RGS2

Summary

RGS2 (regulator of G protein signaling 2, HGNC:9998) is a protein-coding gene on chromosome 1q31.2, encoding Regulator of G-protein signaling 2 (P41220). Regulates G protein-coupled receptor signaling cascades.

Regulator of G protein signaling (RGS) family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. RGS proteins are able to deactivate G protein subunits of the Gi alpha, Go alpha and Gq alpha subtypes. They drive G proteins into their inactive GDP-bound forms. Regulator of G protein signaling 2 belongs to this family. The protein acts as a mediator of myeloid differentiation and may play a role in leukemogenesis.

Source: NCBI Gene 5997 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 18 total — 1 likely-pathogenic
• MANE Select transcript: NM_002923

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9998
Approved symbol	RGS2
Name	regulator of G protein signaling 2
Location	1q31.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000116741
Ensembl biotype	protein_coding
OMIM	600861
Entrez	5997

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000235382, ENST00000464302, ENST00000483295, ENST00000487236

RefSeq mRNA: 1 — MANE Select: NM_002923 NM_002923

CCDS: CCDS1377

Canonical transcript exons

ENST00000235382 — 5 exons

Exon	Start	End
ENSE00000790952	192810981	192811147
ENSE00000869804	192809039	192809181
ENSE00000869805	192811402	192812275
ENSE00003576333	192810370	192810431
ENSE00003582378	192810166	192810267

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 72.7719 / max 8546.9079, expressed in 1662 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7455	72.6785	1662
7454	0.0934	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.99	gold quality
secondary oocyte	CL:0000655	99.99	gold quality
periodontal ligament	UBERON:0008266	99.68	gold quality
monocyte	CL:0000576	99.63	gold quality
mononuclear cell	CL:0000842	99.63	gold quality
leukocyte	CL:0000738	99.62	gold quality
cauda epididymis	UBERON:0004360	99.58	gold quality
mucosa of stomach	UBERON:0001199	99.50	gold quality
granulocyte	CL:0000094	99.48	gold quality
lower esophagus	UBERON:0013473	99.39	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.39	gold quality
seminal vesicle	UBERON:0000998	99.30	gold quality
mucosa of urinary bladder	UBERON:0001259	99.29	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.27	gold quality
bone marrow	UBERON:0002371	99.26	gold quality
jejunal mucosa	UBERON:0000399	99.19	gold quality
gall bladder	UBERON:0002110	99.18	gold quality
blood	UBERON:0000178	99.11	gold quality
duodenum	UBERON:0002114	99.11	gold quality
left uterine tube	UBERON:0001303	99.07	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.02	gold quality
decidua	UBERON:0002450	98.92	gold quality
adenohypophysis	UBERON:0002196	98.88	gold quality
trabecular bone tissue	UBERON:0002483	98.88	gold quality
pituitary gland	UBERON:0000007	98.85	gold quality
caput epididymis	UBERON:0004358	98.85	gold quality
body of uterus	UBERON:0009853	98.85	gold quality
myometrium	UBERON:0001296	98.72	gold quality
spleen	UBERON:0002106	98.63	gold quality
corpus epididymis	UBERON:0004359	98.58	gold quality

Single-cell (SCXA)

Detected in 30 experiment(s), a significant marker in 24.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	2832.89
E-CURD-114	yes	2442.75
E-MTAB-8322	yes	1923.17
E-MTAB-5061	yes	822.06
E-HCAD-4	yes	96.06
E-MTAB-8142	yes	66.55
E-CURD-88	yes	55.39
E-GEOD-135922	yes	41.43
E-MTAB-10553	yes	38.54
E-CURD-46	yes	36.39
E-GEOD-134144	yes	27.70
E-MTAB-9467	yes	24.63
E-MTAB-10287	yes	23.62
E-CURD-112	yes	18.98
E-MTAB-9221	yes	18.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, HSF1, MYC, PITX2, RUNX2, ZNF316

miRNA regulators (miRDB)

46 targeting RGS2, 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-548N	99.98	71.94	4170
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-153-5P	99.89	73.86	6317
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-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-374A-3P	98.87	67.82	1531

Literature-anchored findings (GeneRIF, showing 40)

• RGS2 plays a role in regulating purinergic signaling in human broncheotracheal cells (PMID:12356577)
• Identification of RGS2 and type V adenylyl cyclase interaction sites. (PMID:12604604)
• RGS-2 level in human clinical condition characterized by altered vascular tone. Importance of RGS-2 as key regulator element for Ang II signaling. Links between Bartter’s/Gitelman’s syndrome genetic abnormalities and abnormal vascular tone regulation. (PMID:15292363)
• TSH-dependent RGS 2 mRNA expression and the suppression of TSH-G(q)alpha signaling by the overexpression of RGS 2 imply that RGS 2 is involved in TSHR-induced G(q) signal transduction. (PMID:15362969)
• RGS2 promoted the conversion of more stable Ca2+ elevations into oscillatory signals. (PMID:15383626)
• RGS2 is a novel mediator of myeloid differentiation, and its repression is an important event in Flt3-ITD-induced transformation (PMID:15536149)
• The RGS2 accelerates the GTPase activity of Galpha subunits and act in a G-protein-coupled receptor (GPCR)-specific manner.. (PMID:15793568)
• The N terminus of RGS2 was required for association with alpha1A-ARs and inhibition of signaling, and amino acids Lys219, Ser220, and Arg238 within the alpha1A-AR i3 loop were found to be essential for this interaction (PMID:15917235)
• Genetic variations of RGS2 were studied in hypertensive patients and in the general population. (PMID:16003176)
• RGS2 is genetically conserved within coding regions, but intronic in/del define ethnicity-specific haplotypes. Certain RGS2 variants that occur at greater frequency in hypertensive blacks may serve as ethnicity-specific genetic variants for this disease. (PMID:16432041)
• our results suggest RGS2 as a novel regulator of androgen receptor signaling and its repression may be an important step during prostate tumorigenesis and progression. (PMID:16449965)
• RGS2 alterations in expression levels or functionality could be implicated in deregulations of Ang II signaling and abnormal aldosterone secretion by the adrenal gland (PMID:16627589)
• Low expression of RGS2 contributes to increased G-protein-coupled signaling in hypertensive patients. The allele 1114G is associated with low RGS2 expression and blood pressure increase in humans. (PMID:16685212)
• variations of the Rgs2 gene play a role also for the development of anxiety in humans (PMID:16736243)
• Acts as a novel binding partner and inhibitor of calcium channel TRPV6 and has a putative role in active Ca2+ absorption. (PMID:16895908)
• examined function, receptor specificity, and expression of R4 subfamily RGS proteins, RGS2, -3, -4, -5, and -8 via missense mutations introduced (PMID:17220356)
• RGS2 is a key point of integration for multiple intracellular signaling pathways, and they highlight the role of RGS proteins as dynamic, multifunctional signaling centers that coordinate a diverse range of cellular functions. (PMID:17244887)
• Results indicate that cAMP stimulates RGS2 expression, which in turn leads to a decrease in the cAMP production by inactivating the G-protein signaling in the mechanically stressed periodontal ligament cells. (PMID:17294519)
• Five out of six single nucleotide polymorphisms within or flanking the RGS2 gene were nominally associated with development or worsening of parkinsonian symptoms induced by treatment with antipsychotic medication. (PMID:17558307)
• These findings suggest that RGS2 is genetically involved in the biological susceptibility to suicide in the Japanese population. (PMID:17728697)
• alternative translation initiation of RGS2 is part of a novel negative feedback control pathway for adenylyl cyclase signaling (PMID:17901199)
• Functional analysis proved RGS2 to be a modulator of oxytocin receptor signalling. It was also over-expressed in most breast cancers, identifying the product of this gene, or the pathway(s) it regulates, as potentially significant therapeutic targets. (PMID:18067675)
• These data are consistent with the notion that a R44H missense mutation in human RGS2 produces a hypomorphic allele that may lead to altered receptor-mediated G(q) inhibition and contribute to the development of hypertension in affected subjects. (PMID:18230714)
• the RGS2 1114G allele may be considered a genetic marker that predicts an individual’s predisposition to gaining weight (PMID:18249218)
• RGS2 genotypes predicted severity of baseline symptoms in schizophrenia. These data suggest a possible role for multiple RGS proteins in schizophrenia. (PMID:18262772)
• Further evidence for association of the RGS2 gene with antipsychotic-induced parkinsonism: protective role of a functional polymorphism in the 3’-untranslated region. (PMID:18347610)
• Silencing RGS-2 in Bartters syndrome/Gitelman’s syndrome patients increased Ang II-induced Cai2+ release and signaling in silenced cells compared with not silenced cells (PMID:18398336)
• RGS2 gene is prevalent in generalized anxiety disorder. (PMID:18833580)
• RGS2 function contributes to blood pressure regulation; a reduced expression is associated with HT and an increased expression with low blood pressure. (PMID:19023274)
• Regulators of G protein signaling-2 (RGS2) can interact with G-protein coupled receptors to modulate their signaling and provide a molecular basis for RGS2 recognition by cholecystokinin-2 receptor. (PMID:19064631)
• Varian in RGS2 moderates posttraumatic stress symptoms following a traumatic event exposure. (PMID:19162436)
• RGS2 expression was upregulated by LH receptor and FP receptor activation and modulation of partner receptor signaling by RGS2 may require RGS2 translocation from the nucleus to the plasma membrane. (PMID:19175184)
• Results suggest the association of G/G 1114 RGS2 genotype with the number of episodes of neurally mediated syncope. Molecular mechanism of the influence of the polymorphism on syncopal number is associated with the reduced expression of RGS2 gene. (PMID:19427970)
• Study determined a model of the triple mutant RGS2 in complex with a transition state mimetic form of Galpha(i) at 2.8-A resolution. (PMID:19478087)
• Phosphoglycerate kinase 2 (PGK2) showed a difference between follicular cells from follicles leading to a pregnancy or developmental failure. (PMID:19778949)
• RGS2 rs4606 is related to risk of current suicidal ideation in stressor-exposed adults. (PMID:19813112)
• rs4606 does not affect AIEPSs in Japanese subjects. (PMID:19931593)
• down-regulation of RGS2 might play an important role in colorectal cancer (CRC) metastasis and predict poor prognosis in stage II and III CRC patients. (PMID:20001967)
• Ischemic stress increases RGS2 expression and that this condition contributes to enhanced apoptosis in C6 cells and primary astrocytes. (PMID:20032508)
• The D allele of the 1891-1892TC insertion/deletion locus of the RGS2 gene is an independent risk factor for hypertension in a Chinese population. (PMID:20140863)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rgs2	ENSDARG00000098761
mus_musculus	Rgs2	ENSMUSG00000026360
rattus_norvegicus	Rgs2	ENSRNOG00000003687

Paralogs (23): RGS11 (ENSG00000076344), RGS1 (ENSG00000090104), RGS17 (ENSG00000091844), AXIN1 (ENSG00000103126), RGS9 (ENSG00000108370), 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), RGS7 (ENSG00000182901), RGS21 (ENSG00000253148)

Protein

Protein identifiers

Regulator of G-protein signaling 2 — P41220 (reviewed: P41220)

Alternative names: Cell growth-inhibiting gene 31 protein, G0/G1 switch regulatory protein 8

All UniProt accessions (1): P41220

UniProt curated annotations — full annotation on UniProt →

Function. Regulates G protein-coupled receptor signaling cascades. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form. It is involved in the negative regulation of the angiotensin-activated signaling pathway. Plays a role in the regulation of blood pressure in response to signaling via G protein-coupled receptors and GNAQ. Plays a role in regulating the constriction and relaxation of vascular smooth muscle. Binds EIF2B5 and blocks its activity, thereby inhibiting the translation of mRNA into protein.

Subunit / interactions. Interacts with GNAQ. Does not interact with GNAI1 and GNAI3. Interacts with EIF2B5. Interacts with PRKG1 (isoform alpha). Interacts with FBXO44; this interaction mediates RGS2 ubiquitination and subsequent degradation.

Subcellular location. Cell membrane. Cytoplasm. Nucleus. Nucleolus Cell membrane. Mitochondrion.

Tissue specificity. Expressed in acute myelogenous leukemia (AML) and in acute lymphoblastic leukemia (ALL).

Post-translational modifications. Phosphorylated by protein kinase C. Phosphorylation by PRKG1 leads to activation of RGS2 activity. Phosphorylation of Ser-3 protects RGS2 from FBXO44-mediated proteasomal degradation. Ubiquitinated by the cullin-RING ligase (CRL) complex composed of CUL4B, DDB1 and FBXO44; ubiquitination leads to RGS2 proteasomal degradation.

Miscellaneous. Lacks type V adenylyl cyclase (AC) inhibitory function. Lacks type V adenylyl cyclase (AC) inhibitory function.

Isoforms (4)

UniProt ID	Names	Canonical?
P41220-1	1	yes
P41220-2	2
P41220-3	3
P41220-4	4

RefSeq proteins (1): NP_002914* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016137	RGS	Domain
IPR024066	RGS_subdom1/3	Homologous_superfamily
IPR034947	RGS2_RGS	Domain
IPR036305	RGS_sf	Homologous_superfamily
IPR044926	RGS_subdomain_2	Homologous_superfamily

Pfam: PF00615

UniProt features (65 total): mutagenesis site 26, sequence variant 16, helix 10, region of interest 4, splice variant 3, turn 2, chain 1, domain 1, modified residue 1, cross-link 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2AF0	X-RAY DIFFRACTION	2.3
4EKD	X-RAY DIFFRACTION	2.71
2V4Z	X-RAY DIFFRACTION	2.8
4EKC	X-RAY DIFFRACTION	7.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41220-F1	80.86	0.60

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 (2): 3, 200

Mutagenesis-validated functional residues (26):

Position	Phenotype
1	loss of isoform 1 expression.
3	expressed at significantly lower levels than wt.
3	complete suppression of the response to proteasome inhibitor mg132.
5	loss of isoform 2 expression.
16	loss of isoform 3 expression.
33	loss of isoform 4 expression.
37	impairs association with plasma membrane.
38	impairs association with plasma membrane.
41	impairs association with plasma membrane.
45	impairs association with plasma membrane.
48	impairs association with plasma membrane.
49	impairs association with plasma membrane.
79	near loss of eif2b5 binding and inhibition of in vitro translation; when associated with e-86; l-87; s-90; k-102; f-105;
86	near loss of eif2b5 binding and inhibition of in vitro translation; when associated with l-79; l-87; s-90; k-102; f-105;
87	near loss of eif2b5 binding and inhibition of in vitro translation; when associated with l-79; e-86; s-90; k-102; f-105;
90	near loss of eif2b5 binding and inhibition of in vitro translation; when associated with l-79; e-86; l-87; k-102; f-105;
102	near loss of eif2b5 binding and inhibition of in vitro translation; when associated with l-79; e-86; l-87; s-90; f-105;
105	near loss of eif2b5 binding and inhibition of in vitro translation; when associated with l-79; e-86; l-87; s-90; k-102;
106	changes specificity and confers gnai1 binding; when associated with d-184. strongly increases affinity for gnai1 and gna
110	near loss of eif2b5 binding and inhibition of in vitro translation; when associated with l-79; e-86; l-87; s-90; k-102;
111	near loss of eif2b5 binding and inhibition of in vitro translation; when associated with l-79; e-86; l-87; s-90; k-102;
114	near loss of eif2b5 binding and inhibition of in vitro translation; when associated with l-79; e-86; l-87; s-90; k-102;
149	decreases gtpase accelerating function but has no effect on translation inhibitory activity, suggesting that its role in
184	changes specificity and confers gnai1 binding; when associated with d-184. strongly increases affinity for gnai1 and gna
191	strongly increases affinity for gnai1 and gnai3; when associated with s-106 and d-184.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 660 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_RESPONSE_TO_ETHANOL, GOBP_MUSCLE_TISSUE_DEVELOPMENT, MCLACHLAN_DENTAL_CARIES_UP, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_NEGATIVE_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_AMINE, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, MODULE_45

GO Biological Process (21): response to amphetamine (GO:0001975), G protein-coupled receptor signaling pathway (GO:0007186), spermatogenesis (GO:0007283), regulation of G protein-coupled receptor signaling pathway (GO:0008277), negative regulation of cardiac muscle hypertrophy (GO:0010614), positive regulation of neuron projection development (GO:0010976), negative regulation of translation (GO:0017148), response to ethanol (GO:0045471), negative regulation of G protein-coupled receptor signaling pathway (GO:0045744), negative regulation of JNK cascade (GO:0046329), brown fat cell differentiation (GO:0050873), relaxation of cardiac muscle (GO:0055119), relaxation of vascular associated smooth muscle (GO:0060087), maternal process involved in female pregnancy (GO:0060135), positive regulation of cardiac muscle contraction (GO:0060452), negative regulation of cell growth involved in cardiac muscle cell development (GO:0061052), regulation of adenylate cyclase-inhibiting adrenergic receptor signaling pathway (GO:0071877), positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway (GO:1900738), negative regulation of glycine import across plasma membrane (GO:1900924), regulation of translation (GO:0006417), negative regulation of signal transduction (GO:0009968)

GO Molecular Function (7): G-protein alpha-subunit binding (GO:0001965), GTPase activity (GO:0003924), GTPase activator activity (GO:0005096), calmodulin binding (GO:0005516), adenylate cyclase inhibitor activity (GO:0010855), beta-tubulin binding (GO:0048487), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), nucleolus (GO:0005730), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
G protein-coupled receptor signaling pathway	2
translation	2
regulation of G protein-coupled receptor signaling pathway	2
protein binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
response to amine	1
G protein-coupled receptor activity	1
signal transduction	1
developmental process involved in reproduction	1
male gamete generation	1
regulation of signal transduction	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
negative regulation of muscle hypertrophy	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
response to alcohol	1
negative regulation of signal transduction	1
JNK cascade	1
negative regulation of MAPK cascade	1
regulation of JNK cascade	1
fat cell differentiation	1
relaxation of muscle	1
vasodilation	1
relaxation of smooth muscle	1
negative regulation of smooth muscle contraction	1
female pregnancy	1
multicellular organismal reproductive process	1
positive regulation of heart contraction	1
positive regulation of striated muscle contraction	1
regulation of cardiac muscle contraction	1
cardiac muscle contraction	1
negative regulation of cardiac muscle hypertrophy	1
negative regulation of cell growth	1

Protein interactions and networks

STRING

1816 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RGS2	GNAQ	P50148	960
RGS2	PPP1R9B	Q96SB3	875
RGS2	GDE1	Q9NZC3	690
RGS2	ADCY2	Q08462	674
RGS2	TMTC1	Q8IUR5	673
RGS2	ADCY3	O60266	649
RGS2	SAG	P10523	647
RGS2	PRKG1	P14619	621
RGS2	CRTC3	Q6UUV7	608
RGS2	RASA1	P20936	606
RGS2	CALM1	P02593	603
RGS2	CALML3	P27482	603
RGS2	CALML6	Q8TD86	603
RGS2	CALML4	Q96GE6	603
RGS2	CALML5	Q9NZT1	602

IntAct

87 interactions, top by confidence:

A	B	Type	Score
LRRK2	RGS2	psi-mi:“MI:0915”(physical association)	0.570
LRRK2	RGS2	psi-mi:“MI:0403”(colocalization)	0.570
RGS2	LRRK2	psi-mi:“MI:0403”(colocalization)	0.570
LRRK2	RGS2	psi-mi:“MI:0217”(phosphorylation reaction)	0.570
RGS2	MTUS2	psi-mi:“MI:0915”(physical association)	0.560
MTUS2	RGS2	psi-mi:“MI:0915”(physical association)	0.560
CIAO1	RGS2	psi-mi:“MI:0915”(physical association)	0.560
PRKN	RGS2	psi-mi:“MI:0915”(physical association)	0.560
RGS2	CTSB	psi-mi:“MI:0915”(physical association)	0.550
DDR1	RGS2	psi-mi:“MI:0915”(physical association)	0.550
RGS2	DYNLL1	psi-mi:“MI:0915”(physical association)	0.550
RGS2	GIT1	psi-mi:“MI:0915”(physical association)	0.550
HSPA8	RGS2	psi-mi:“MI:0915”(physical association)	0.550
RGS2	LRFN1	psi-mi:“MI:0915”(physical association)	0.550
RGS2	NIPSNAP1	psi-mi:“MI:0915”(physical association)	0.550
RGS2	PRKN	psi-mi:“MI:0915”(physical association)	0.550
RGS2	PRKCSH	psi-mi:“MI:0915”(physical association)	0.550
RGS2	VPS29	psi-mi:“MI:0915”(physical association)	0.550
WDR74	RGS2	psi-mi:“MI:0915”(physical association)	0.550

BioGRID (110): MTUS2 (Two-hybrid), NINL (Two-hybrid), FBXO44 (Affinity Capture-Western), RGS2 (Affinity Capture-Western), DDB1 (Affinity Capture-Western), MTUS2 (Two-hybrid), NINL (Affinity Capture-MS), MIPOL1 (Affinity Capture-MS), PTPN13 (Affinity Capture-MS), STXBP4 (Affinity Capture-MS), METAP2 (Affinity Capture-MS), STRIP1 (Affinity Capture-MS), KBTBD7 (Affinity Capture-MS), STK26 (Affinity Capture-MS), SERPINA10 (Affinity Capture-MS)

ESM2 similar proteins: A1A643, O08849, O08850, O14921, O15539, O35119, O43665, O46470, O54829, P34295, P41220, P49758, P49800, P49802, P49803, P49806, P49808, P49809, P79100, P97844, Q08116, Q09777, Q0P5H5, Q10955, Q2KHW7, Q2M5E4, Q3S853, Q3T0T8, Q4L0E8, Q5M8L6, Q62240, Q6DGI0, Q6RG78, Q864Z2, Q8K443, Q8VYB9, Q99PG4, Q9CQE5, Q9FLY5, Q9JHX0

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

2 interactions.

A	Effect	B	Mechanism
PRKG1	“up-regulates activity”	RGS2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	10
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
372899	NM_002923.4(RGS2):c.274+1G>T	Likely pathogenic

SpliceAI

392 predictions. Top by Δscore:

Variant	Effect	Δscore
1:192809177:ACCCT:A	donor_gain	1.0000
1:192809178:CCCT:C	donor_gain	1.0000
1:192809179:CCT:C	donor_gain	1.0000
1:192809180:CT:C	donor_gain	1.0000
1:192809181:TG:T	donor_loss	1.0000
1:192809182:G:GG	donor_gain	1.0000
1:192809183:T:A	donor_loss	1.0000
1:192809184:GA:G	donor_gain	1.0000
1:192809186:G:GG	donor_gain	1.0000
1:192810158:T:A	acceptor_gain	1.0000
1:192810164:A:AG	acceptor_gain	1.0000
1:192810165:G:GG	acceptor_gain	1.0000
1:192810165:GT:G	acceptor_gain	1.0000
1:192810165:GTT:G	acceptor_gain	1.0000
1:192810165:GTTT:G	acceptor_gain	1.0000
1:192810165:GTTTA:G	acceptor_gain	1.0000
1:192810263:ATCAA:A	donor_gain	1.0000
1:192810264:TCAA:T	donor_gain	1.0000
1:192810265:CAA:C	donor_gain	1.0000
1:192810266:AA:A	donor_gain	1.0000
1:192810267:AGTA:A	donor_loss	1.0000
1:192810268:G:GG	donor_gain	1.0000
1:192810268:GT:G	donor_loss	1.0000
1:192810269:TAA:T	donor_loss	1.0000
1:192810273:T:G	donor_gain	1.0000
1:192810364:TTGCA:T	acceptor_loss	1.0000
1:192810365:TGCA:T	acceptor_loss	1.0000
1:192810366:GCAG:G	acceptor_loss	1.0000
1:192810367:CA:C	acceptor_loss	1.0000
1:192810368:A:AG	acceptor_gain	1.0000

AlphaMissense

1411 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:192810996:T:C	F97S	1.000
1:192811004:T:C	F100L	1.000
1:192811006:T:A	F100L	1.000
1:192811006:T:G	F100L	1.000
1:192811029:A:T	E108V	1.000
1:192811040:T:C	F112L	1.000
1:192811041:T:C	F112S	1.000
1:192811042:C:A	F112L	1.000
1:192811042:C:G	F112L	1.000
1:192811043:T:A	W113R	1.000
1:192811043:T:C	W113R	1.000
1:192811053:G:A	C116Y	1.000
1:192811054:T:G	C116W	1.000
1:192811121:T:C	F139L	1.000
1:192811122:T:C	F139S	1.000
1:192811123:C:A	F139L	1.000
1:192811123:C:G	F139L	1.000
1:192811407:C:A	N149K	1.000
1:192811407:C:G	N149K	1.000
1:192811469:T:C	F170S	1.000
1:192811478:C:A	A173D	1.000
1:192811502:T:C	M181T	1.000
1:192811516:T:G	Y186D	1.000
1:192811525:T:C	F189L	1.000
1:192811526:T:C	F189S	1.000
1:192811527:C:A	F189L	1.000
1:192811527:C:G	F189L	1.000
1:192810395:T:A	W80R	0.999
1:192810395:T:C	W80R	0.999
1:192810417:T:C	L87P	0.999

dbSNP variants (sampled 300 via entrez): RS1000027668 (1:192807963 A>C,G), RS1000453568 (1:192812051 AGTTCTTAT>A), RS1000772860 (1:192812733 C>G), RS1000789371 (1:192808848 G>A,C), RS1000790169 (1:192810459 T>C), RS1000841714 (1:192808355 C>G), RS1001121171 (1:192809542 C>G), RS1001147402 (1:192811291 G>A,C), RS1002879466 (1:192810756 T>C), RS1002915741 (1:192810060 T>C), RS1003200949 (1:192812698 G>T), RS1004443395 (1:192807148 A>G), RS1004654781 (1:192810887 A>G), RS1004700506 (1:192811255 A>G), RS1004877458 (1:192810325 G>A)

Disease associations

OMIM: gene MIM:600861 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002097_33	Coronary artery calcification	4.000000e-06
GCST006295_10	Response to quetiapine in schizophrenia	5.000000e-06
GCST006295_8	Response to quetiapine in schizophrenia	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4606	Toxicity	3	antipsychotics	Schizophrenia

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4606	RGS2	3	2.00	1	antipsychotics
rs34717272	RGS2		0.00	0
rs1933695	RGS2		0.00	0
rs2179652	RGS2		0.00	0
rs1819741	RGS2		0.00	0
rs1152746	RGS2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — R4 family

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	6
Arsenic Trioxide	decreases expression, increases expression	5
Cisplatin	affects cotreatment, increases expression	5
Benzo(a)pyrene	decreases expression, increases expression, increases methylation	3
Estradiol	affects cotreatment, increases expression	3
Progesterone	affects cotreatment, increases expression	3
Valproic Acid	increases expression, affects expression, decreases methylation	3
methylmercuric chloride	affects reaction, increases expression	2
trichostatin A	affects expression, increases expression	2
cobaltous chloride	increases expression	2
manganese chloride	decreases expression, increases abundance, increases expression	2
potassium chromate(VI)	affects cotreatment, increases expression	2
chromium hexavalent ion	increases expression, increases abundance	2
Decitabine	increases expression, affects cotreatment, affects expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Cadmium	increases expression	2
Formaldehyde	increases expression	2
Manganese	decreases expression, increases abundance, increases expression	2
Silver	increases expression	2
Tetrachlorodibenzodioxin	affects expression, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Tretinoin	increases expression	2
Cyclosporine	increases expression, decreases expression	2
Aflatoxin B1	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
diethyl phthalate	affects cotreatment, decreases reaction, increases expression	1

Clinical trials (associated diseases)

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