GNB3

Summary

GNB3 (G protein subunit beta 3, HGNC:4400) is a protein-coding gene on chromosome 12p13.31, encoding Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (P16520). Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems.

Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit which belongs to the WD repeat G protein beta family. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. A single-nucleotide polymorphism (C825T) in this gene is associated with essential hypertension and obesity. This polymorphism is also associated with the occurrence of the splice variant GNB3-s, which appears to have increased activity. GNB3-s is an example of alternative splicing caused by a nucleotide change outside of the splice donor and acceptor sites. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.

Source: NCBI Gene 2784 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital stationary night blindness 1H (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 287 total — 2 pathogenic
• Phenotypes (HPO): 12
• MANE Select transcript: NM_002075

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4400
Approved symbol	GNB3
Name	G protein subunit beta 3
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000111664
Ensembl biotype	protein_coding
OMIM	139130
Entrez	2784

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000229264, ENST00000435982, ENST00000537035, ENST00000539127, ENST00000540458, ENST00000541257, ENST00000541978, ENST00000542751, ENST00000542868, ENST00000675241, ENST00000884021

RefSeq mRNA: 2 — MANE Select: NM_002075 NM_001297571, NM_002075

CCDS: CCDS73427, CCDS8564

Canonical transcript exons

ENST00000229264 — 10 exons

Exon	Start	End
ENSE00000866965	6841258	6841344
ENSE00000866966	6841586	6841624
ENSE00003501177	6845586	6845802
ENSE00003501983	6842970	6843076
ENSE00003538225	6843363	6843525
ENSE00003590043	6846792	6847393
ENSE00003623159	6843174	6843237
ENSE00003672452	6843632	6843698
ENSE00003791618	6843777	6843978
ENSE00003901853	6840925	6841033

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 95.24.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.0545 / max 1180.2794, expressed in 80 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123770	3.0417	80
123771	0.0128	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	95.24	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.95	gold quality
cerebellar hemisphere	UBERON:0002245	94.56	gold quality
cerebellar cortex	UBERON:0002129	94.36	gold quality
pituitary gland	UBERON:0000007	94.28	gold quality
cerebellum	UBERON:0002037	92.09	gold quality
apex of heart	UBERON:0002098	89.70	gold quality
right frontal lobe	UBERON:0002810	85.93	gold quality
right ovary	UBERON:0002118	85.57	gold quality
pigmented layer of retina	UBERON:0001782	84.99	gold quality
retina	UBERON:0000966	84.98	gold quality
right coronary artery	UBERON:0001625	84.94	gold quality
body of uterus	UBERON:0009853	84.57	gold quality
left ovary	UBERON:0002119	84.15	gold quality
descending thoracic aorta	UBERON:0002345	83.93	gold quality
thoracic aorta	UBERON:0001515	83.02	gold quality
ascending aorta	UBERON:0001496	82.96	gold quality
stromal cell of endometrium	CL:0002255	82.92	gold quality
heart left ventricle	UBERON:0002084	82.38	gold quality
nucleus accumbens	UBERON:0001882	82.34	gold quality
cardiac ventricle	UBERON:0002082	81.96	gold quality
cingulate cortex	UBERON:0003027	81.36	gold quality
tendon of biceps brachii	UBERON:0008188	81.34	gold quality
anterior cingulate cortex	UBERON:0009835	81.31	gold quality
endocervix	UBERON:0000458	81.23	gold quality
right atrium auricular region	UBERON:0006631	81.21	gold quality
pancreatic ductal cell	CL:0002079	81.02	silver quality
aorta	UBERON:0000947	80.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.42	gold quality
left coronary artery	UBERON:0001626	80.10	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	4749.52
E-GEOD-137537	yes	2724.71
E-MTAB-7316	yes	26.77
E-ANND-3	yes	3.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

39 targeting GNB3, 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-6778-3P	99.96	67.29	2693
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-4650-3P	99.01	68.39	1062
HSA-MIR-6831-5P	98.26	67.20	990
HSA-MIR-3665	97.73	65.08	975
HSA-MIR-3927-3P	97.68	66.76	892

Literature-anchored findings (GeneRIF, showing 40)

• association between left ventricular hypertrophy and the C825T allele of the G-protein beta3 subunit gene in Arabs (PMID:11768721)
• Polymorphisms of genes encoding G-protein beta3 subunit as risk factors for orthostatic hypotension. (PMID:11910300)
• possible association between the prophylactic efficacy of lithium in mood disorders and the following gene variants: catechol-O-methyltransferase (COMT) G158A, monoamine oxydase A (MAO-A) 30-bp repeat, G-protein beta 3-subunit (Gbeta3) C825T (PMID:11992559)
• polymorphism in GNB3 does not have a role in left ventricular hypertrophy/hypertension (PMID:12011775)
• relationship between the 825T allele of GNB3 and insulin resistance in the essential hypertensive patients studied, which seems to be independent of body mass index (PMID:12109775)
• Data show that the T825 variant of the G-protein beta3 subunit gene (GNB3) was not associated with type 2 diabetes itself, nor with overweight and obesity, but was associated with diabetic hypertension. (PMID:12165748)
• The GNB3 C825T polymorphism is potentially an attractive pharmacogenetic marker to predict hormone-mediated responses in humans. (PMID:12172218)
• There is a positive association of the maternal G protein beta3 subunit 825T allele with reduced head circumference at birth. Expression of this allele in the mother may exert influence on fetal metabolic environment. (PMID:12409514)
• these results suggest that G beta 3s2 is a biologically active G beta variant which may play a role in the manifestation of the complex phenotype associated with the 825T-allele. (PMID:12431187)
• In transplant recipients who did not lose their graft during the first 3 years after transplantation, the G3-TT genotype contributed to accelerated loss of allograft function by exaggeration of posttransplant hypertension. (PMID:12460053)
• combined action of this protein and kininase ii in major depression; may have a link to cardiovascular disease (PMID:12476328)
• association of the G protein beta 3 subunit (GNB3) C825T polymorphism, a determinant of intracellular signal transduction, with the drug response to sildenafil in patients with erectile dysfunction. (PMID:12576843)
• When expressed in rat sympathetic neurons, human Gbeta3-s (an alternative splice variant of GNB3 with single-nucleotide polymorphism C825T) appears to lack channel-modulating activity. (PMID:12595577)
• GNB3 825T polymorphism is associated with angiographically documented coronary artery disease. (PMID:12618278)
• The GNB3 825T allele is associated with reduced insulin sensitivity in men with abdominal-type fat distribution and with more advanced carotid atherosclerosis in middle-aged white men and women (PMID:12624279)
• G protein beta3 subunit 825T allele carriers displayed higher levels of depression. G protein beta3 subunit 825T allele is predictive of depressive mood in a young, healthy population. (PMID:12634518)
• higher blood pressure in TT homozygous men might arise via a metabolic pathway characterized by obesity and insulin resistance as well as via increased peripheral resistance secondary to higher haematocrit. (PMID:12658019)
• Polymorphism is associated with weight gain in pregnancy (PMID:12668921)
• Characterization of the splice variant Gbeta3v. (PMID:12697327)
• The 825T allele of a polymorphism at GNB3 is associated with an enhanced coronary blood flow (CBF) and reduction in response to alpha(2). (PMID:12724620)
• The TC-genotype is not associated with a primary defect in insulin secretion or sensitivity suggesting that obesity and hypertension in carriers of 825T do not likely result from primary alterations in glucose and insulin homeostasis (PMID:12730030)
• in TT homozygotes of both generations, early left ventricular relaxation was reduced. the observation might be because of the higher systolic pressure associated with the TT genotype. (PMID:12756405)
• Low concentrations of agonists resulted in enhanced platelet aggregation in subjects with the GNB3 CC-genotype compared to carriers of a 825T-allele. Both genetic markers contribute synergistically to increased platelet aggregation. (PMID:12818251)
• GNB3 gene is associated with left ventricular hypertrophy in patients with hypertension. (PMID:12891286)
• Polymorphism is not associated with body mass index and hypertension. (PMID:13679998)
• The G(beta)3 C825T polymorphism was associated with SAD in our study sample. This finding strengthens the evidence for the involvement of G protein-coupled signal transduction in the pathogenesis of affective disorder. (PMID:14512207)
• Depressed patients under 25 T allele of G protein beta3 subunit associated with a markedly poorer response to nortriptyline, patients 25 yr or older, the G protein beta3 polymorphisms did not predict antidepressant response (PMID:14604448)
• The T allele of the C825T polymorphism in the GNB3 gene is associated with symptom severity of major depressive disorders in a Korean sample population. (PMID:14647404)
• Polymorphism of the G protein beta3 gene is associated with a high relapse rate in patients with chronic lymphocytic leukaemia (PMID:14692527)
• study indicated that the G-protein beta3 subunit gene (GNB3) C825T polymorphism is not a significant factor for overweight in Japanese people (PMID:14742836)
• The 825C>T polymorphism of the G-protein beta-3 subunit gene is associated with the development of metastasis in low-grade breast cancer (PMID:15019160)
• The polymorphisms in GNB3 gene, solely or combined, did not confer a significantly increased risk for the development of EH in the Kazakh isolate of northeast China. (PMID:15042113)
• The GNB3/C825T polymorphism was not associated with hypertensive status in either male or female subjects. (PMID:15055253)
• Homozygous GNB3 825C carrier status is associated with unexplained predominantly upper abdominal symptoms. (PMID:15057736)
• the C825T polymorphism is not a significant factor for hypertension or blood pressures in Japanese people. (PMID:15076154)
• study concluded that the C825T polymorphism in the G protein beta3 subunit played an important role in the determination of obesity in a German population (PMID:15090636)
• The C825T GNB3 polymorphism had a mild influence on occurrence/initiation of IgA nephropathy, but played no significant role in the progression of the disease. (PMID:15200440)
• Single-nucleotide polymorphisms (SNPs) in the G protein beta3 subunit (GNB3) allelic frequencies were analyzed in Alzheimer’s disease. The combination of GNB3 and beta1-adrenergic receptor polymorphisms produces AD susceptibility. (PMID:15212839)
• Haplotype analyses confirmed the effects of the GNB3 gene-obesity interaction on hypertension risk. (PMID:15226674)
• Polymorphic markers of GNB3 candidate genes influence clinical diversity of pathological signs in DM2 patients through modification of AH and LVH severity. (PMID:15332573)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnb3b	ENSDARG00000002696
danio_rerio	gnb3a	ENSDARG00000004358
mus_musculus	Gnb3	ENSMUSG00000023439
rattus_norvegicus	Gnb3	ENSRNOG00000015541
drosophila_melanogaster	Gbeta13F	FBGN0001105
caenorhabditis_elegans		WBGENE00001679

Paralogs (4): GNB5 (ENSG00000069966), GNB1 (ENSG00000078369), GNB4 (ENSG00000114450), GNB2 (ENSG00000172354)

Protein

Protein identifiers

Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 — P16520 (reviewed: P16520)

Alternative names: Transducin beta chain 3

All UniProt accessions (8): P16520, A0A6Q8PF84, E9PCP0, F1T0G5, F5GZN8, F5H0S8, F5H100, F5H8J8

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.

Subunit / interactions. G proteins are composed of 3 units, alpha, beta and gamma. Interacts with RASD2.

Disease relevance. Night blindness, congenital stationary, 1H (CSNB1H) [MIM:617024] A form of congenital stationary night blindness, a non-progressive retinal disorder characterized by impaired night vision or in dim light, with good vision only on bright days. CSNB1H patients present with childhood-onset night blindness and middle age-onset photophobia, but have near-normal vision and do not exhibit nystagmus or high myopia. CSNB1H inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the WD repeat G protein beta family.

Isoforms (2)

UniProt ID	Names	Canonical?
P16520-1	1	yes
P16520-2	2

RefSeq proteins (2): NP_001284500, NP_002066* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001632	WD40_G-protein_beta-like	Domain
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016346	G-protein_beta_1-5	Family
IPR019775	WD40_repeat_CS	Conserved_site
IPR020472	WD40_PAC1	Repeat
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily

Pfam: PF25391

UniProt features (18 total): sequence variant 9, repeat 7, chain 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9M8K	ELECTRON MICROSCOPY	3
9M8L	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16520-F1	97.19	0.97

Function

Pathways and Gene Ontology

Reactome pathways

31 pathways

ID	Pathway
R-HSA-1296041	Activation of G protein gated Potassium channels
R-HSA-163359	Glucagon signaling in metabolic regulation
R-HSA-202040	G-protein activation
R-HSA-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
R-HSA-381771	Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)
R-HSA-392170	ADP signalling through P2Y purinoceptor 12
R-HSA-392451	G beta:gamma signalling through PI3Kgamma
R-HSA-392851	Prostacyclin signalling through prostacyclin receptor
R-HSA-400042	Adrenaline,noradrenaline inhibits insulin secretion
R-HSA-4086398	Ca2+ pathway
R-HSA-416476	G alpha (q) signalling events
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-418217	G beta:gamma signalling through PLC beta
R-HSA-418555	G alpha (s) signalling events
R-HSA-418592	ADP signalling through P2Y purinoceptor 1
R-HSA-418594	G alpha (i) signalling events
R-HSA-418597	G alpha (z) signalling events
R-HSA-420092	Glucagon-type ligand receptors
R-HSA-428930	Thromboxane signalling through TP receptor
R-HSA-432040	Vasopressin regulates renal water homeostasis via Aquaporins
R-HSA-456926	Thrombin signalling through proteinase activated receptors (PARs)
R-HSA-500657	Presynaptic function of Kainate receptors
R-HSA-6814122	Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding
R-HSA-8964315	G beta:gamma signalling through BTK
R-HSA-8964616	G beta:gamma signalling through CDC42
R-HSA-9009391	Extra-nuclear estrogen signaling
R-HSA-9634597	GPER1 signaling
R-HSA-9660821	ADORA2B mediated anti-inflammatory cytokines production
R-HSA-9717207	Sensory perception of sweet, bitter, and umami (glutamate) taste
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells

MSigDB gene sets: 260 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, REACTOME_GLUCAGON_TYPE_LIGAND_RECEPTORS, MYOGENIN_Q6, GOBP_BEHAVIOR, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_REGULATION_OF_TRIGLYCERIDE_METABOLIC_PROCESS, REACTOME_ADRENALINE_NORADRENALINE_INHIBITS_INSULIN_SECRETION, BROWNE_HCMV_INFECTION_8HR_UP, REACTOME_POTASSIUM_CHANNELS, REACTOME_INWARDLY_RECTIFYING_K_CHANNELS, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, REACTOME_G_ALPHA_Z_SIGNALLING_EVENTS

GO Biological Process (11): cell volume homeostasis (GO:0006884), G protein-coupled receptor signaling pathway (GO:0007186), regulation of blood pressure (GO:0008217), regulation of gene expression (GO:0010468), regulation of glucose metabolic process (GO:0010906), regulation of hormone metabolic process (GO:0032350), regulation of fat cell differentiation (GO:0045598), regulation of cholesterol metabolic process (GO:0090181), regulation of triglyceride metabolic process (GO:0090207), regulation of phospholipid metabolic process (GO:1903725), signal transduction (GO:0007165)

GO Molecular Function (5): GTPase activity (GO:0003924), signaling receptor complex adaptor activity (GO:0030159), spectrin binding (GO:0030507), GTPase binding (GO:0051020), protein binding (GO:0005515)

GO Cellular Component (7): cytoplasm (GO:0005737), cytosol (GO:0005829), heterotrimeric G-protein complex (GO:0005834), plasma membrane (GO:0005886), dendrite (GO:0030425), cell body (GO:0044297), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
GPCR downstream signalling	5
Signal amplification	3
Regulation of insulin secretion	2
G-protein beta:gamma signalling	2
G protein gated Potassium channels	1
Integration of energy metabolism	1
Opioid Signalling	1
Incretin synthesis, secretion, and inactivation	1
Platelet homeostasis	1
Beta-catenin independent WNT signaling	1
Class B/2 (Secretin family receptors)	1
Aquaporin-mediated transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of small molecule metabolic process	2
regulation of lipid metabolic process	2
regulation of cell size	1
cellular homeostasis	1
G protein-coupled receptor activity	1
signal transduction	1
blood circulation	1
regulation of biological quality	1
gene expression	1
regulation of macromolecule biosynthetic process	1
glucose metabolic process	1
regulation of carbohydrate metabolic process	1
regulation of hormone levels	1
regulation of metabolic process	1
hormone metabolic process	1
fat cell differentiation	1
regulation of cell differentiation	1
cholesterol metabolic process	1
regulation of steroid metabolic process	1
triglyceride metabolic process	1
phospholipid metabolic process	1
regulation of phosphorus metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ribonucleoside triphosphate phosphatase activity	1
signaling receptor binding	1
signaling adaptor activity	1
cytoskeletal protein binding	1
protein-containing complex binding	1
enzyme binding	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
extrinsic component of cytoplasmic side of plasma membrane	1
plasma membrane protein complex	1
GTPase complex	1

Protein interactions and networks

STRING

3049 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNB3	GNG13	Q9P2W3	918
GNB3	GNGT1	P63211	883
GNB3	PLCB2	Q00722	799
GNB3	ADD1	P35611	790
GNB3	GNGT2	O14610	786
GNB3	ACE	P12821	779
GNB3	GNG4	P50150	720
GNB3	SUCLG2	Q96I99	720
GNB3	GNAO1	P09471	699
GNB3	GNAS	Q5JWF2	690
GNB3	GRIK2	Q13002	649
GNB3	GNG2	P59768	627
GNB3	REN	P00797	626
GNB3	CYP3A5	P20815	625
GNB3	GNAT2	P19087	624

IntAct

78 interactions, top by confidence:

A	B	Type	Score
GNB1	GNG7	psi-mi:“MI:0914”(association)	0.640
GNGT1	GNB3	psi-mi:“MI:0914”(association)	0.620
GNG2	GNB3	psi-mi:“MI:0914”(association)	0.530
GNG5	GNB3	psi-mi:“MI:0914”(association)	0.530
GNG10	GNB3	psi-mi:“MI:0914”(association)	0.530
GNG10	GNAS	psi-mi:“MI:0914”(association)	0.530
GNG2	GNB5	psi-mi:“MI:0914”(association)	0.530
GNG5	GNAS	psi-mi:“MI:0914”(association)	0.530
ERBB2	NDUFA4	psi-mi:“MI:0914”(association)	0.530
GNG11	GNB3	psi-mi:“MI:0914”(association)	0.500
GNB3	GNG11	psi-mi:“MI:0915”(physical association)	0.500
ZNF131	GNB3	psi-mi:“MI:0915”(physical association)	0.400
SLC36A3	GNB3	psi-mi:“MI:0915”(physical association)	0.400
POLR2A	GNB3	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (78): GNB3 (Affinity Capture-Western), GNB3 (Affinity Capture-MS), GNB3 (Affinity Capture-Western), GNB3 (Affinity Capture-MS), GNB3 (Affinity Capture-MS), GNB3 (Affinity Capture-Western), GNB3 (Affinity Capture-Western), GNB3 (Affinity Capture-MS), GNB3 (Affinity Capture-MS), GNB3 (Affinity Capture-MS), GNB3 (Affinity Capture-MS), GNG2 (Affinity Capture-Western), CUL4A (Affinity Capture-Western), GNB3 (Affinity Capture-Western), DDB1 (Affinity Capture-Western)

ESM2 similar proteins: A0A223GEB2, G1SJB4, G4MQX3, O18640, O24076, O24456, O35353, O42248, O42249, P16520, P17343, P23232, P25387, P26308, P29387, P38011, P46800, P49026, P49027, P52287, P54311, P62871, P63243, P63244, P63245, P63246, P63247, P68040, P69103, P69104, P79147, P83774, P93340, Q01369, Q08706, Q10281, Q20636, Q21215, Q25189, Q39336

Diamond homologs: A0A223GEB2, A1CJY4, A1D7I5, A1L271, A2QEV8, A4R3M4, A4RDD7, A6H603, A7THX0, A8ILK1, B0XYC8, B3MJV8, B4HWV6, B4Q9T6, B6QC56, B8AP31, B8M0Q1, E3LB80, G0SC29, O14435, O14775, O35353, O45040, P11017, P16520, P17343, P18851, P23232, P26308, P29387, P29829, P36408, P49177, P49178, P52287, P54311, P54313, P61480, P62871, P62872

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
GNB3	up-regulates	PIK3CA	binding
SMO	up-regulates	GNB3	binding
FZD3	up-regulates	GNB3	binding
“lysophosphatidic acids”	up-regulates	GNB3	“chemical activation”
GNB3	up-regulates	PLCG1	binding
GNB3	up-regulates	PI3K	binding
PTGER3	up-regulates	GNB3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Prostacyclin signalling through prostacyclin receptor	15	322.0×	2e-36
G beta:gamma signalling through BTK	14	317.2×	5e-34
G beta:gamma signalling through PLC beta	14	285.5×	4e-33
G beta:gamma signalling through CDC42	14	285.5×	4e-33
ADP signalling through P2Y purinoceptor 12	16	283.7×	3e-37
Presynaptic function of Kainate receptors	14	271.9×	1e-32
G-protein activation	14	237.9×	1e-31
Thromboxane signalling through TP receptor	14	237.9×	1e-31

GO biological processes:

GO term	Partners	Fold	FDR
G protein-coupled receptor signaling pathway	18	21.7×	8e-19

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	138
Likely benign	121
Benign	17

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1807708	GRCh37/hg19 12p13.33-13.31(chr12:173787-8320544)x3	Pathogenic
242985	NM_002075.4(GNB3):c.170_172del (p.Lys57del)	Pathogenic

SpliceAI

1508 predictions. Top by Δscore:

Variant	Effect	Δscore
12:6841315:G:GT	donor_gain	1.0000
12:6841332:G:GT	donor_gain	1.0000
12:6841345:G:GG	donor_gain	1.0000
12:6841384:C:G	donor_gain	1.0000
12:6841622:GAG:G	donor_gain	1.0000
12:6841625:G:C	donor_loss	1.0000
12:6841626:T:G	donor_loss	1.0000
12:6842968:AGCT:A	acceptor_gain	1.0000
12:6842969:GCT:G	acceptor_gain	1.0000
12:6842969:GCTG:G	acceptor_gain	1.0000
12:6843069:GATTC:G	donor_gain	1.0000
12:6843073:C:CG	donor_gain	1.0000
12:6843073:C:G	donor_gain	1.0000
12:6843077:G:GG	donor_gain	1.0000
12:6843771:T:TA	acceptor_gain	1.0000
12:6843772:G:A	acceptor_gain	1.0000
12:6843774:CA:C	acceptor_loss	1.0000
12:6843775:A:AG	acceptor_gain	1.0000
12:6843775:A:C	acceptor_loss	1.0000
12:6843775:AGT:A	acceptor_gain	1.0000
12:6843776:G:GC	acceptor_gain	1.0000
12:6843776:GT:G	acceptor_gain	1.0000
12:6843776:GTG:G	acceptor_gain	1.0000
12:6843776:GTGC:G	acceptor_gain	1.0000
12:6843776:GTGCC:G	acceptor_gain	1.0000
12:6843881:C:A	acceptor_gain	1.0000
12:6843882:G:A	acceptor_gain	1.0000
12:6843974:TCTGT:T	donor_gain	1.0000
12:6843975:CTGT:C	donor_gain	1.0000
12:6843977:GT:G	donor_gain	1.0000

AlphaMissense

2244 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:6843030:G:A	G53R	1.000
12:6843030:G:C	G53R	1.000
12:6843031:G:A	G53E	1.000
12:6843033:C:G	H54D	1.000
12:6843034:A:G	H54R	1.000
12:6843035:C:A	H54Q	1.000
12:6843035:C:G	H54Q	1.000
12:6843039:G:C	A56P	1.000
12:6843042:A:C	K57Q	1.000
12:6843042:A:G	K57E	1.000
12:6843043:A:T	K57M	1.000
12:6843044:G:C	K57N	1.000
12:6843044:G:T	K57N	1.000
12:6843051:G:C	A60P	1.000
12:6843060:T:A	W63R	1.000
12:6843060:T:C	W63R	1.000
12:6843184:A:C	S72R	1.000
12:6843185:G:T	S72I	1.000
12:6843186:T:A	S72R	1.000
12:6843186:T:G	S72R	1.000
12:6843188:C:A	A73D	1.000
12:6843190:T:C	S74P	1.000
12:6843191:C:G	S74W	1.000
12:6843191:C:T	S74L	1.000
12:6843195:A:C	Q75H	1.000
12:6843195:A:T	Q75H	1.000
12:6843196:G:C	D76H	1.000
12:6843196:G:T	D76Y	1.000
12:6843197:A:C	D76A	1.000
12:6843197:A:G	D76G	1.000

dbSNP variants (sampled 300 via entrez): RS1001237782 (12:6847183 C>A,T), RS1002316792 (12:6841601 T>C), RS1003286664 (12:6839006 G>A,C,T), RS1003311817 (12:6842589 G>A), RS1003351082 (12:6842305 T>C), RS1004325225 (12:6839491 C>T), RS1004340210 (12:6839219 T>C), RS1005304092 (12:6842687 G>A), RS1005325836 (12:6840773 C>A,T), RS1005900706 (12:6844258 T>C), RS1006284085 (12:6844703 G>A,C), RS1006915117 (12:6840838 C>G,T), RS1007058310 (12:6846461 A>G), RS1007248828 (12:6839558 C>A), RS1007441156 (12:6845330 G>A)

Disease associations

OMIM: gene MIM:139130 | disease phenotypes: MIM:617024

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital stationary night blindness 1H	Strong	Autosomal recessive
congenital stationary night blindness	Supportive	Autosomal dominant

Mondo (3): congenital stationary night blindness 1H (MONDO:0014872), inherited retinal dystrophy (MONDO:0019118), congenital stationary night blindness (MONDO:0016293)

Orphanet (1): OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

12 total (13 of 12 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000540	Hypermetropia
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000662	Nyctalopia
HP:0001426	Non-Mendelian inheritance
HP:0003581	Adult onset
HP:0004421	Elevated systolic blood pressure
HP:0004972	Elevated mean arterial pressure
HP:0005117	Elevated diastolic blood pressure
HP:0011463	Childhood onset
HP:0025573	Mild myopia
HP:0000556	Retinal dystrophy

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001450_2	Response to Vitamin E supplementation	4.000000e-06
GCST003997_3	Myopia	2.000000e-14
GCST006291_121	Spherical equivalent or myopia (age of diagnosis)	5.000000e-15
GCST006976_15	Macular thickness	6.000000e-26
GCST009474_3	Central retinal vein equivalent	7.000000e-10
GCST009962_3	High myopia	1.000000e-08
GCST010002_206	Refractive error	3.000000e-62
GCST012403_45	High myopia	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0010554	retinal vasculature measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D058499	Retinal Dystrophies	C11.768.585.658
C536122	Night blindness, congenital stationary (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

18 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11064426	Efficacy	3	atenolol	Essential hypertension
rs2301339	Efficacy	3	atenolol	Essential hypertension
rs5441	Efficacy	3	sertraline	Major Depressive Disorder
rs5443	Toxicity	3	olanzapine	Schizophrenia;Weight gain
rs5443	Efficacy	3	hydralazine / isosorbide dinitrate	Heart Failure
rs5443	Efficacy	3	nortriptyline	Major Depressive Disorder
rs5443	Efficacy	3	sildenafil	Erectile Dysfunction
rs5443	Efficacy	3	atenolol	Essential hypertension
rs5443	Efficacy	3	HMG-CoA reductase inhibitors	Hypercholesterolemia;Myocardial Infarction
rs5443	Efficacy	4	antidepressants	Major Depressive Disorder
rs5443	Efficacy	3	sumatriptan	Cluster Headache
rs5443	Efficacy	3	clonidine	Liver Cirrhosis
rs5443	Other	3	Beta Blocking Agents
rs5443	Efficacy	3	telmisartan	Essential hypertension
rs5443	Toxicity	3	Thiazides;plain	Diabetes Mellitus
rs5443	Efficacy	3	bumetanide;furosemide;torasemide
rs5443	Toxicity	3	methadone	Opioid-Related Disorders
rs5443	Efficacy	3	sibutramine	Obesity

PharmGKB variants

7 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs5442	CDCA3, GNB3, USP5		0.00	0
rs5443	CDCA3, GNB3, USP5	3	5.00	15	bumetanide;furosemide;torasemide;methadone;atenolol;antidepressants;HMG-CoA reductase inhibitors;sumatriptan;olanzapine;sildenafil;nortriptyline;Beta Blocking Agents
rs5445	CDCA3, GNB3		0.00	0
rs2301339	CDCA3, GNB3, USP5	3	9.25	1	atenolol
rs11064426	GNB3	3	9.25	1	atenolol
rs45476395	GNB3		0.00	0
rs5441	GNB3, P3H3	3	2.75	1	sertraline

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Clozapine	affects response to substance, decreases response to substance, increases response to substance	2
Estradiol	affects cotreatment, increases expression, affects binding, increases reaction	2
ferrous chloride	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
thifluzamide	decreases expression	1
asparanin A	decreases expression	1
jinfukang	increases expression	1
picoxystrobin	decreases expression	1
Rosiglitazone	affects expression	1
Sunitinib	increases expression	1
Leflunomide	decreases expression	1
Atrazine	increases expression	1
Vehicle Emissions	decreases expression	1
Barium	affects binding, decreases reaction, increases transport	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1
Cytarabine	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Folic Acid	decreases expression	1
Gallic Acid	decreases expression	1
Nitroglycerin	affects response to substance	1
Lipids	affects metabolic processing	1
Nortriptyline	decreases response to substance, increases response to substance	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	increases expression	1
Urethane	decreases expression	1
Valproic Acid	increases methylation	1
Particulate Matter	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7QS	Ubigene A-549 GNB3 KO	Cancer cell line	Male
CVCL_E0DY	Ubigene HeLa GNB3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT02909985	Not specified	COMPLETED	Visual Activity Evoked by Infrared in Humans After Dark Adaptation
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases
NCT01876147	Not specified	COMPLETED	Visual and Functional Assessment in Low Vision Patients
NCT01920867	Not specified	UNKNOWN	Stem Cell Ophthalmology Treatment Study
NCT02014389	Not specified	RECRUITING	Evaluation of Objective Perimetry Using Chromatic Multifocal Pupillometer
NCT02983305	Not specified	COMPLETED	Optical Head-Mounted Display Technology for Low Vision Rehabilitation
NCT03592017	Not specified	COMPLETED	Performance of Long-wavelength Autofluorescence Imaging
NCT03662386	Not specified	TERMINATED	Prospective Analysis of Genotype-phenotype Correlations Observed in a Large Cohort of Patients With Hereditary Retinal Dystrophies - GEPHIRD
NCT03691168	Not specified	UNKNOWN	Multi-center Observation of the Natural Course of Inherited Retinal Dystrophies
NCT03843840	Not specified	COMPLETED	Dual Wavelength OCT
NCT03853252	Not specified	COMPLETED	iPS Cells of Patients for Models of Retinal Dystrophies
NCT05130385	Not specified	UNKNOWN	High Resolution Optical Coherence Tomography
NCT05294978	Not specified	RECRUITING	EyeConic: Qualification for Cone-Optogenetics
NCT05573984	Not specified	ACTIVE_NOT_RECRUITING	Natural History of PRPF31 Mutation-Associated Retinal Dystrophy
NCT05793515	Not specified	COMPLETED	Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models
NCT05820100	Not specified	COMPLETED	Observational Study to Assess the Reliability and Validity of the MLYMT and MLSDT
NCT05976139	Not specified	RECRUITING	Micropulsed Laser in Patients With Macular Oedema in Retinal Dystrophies
NCT06162585	Not specified	ACTIVE_NOT_RECRUITING	Non-Interventional Long Term Follow-up Study of Participants Previously Enrolled in the RESTORE Study
NCT06177977	Not specified	RECRUITING	SS-HH-OCT as a Novel Diagnostic Modality for Early-Onset Retinal Dystrophies (EORDs)
NCT06375239	Not specified	RECRUITING	Observational Study to Assess Endpoint Operational Feasibility & Measurement Properties in Patients with Retinal Degeneration
NCT06908161	Not specified	NOT_YET_RECRUITING	Functional Assessments in Vision Impairment
NCT07085533	Not specified	RECRUITING	Natural History Study of Inherited Retinal Diseases
NCT07502664	Not specified	RECRUITING	Development and Evaluation of Functional Visual Field and Navigation Endpoints in Moderate to Profound Inherited Retinal Disease (DEFINE-IRD)