GPR146

Summary

GPR146 (G protein-coupled receptor 146, HGNC:21718) is a protein-coding gene on chromosome 7p22.3, encoding G-protein coupled receptor 146 (Q96CH1). G-protein coupled receptor required for the regulation of plasma cholesterol levels.

Enables G protein-coupled receptor activity. Involved in adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway and regulation of cholesterol biosynthetic process. Is active in plasma membrane.

Source: NCBI Gene 115330 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 1 total
• Druggable target: yes
• MANE Select transcript: NM_001303473

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21718
Approved symbol	GPR146
Name	G protein-coupled receptor 146
Location	7p22.3
Locus type	gene with protein product
Status	Approved
Aliases	PGR8
Ensembl gene	ENSG00000164849
Ensembl biotype	protein_coding
OMIM	621173
Entrez	115330

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 25 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000397095, ENST00000427680, ENST00000444847, ENST00000474396, ENST00000481403, ENST00000853316, ENST00000853317, ENST00000853318, ENST00000853319, ENST00000853320, ENST00000853321, ENST00000853322, ENST00000853323, ENST00000853324, ENST00000853325, ENST00000853326, ENST00000853327, ENST00000853328, ENST00000969949, ENST00000969950, ENST00000969951, ENST00000969952, ENST00000969953, ENST00000969954, ENST00000969955, ENST00000969956, ENST00000969957

RefSeq mRNA: 3 — MANE Select: NM_001303473 NM_001303473, NM_001303474, NM_138445

CCDS: CCDS5321

Canonical transcript exons

ENST00000444847 — 2 exons

Exon	Start	End
ENSE00001527270	1057492	1059261
ENSE00001759096	1044546	1044658

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 93.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.5979 / max 285.9222, expressed in 1244 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76905	2.8758	932
76908	1.2240	342
76904	1.1160	623
76906	0.2286	130
76907	0.1535	101

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
subcutaneous adipose tissue	UBERON:0002190	93.00	gold quality
adipose tissue	UBERON:0001013	92.54	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.51	gold quality
omental fat pad	UBERON:0010414	92.49	gold quality
peritoneum	UBERON:0002358	92.41	gold quality
apex of heart	UBERON:0002098	89.14	gold quality
mucosa of stomach	UBERON:0001199	88.77	gold quality
right lung	UBERON:0002167	87.86	gold quality
tibial nerve	UBERON:0001323	86.84	gold quality
blood	UBERON:0000178	86.65	gold quality
heart left ventricle	UBERON:0002084	85.79	gold quality
body of stomach	UBERON:0001161	85.77	gold quality
upper lobe of left lung	UBERON:0008952	85.74	gold quality
body of uterus	UBERON:0009853	85.42	gold quality
cardiac ventricle	UBERON:0002082	85.29	gold quality
upper lobe of lung	UBERON:0008948	85.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	85.07	gold quality
muscle layer of sigmoid colon	UBERON:0035805	84.91	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.89	gold quality
lower esophagus	UBERON:0013473	84.82	gold quality
left uterine tube	UBERON:0001303	84.77	gold quality
right lobe of thyroid gland	UBERON:0001119	84.45	gold quality
gastrocnemius	UBERON:0001388	83.76	gold quality
right lobe of liver	UBERON:0001114	83.51	gold quality
tendon of biceps brachii	UBERON:0008188	83.46	gold quality
left coronary artery	UBERON:0001626	83.02	gold quality
coronary artery	UBERON:0001621	82.85	gold quality
right coronary artery	UBERON:0001625	82.77	gold quality
medial globus pallidus	UBERON:0002477	82.69	gold quality
fundus of stomach	UBERON:0001160	82.68	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	78.17
E-MTAB-6678	yes	6.24
E-ANND-3	yes	4.91

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA2, HES1, IRF3, STAT1

miRNA regulators (miRDB)

37 targeting GPR146, 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-6825-5P	99.96	69.81	3431
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-1237-3P	98.55	67.65	1423
HSA-MIR-211-3P	98.14	66.77	1052
HSA-MIR-892B	98.00	67.11	821
HSA-MIR-558	97.50	67.16	977
HSA-MIR-4800-5P	97.22	65.91	324
HSA-MIR-939-5P	97.10	65.80	1579

Literature-anchored findings (GeneRIF, showing 7)

• Knockdown of GPR146 blocked C-peptide-induced cFos expression in KATOIII cells. (PMID:23980258)
• these findings outline a regulatory role for the GPR146/ERK axis in systemic cholesterol metabolism. (PMID:31778654)
• Hypercholesterolemia risk-associated GPR146 is an orphan G-protein coupled receptor that regulates blood cholesterol levels in humans and mice. (PMID:32203133)
• GPR146: an emerging therapeutic target for hypercholesterolemia and atherosclerosis. (PMID:32491159)
• Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile. (PMID:36047410)
• GPR146 regulates pulmonary vascular remodeling by promoting pulmonary artery smooth muscle cell proliferation through 5-lipoxygenase. (PMID:37926274)
• G protein-coupled receptor 146: new insights from genetics and model systems. (PMID:38465903)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gpr146	ENSMUSG00000044197
rattus_norvegicus	Gpr146	ENSRNOG00000001288

Paralogs (7): GPR174 (ENSG00000147138), GPR183 (ENSG00000169508), GPR151 (ENSG00000173250), RXFP3 (ENSG00000182631), GPR132 (ENSG00000183484), GPR141 (ENSG00000187037), P2RY11 (ENSG00000244165)

Protein

Protein identifiers

G-protein coupled receptor 146 — Q96CH1 (reviewed: Q96CH1)

Alternative names: G-protein coupled receptor PGR8

All UniProt accessions (3): A4D2Q3, C9J5X5, Q96CH1

UniProt curated annotations — full annotation on UniProt →

Function. G-protein coupled receptor required for the regulation of plasma cholesterol levels. Receptor for CHLSN, a gut derived hormone which mediates an inhibitory effect of intestinal cholesterol absorption on hepatic cholesterol synthesis. Cholesin-binding exerts an antagonistic effect by inhibiting PKA signaling and suppressing SREBF2-controlled cholesterol in the liver.

Subcellular location. Cell membrane.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (3): NP_001290402, NP_001290403, NP_612454 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR037487	GPR146	Family
IPR047143	GPER1-like	Family

Pfam: PF00001

UniProt features (17 total): topological domain 8, transmembrane region 7, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96CH1-F1	78.00	0.36

Functional residue map

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

Glycosylation sites (1): 8

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 197 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_RESPONSE_TO_PEPTIDE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_RESPONSE_TO_INTERFERON_BETA, chr7p22, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_CHOLESTEROL_BIOSYNTHETIC_PROCESS, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, MODULE_206, GOBP_STEROID_BIOSYNTHETIC_PROCESS

GO Biological Process (9): adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), response to type II interferon (GO:0034341), response to interferon-beta (GO:0035456), regulation of cholesterol biosynthetic process (GO:0045540), defense response to virus (GO:0051607), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), response to virus (GO:0009615), positive regulation of cholesterol biosynthetic process (GO:0045542)

GO Molecular Function (1): G protein-coupled receptor activity (GO:0004930)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to cytokine	2
cholesterol biosynthetic process	2
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
innate immune response	1
regulation of cholesterol metabolic process	1
regulation of sterol biosynthetic process	1
regulation of alcohol biosynthetic process	1
defense response	1
response to virus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
response to other organism	1
regulation of cholesterol biosynthetic process	1
positive regulation of cholesterol metabolic process	1
positive regulation of sterol biosynthetic process	1
positive regulation of alcohol biosynthetic process	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR146	GPR107	Q5VW38	665
GPR146	GPR139	Q6DWJ6	620
GPR146	GPR162	Q16538	523
GPR146	GPR153	Q6NV75	472
GPR146	GPR142	Q7Z601	453
GPR146	PSMG3	Q9BT73	449
GPR146	GPR82	Q96P67	445
GPR146	GPR148	Q8TDV2	439
GPR146	TRH	P20396	426
GPR146	LIN52	Q52LA3	425
GPR146	NMU	P48645	424
GPR146	GHRL	Q9UBU3	422
GPR146	GPR160	Q9UJ42	417
GPR146	GPR150	Q8NGU9	400
GPR146	RFXAP	O00287	395
GPR146	GPR152	Q8TDT2	395

IntAct

3 interactions, top by confidence:

A	B	Type	Score
GPR146	GPR35	psi-mi:“MI:0915”(physical association)	0.370
GPR146	LTB4R2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (2): GPR146 (Two-hybrid), GPR146 (Two-hybrid)

ESM2 similar proteins: A0A0R4IM31, A0A0R4IP11, E9QJ73, F8VQN3, O00270, O00421, O15218, O35457, O97663, P31392, P32302, P34997, P43142, P49685, Q04683, Q0II78, Q0VDU3, Q149R9, Q16570, Q3ZC80, Q67ES2, Q6XKD3, Q75ZH0, Q7TMA4, Q7TQA9, Q7TQP4, Q7TSN5, Q7TSN6, Q863H8, Q8BZR0, Q8TDV2, Q95LF2, Q95LF3, Q95LF4, Q95LF5, Q95LF7, Q95LF9, Q95LG5, Q96CH1, Q96G91

Diamond homologs: Q6P7G9, Q96CH1, Q99LE2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

476 predictions. Top by Δscore:

Variant	Effect	Δscore
7:1055481:AAGGT:A	donor_loss	1.0000
7:1055482:AGGTG:A	donor_loss	1.0000
7:1055484:GT:G	donor_loss	1.0000
7:1057486:CCGCA:C	acceptor_loss	0.9900
7:1057487:CGCAG:C	acceptor_loss	0.9900
7:1057488:GCAG:G	acceptor_loss	0.9900
7:1057489:CAGG:C	acceptor_loss	0.9900
7:1057490:A:AG	acceptor_gain	0.9900
7:1057490:A:AT	acceptor_loss	0.9900
7:1057490:AG:A	acceptor_gain	0.9900
7:1057491:G:GG	acceptor_gain	0.9900
7:1057491:GG:G	acceptor_gain	0.9900
7:1057491:GGGT:G	acceptor_gain	0.9900
7:1057491:GGGTC:G	acceptor_gain	0.9900
7:1055481:AAG:A	donor_gain	0.9800
7:1055484:G:GG	donor_gain	0.9700
7:1057490:AGG:A	acceptor_gain	0.9700
7:1057491:GGG:G	acceptor_gain	0.9700
7:1057487:C:CA	acceptor_gain	0.9600
7:1056827:GCT:G	donor_gain	0.9400
7:1055477:A:G	donor_gain	0.9100
7:1056830:G:GG	donor_gain	0.9100
7:1055478:G:GG	donor_gain	0.8800
7:1055482:A:G	donor_gain	0.8600
7:1056201:G:GT	donor_gain	0.8600
7:1057406:G:GT	donor_gain	0.8600
7:1056834:GTCCC:G	donor_gain	0.8500
7:1056835:TCCCT:T	donor_gain	0.8500
7:1057407:A:T	donor_gain	0.8500
7:1045797:TGTTG:T	donor_gain	0.8400

AlphaMissense

2126 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:1057969:T:A	W152R	0.995
7:1057969:T:C	W152R	0.995
7:1057990:A:C	S159R	0.995
7:1057992:C:A	S159R	0.995
7:1057992:C:G	S159R	0.995
7:1057885:A:C	S124R	0.993
7:1057887:C:A	S124R	0.993
7:1057887:C:G	S124R	0.993
7:1057719:C:A	N68K	0.992
7:1057719:C:G	N68K	0.992
7:1058111:C:G	P199R	0.992
7:1057963:T:C	F150L	0.991
7:1057965:C:A	F150L	0.991
7:1057965:C:G	F150L	0.991
7:1058111:C:A	P199Q	0.990
7:1057892:A:T	D126V	0.987
7:1057708:T:G	Y65D	0.984
7:1057971:G:C	W152C	0.984
7:1057971:G:T	W152C	0.984
7:1057979:C:A	A155E	0.984
7:1057892:A:C	D126A	0.983
7:1057972:G:C	G153R	0.982
7:1057975:G:C	G154R	0.982
7:1057976:G:A	G154D	0.982
7:1058377:A:C	S288R	0.981
7:1058379:C:A	S288R	0.981
7:1058379:C:G	S288R	0.981
7:1057723:G:C	A70P	0.980
7:1057711:T:C	F66L	0.979
7:1057712:T:C	F66S	0.979

dbSNP variants (sampled 300 via entrez): RS1000172939 (7:1053060 G>T), RS1000353609 (7:1048697 C>T), RS1000450758 (7:1045920 A>G,T), RS1000523743 (7:1054137 C>T), RS1000562729 (7:1052000 A>G), RS1000591452 (7:1050952 G>A), RS1000629548 (7:1052954 G>A), RS1000634271 (7:1047904 C>G,T), RS1000802998 (7:1043070 G>A), RS1000911510 (7:1052228 G>A,C), RS1001047163 (7:1055033 G>A), RS1001163733 (7:1057404 A>G), RS1001166499 (7:1054043 C>T), RS1001345441 (7:1059028 A>G), RS1001956311 (7:1046314 A>C,G)

Disease associations

OMIM: gene MIM:621173 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002221_53	Cholesterol, total	3.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523904 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Class A Orphans with emerging pharmacology

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	increases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine	increases expression, decreases reaction	1
sotorasib	affects cotreatment, decreases expression	1
propionaldehyde	decreases expression	1
kojic acid	decreases expression	1
trichostatin A	affects expression	1
motexafin gadolinium	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
bisphenol S	decreases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Atrazine	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	decreases expression	1
Nickel	decreases expression	1
Oxygen	decreases reaction, increases expression	1
Quercetin	affects expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Okadaic Acid	decreases expression	1
Zinc Acetate	increases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4623545	Binding	Activation of human GPR146 expressed in CHO-K1 cells assessed as increase in dynamic mass redistribution response at 100 uM by DMR assay	Is GPR146 really the receptor for proinsulin C-peptide? — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 1 induced pluripotent stem cell, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B5QH	ITXi001-A-1	Induced pluripotent stem cell	Female
CVCL_KX36	PathHunter CHO-K1 GPR146 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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