RGS18

Summary

RGS18 (regulator of G protein signaling 18, HGNC:14261) is a protein-coding gene on chromosome 1q31.2, encoding Regulator of G-protein signaling 18 (Q9NS28). Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form.

This gene encodes a member of the regulator of G-protein signaling family. This protein is contains a conserved, 120 amino acid motif called the RGS domain. The protein attenuates the signaling activity of G-proteins by binding to activated, GTP-bound G alpha subunits and acting as a GTPase activating protein (GAP), increasing the rate of conversion of the GTP to GDP. This hydrolysis allows the G alpha subunits to bind G beta/gamma subunit heterodimers, forming inactive G-protein heterotrimers, thereby terminating the signal. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.

Source: NCBI Gene 64407 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inherited bleeding disorder, platelet-type (Limited, GenCC)
• GWAS associations: 10
• Clinical variants (ClinVar): 36 total
• MANE Select transcript: NM_130782

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14261
Approved symbol	RGS18
Name	regulator of G protein signaling 18
Location	1q31.2
Locus type	gene with protein product
Status	Approved
Aliases	RGS13
Ensembl gene	ENSG00000150681
Ensembl biotype	protein_coding
OMIM	607192
Entrez	64407

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000367460, ENST00000481707, ENST00000491030, ENST00000492967

RefSeq mRNA: 1 — MANE Select: NM_130782 NM_130782

CCDS: CCDS1374

Canonical transcript exons

ENST00000367460 — 5 exons

Exon	Start	End
ENSE00000995890	192181292	192181458
ENSE00001444555	192184297	192185815
ENSE00001444556	192158462	192158756
ENSE00003615606	192159220	192159321
ENSE00003655104	192160378	192160439

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 99.34.

FANTOM5 (CAGE): breadth broad, TPM avg 12.3060 / max 1996.8440, expressed in 374 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7415	10.7953	363
7416	1.0639	142
7414	0.2465	30
7417	0.2003	78

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.34	gold quality
leukocyte	CL:0000738	99.07	gold quality
granulocyte	CL:0000094	93.39	gold quality
blood	UBERON:0000178	93.35	gold quality
trabecular bone tissue	UBERON:0002483	93.03	gold quality
bone marrow	UBERON:0002371	92.54	gold quality
bone marrow cell	CL:0002092	91.35	gold quality
vermiform appendix	UBERON:0001154	87.07	gold quality
spleen	UBERON:0002106	84.69	gold quality
right lung	UBERON:0002167	84.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.57	gold quality
caecum	UBERON:0001153	77.09	gold quality
gall bladder	UBERON:0002110	76.43	gold quality
palpebral conjunctiva	UBERON:0001812	75.87	gold quality
smooth muscle tissue	UBERON:0001135	75.59	gold quality
lymph node	UBERON:0000029	75.38	gold quality
decidua	UBERON:0002450	75.23	gold quality
upper lobe of left lung	UBERON:0008952	74.85	gold quality
rectum	UBERON:0001052	74.60	gold quality
upper lobe of lung	UBERON:0008948	73.69	gold quality
lung	UBERON:0002048	71.89	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	67.98	gold quality
right coronary artery	UBERON:0001625	67.75	gold quality
descending thoracic aorta	UBERON:0002345	66.89	gold quality
adipose tissue of abdominal region	UBERON:0007808	66.83	gold quality
omental fat pad	UBERON:0010414	66.01	gold quality
peritoneum	UBERON:0002358	65.95	gold quality
ileal mucosa	UBERON:0000331	65.58	silver quality
left uterine tube	UBERON:0001303	65.49	gold quality
spinal cord	UBERON:0002240	65.43	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-10432	yes	9766.39
E-MTAB-9221	yes	7083.42
E-HCAD-10	yes	1654.10
E-CURD-6	yes	175.85
E-HCAD-4	yes	44.94
E-CURD-112	yes	37.67
E-CURD-122	yes	25.91
E-HCAD-6	yes	19.41
E-MTAB-9067	yes	14.11
E-HCAD-1	yes	10.00
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

68 targeting RGS18, 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-126-5P	100.00	72.71	3180
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-6832-5P	99.58	64.82	1132

Literature-anchored findings (GeneRIF, showing 7)

• molecular cloning and characterization of RGS18 as a regulator of G protein signalling in human platelets (PMID:11955952)
• gene mapped to chromosome 1. (PMID:16484797)
• Data show that that SPL/RGS/SHP1 complexes are present in resting platelets where constitutive phosphorylation of SPL(Y398) creates an atypical binding site for SHP-1. (PMID:22210881)
• These findings indicate cross-talk between platelet activation and inhibition pathways at the level of RGS18 and Gq. (PMID:22234696)
• Data show that bothregulator of G protein signaling (RGS16 and RGS18) inhibit protease-activated receptor 2 (PAR2)/G-protein, Gi-Go subunits (Galphai/o) -mediated signaling. (PMID:30117167)
• Association between KCNQ2, TCF4 and RGS18 polymorphisms and silent brain infarction based on wholeexome sequencing. (PMID:32319632)
• Regulator of G protein signalling 18 promotes osteocyte proliferation by activating the extracellular signal-regulated kinase signalling pathway. (PMID:38214344)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rgs18	ENSMUSG00000026357
rattus_norvegicus	Rgs18	ENSRNOG00000003959

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), RGS12 (ENSG00000159788), AXIN2 (ENSG00000168646), RGS14 (ENSG00000169220), RGS19 (ENSG00000171700), RGS6 (ENSG00000182732), RGS7 (ENSG00000182901), RGS21 (ENSG00000253148)

Protein

Protein identifiers

Regulator of G-protein signaling 18 — Q9NS28 (reviewed: Q9NS28)

All UniProt accessions (1): Q9NS28

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Binds to G(i) alpha-1, G(i) alpha-2, G(i) alpha-3 and G(q) alpha.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in peripheral leukocytes, bone marrow, platelet, spleen and fetal liver.

RefSeq proteins (1): NP_570138* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF00615

UniProt features (18 total): helix 10, modified residue 3, chain 1, domain 1, strand 1, turn 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2DLV	SOLUTION NMR
2JM5	SOLUTION NMR
2OWI	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NS28-F1	72.53	0.48

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): 49, 216, 218

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-416476	G alpha (q) signalling events
R-HSA-418594	G alpha (i) signalling events

MSigDB gene sets: 119 (showing top): MODULE_169, MODULE_64, PUJANA_CHEK2_PCC_NETWORK, RHEIN_ALL_GLUCOCORTICOID_THERAPY_UP, WTGAAAT_UNKNOWN, MODULE_99, SASAKI_ADULT_T_CELL_LEUKEMIA, VECCHI_GASTRIC_CANCER_EARLY_DN, OCT1_B, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, CONCANNON_APOPTOSIS_BY_EPOXOMICIN_DN, RIZKI_TUMOR_INVASIVENESS_3D_UP, GOCC_CYTOPLASMIC_SIDE_OF_MEMBRANE, ZHENG_BOUND_BY_FOXP3, GOCC_SIDE_OF_MEMBRANE

GO Biological Process (3): G protein-coupled receptor signaling pathway (GO:0007186), regulation of G protein-coupled receptor signaling pathway (GO:0008277), negative regulation of signal transduction (GO:0009968)

GO Molecular Function (3): GTPase activity (GO:0003924), GTPase activator activity (GO:0005096), protein binding (GO:0005515)

GO Cellular Component (2): cytoplasm (GO:0005737), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
GPCR downstream signalling	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
regulation of signal transduction	2
G protein-coupled receptor activity	1
G protein-coupled receptor signaling pathway	1
negative regulation of cell communication	1
negative regulation of signaling	1
negative regulation of response to stimulus	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

2148 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RGS18	GNB5	O14775	876
RGS18	SUCLG2	Q96I99	847
RGS18	GNAQ	P50148	809
RGS18	ARHGEF11	O15085	778
RGS18	RGSL1	A5PLK6	776
RGS18	ARHGEF1	Q92888	773
RGS18	GRK2	P25098	754
RGS18	SUCLG1	P53597	754
RGS18	RGS7BP	Q6MZT1	720
RGS18	GNA13	Q14344	707
RGS18	MCF2	P10911	694
RGS18	PLEK	P08567	686
RGS18	AKAP10	O43572	659
RGS18	PLEK2	Q9NYT0	653
RGS18	ARHGEF25	Q86VW2	634

IntAct

3 interactions, top by confidence:

A	B	Type	Score
Gnao1	RGS18	psi-mi:“MI:0407”(direct interaction)	0.560

BioGRID (10): RGS18 (Two-hybrid), GNAI3 (Reconstituted Complex), GNAQ (Reconstituted Complex), GNAI3 (Reconstituted Complex), GNAI2 (Reconstituted Complex), GNAI1 (Reconstituted Complex), RGS18 (Positive Genetic), TRIM9 (Cross-Linking-MS (XL-MS)), RPL7A (Cross-Linking-MS (XL-MS)), APP (Reconstituted Complex)

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

3 interactions.

A	Effect	B	Mechanism
PRKG1	“up-regulates activity”	RGS18	phosphorylation
PRKACA	“up-regulates activity”	RGS18	phosphorylation
14-3-3	“down-regulates activity”	RGS18	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1289 predictions. Top by Δscore:

Variant	Effect	Δscore
1:192181290:A:AG	acceptor_gain	1.0000
1:192181290:AGAT:A	acceptor_gain	1.0000
1:192181291:G:GG	acceptor_gain	1.0000
1:192181291:GATG:G	acceptor_gain	1.0000
1:192181459:GTAC:G	donor_loss	1.0000
1:192181460:T:G	donor_loss	1.0000
1:192181464:G:GG	donor_gain	1.0000
1:192160377:GA:G	acceptor_gain	0.9900
1:192178998:A:T	donor_gain	0.9900
1:192181286:T:A	acceptor_gain	0.9900
1:192181289:TAGA:T	acceptor_loss	0.9900
1:192181291:GAT:G	acceptor_gain	0.9900
1:192181456:GAG:G	donor_gain	0.9900
1:192181463:A:AG	donor_gain	0.9900
1:192181470:A:G	donor_gain	0.9900
1:192184292:TCCA:T	acceptor_loss	0.9900
1:192184293:CCAG:C	acceptor_loss	0.9900
1:192184294:CA:C	acceptor_loss	0.9900
1:192184296:GGTT:G	acceptor_gain	0.9900
1:192637656:GCTTG:G	donor_gain	0.9900
1:192644329:A:AG	acceptor_gain	0.9900
1:192644330:G:GG	acceptor_gain	0.9900
1:192644400:G:GG	donor_gain	0.9900
1:192647923:A:G	acceptor_gain	0.9900
1:192658199:AGAT:A	acceptor_gain	0.9900
1:192658200:GATG:G	acceptor_gain	0.9900
1:192659332:TTTCA:T	acceptor_loss	0.9900
1:192659333:TTCA:T	acceptor_loss	0.9900
1:192659334:TCA:T	acceptor_loss	0.9900
1:192659335:CAG:C	acceptor_loss	0.9900

AlphaMissense

1570 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:192181315:T:C	F103L	0.999
1:192181317:T:A	F103L	0.999
1:192181317:T:G	F103L	0.999
1:192181319:T:C	L104P	0.999
1:192181352:T:C	F115S	0.999
1:192184394:T:C	L183P	0.999
1:192184421:T:C	F192S	0.999
1:192181330:T:C	F108L	0.998
1:192181332:C:A	F108L	0.998
1:192181332:C:G	F108L	0.998
1:192181351:T:C	F115L	0.998
1:192181353:T:A	F115L	0.998
1:192181353:T:G	F115L	0.998
1:192181432:T:C	F142L	0.998
1:192181434:T:A	F142L	0.998
1:192181434:T:G	F142L	0.998
1:192184411:T:G	Y189D	0.998
1:192184420:T:C	F192L	0.998
1:192184422:T:A	F192L	0.998
1:192184422:T:G	F192L	0.998
1:192160403:T:A	W83R	0.997
1:192160403:T:C	W83R	0.997
1:192181307:T:C	F100S	0.997
1:192181316:T:C	F103S	0.997
1:192181333:A:C	S109R	0.997
1:192181335:T:A	S109R	0.997
1:192181335:T:G	S109R	0.997
1:192181340:A:T	E111V	0.997
1:192184418:G:C	R191P	0.997
1:192160425:T:C	L90P	0.996

dbSNP variants (sampled 300 via entrez): RS1000009884 (1:192180526 T>TA), RS1000017093 (1:192178169 C>G,T), RS1000130110 (1:192185193 G>C), RS1000293859 (1:192159758 T>C), RS1000378363 (1:192165457 C>T), RS1000446173 (1:192180774 A>C,G), RS1000474813 (1:192165166 T>A,G), RS1000558039 (1:192161171 A>T), RS1000711832 (1:192166902 C>T), RS1000845866 (1:192172305 C>T), RS1001033145 (1:192161039 A>G), RS1001293154 (1:192156727 T>C,G), RS1001295657 (1:192184891 G>T), RS1001408765 (1:192156471 C>A,G,T), RS1001437091 (1:192168662 A>G)

Disease associations

OMIM: gene MIM:607192 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
inherited bleeding disorder, platelet-type	Limited	Autosomal dominant

Mondo (1): inherited bleeding disorder, platelet-type (MONDO:0000009)

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST003489_1	Food addiction	2.000000e-07
GCST004557_35	Body mass index	3.000000e-07
GCST004557_79	Body mass index	4.000000e-08
GCST004558_205	Body mass index (joint analysis main effects and physical activity interaction)	1.000000e-08
GCST004558_219	Body mass index (joint analysis main effects and physical activity interaction)	4.000000e-07
GCST004559_149	Body mass index in physically active individuals	8.000000e-08
GCST004559_180	Body mass index in physically active individuals	8.000000e-09
GCST005182_6	Common carotid intima-media thickness in HIV negative individuals	3.000000e-07
GCST005182_8	Common carotid intima-media thickness in HIV negative individuals	3.000000e-06
GCST010002_372	Refractive error	3.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007829	eating behaviour
EFO:0007830	food addiction measurement
EFO:0004340	body mass index
EFO:0008002	physical activity measurement

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 — R4 family

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, decreases expression	2
triphenyl phosphate	affects expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Air Pollutants	decreases expression, increases abundance	1
Cisplatin	increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Nickel	increases expression	1
Tretinoin	increases expression	1
Zinc	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

1 cell lines: 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1YB	WAe001-A-35	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06630572	PHASE4	TERMINATED	Rifaximin in Cirrhosis: Effects on Endotoxin and Haemostatic Indexes
NCT01880047	PHASE2	COMPLETED	Safety and Efficacy of Eltrombopag at Escalated Doses
NCT04312789	PHASE2	WITHDRAWN	Avatrombopag for the Treatment of Thrombocytopenia After Donor Hematopoietic Stem Cell Transplant
NCT05143892	PHASE2	UNKNOWN	Avatrombopag to Promote Platelet Engraftment After Allo-HSCT
NCT06261060	PHASE2	RECRUITING	Low-Dose Sirolimus to Increase Hematopoietic Function in Patients With RUNX1 Familial Platelet Disorder
NCT01839968	Not specified	COMPLETED	Ex-Vivo Reversion of Platelet Inhibition Induced by Prasugrel
NCT02979158	Not specified	COMPLETED	Preoperative Dual Antiplatelet Therapy: Platelet Function and Influence of Cardiopulmonary Bypass
NCT04398628	Not specified	RECRUITING	ATHN Transcends: A Natural History Study of Non-Neoplastic Hematologic Disorders
NCT04419987	Not specified	UNKNOWN	Study of Constitutional Platelet Disease
NCT04842760	Not specified	UNKNOWN	PLATELET Function Assay With Flow Imaging on ImageSTREAM Cytometer
NCT05985668	Not specified	RECRUITING	Towards Improved Diagnostics for Suspected Platelet Function Disorders
NCT06691581	Not specified	ACTIVE_NOT_RECRUITING	Italian Study for Congenital Platelet Disorders