
(2Z)-3-ethyl-2-[(2E,4E)-5-(3-ethyl-1,3-benzothiazol-3-ium-2-yl)penta-2,4-dienylidene]-1,3-benzothiazole;iodide	EC50	6670 nM
(E)-3-(2-furanyl)-N-[(4-sulfamoylphenyl)methyl]-2-propenamide	EC50	7670 nM
4-(2-methylphenyl)-3-pyridin-4-yl-1H-1,2,4-triazole-5-thione	EC50	7760 nM
(4E)-5-methyl-4-[[3-[[(Z)-(3-methyl-1-phenyl-5-sulfanylidene-4-pyrazolylidene)methyl]amino]propylamino]methylidene]-2-phenyl-3-pyrazolethione	EC50	8790 nM
MLS000553854	EC50	11700 nM
4-[5-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl]-2-furanyl]benzenesulfonamide	EC50	11900 nM
3-(3-keto-1,2-benzothiazol-2-yl)-N,N-dimethyl-benzenesulfonamide	IC50	13000 nM
1-[3-(4-nitrophenyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazol-7-ium-7-yl]ethanone;bromide	EC50	13500 nM
(2Z)-3-ethyl-2-[(E)-3-(3-ethyl-1,3-benzothiazol-3-ium-2-yl)-2-methyl-prop-2-enylidene]-1,3-benzothiazole;iodide	EC50	22400 nM
(2Z,4S,6S,12aS)-4-(dimethylamino)-6,10,11,12a-tetrahydroxy-2-[hydroxy-(1-pyrrolidinylmethylamino)methylidene]-6-methyl-4,4a,5,5a-tetrahydrotetracene-1,3,12-trione	EC50	23700 nM
(4E)-4-[[(2-ethylimino-4-methyl-1,3-thiazol-3-yl)amino]methylidene]-2,3-bis(oxidanyl)cyclohexa-2,5-dien-1-one	EC50	29400 nM
UNM-0000305796	EC50	30000 nM
2,4-dimethyl-6-[2-[3-methyl-4-(3-methylphenyl)piperazin-1-yl]-2-oxidanylidene-ethyl]-1,6-naphthyridin-5-one	EC50	30000 nM
2,4-dimethyl-6-[2-oxidanylidene-2-(4-phenylpiperazin-1-yl)ethyl]-7,8-dihydro-1,6-naphthyridin-5-one	EC50	30000 nM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
sodium arsenite	decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Copper	affects cotreatment, decreases expression, affects binding, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
p-Chloromercuribenzoic Acid	increases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
trichostatin A	increases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	increases methylation	1
CGP 52608	increases reaction, affects binding	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
NSC 689534	increases expression, affects binding	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Curcumin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Lead	affects expression	1

Clinical trials (associated diseases)

202 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
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
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice