GNB5

Summary

GNB5 (G protein subunit beta 5, HGNC:4401) is a protein-coding gene on chromosome 15q21.2, encoding Guanine nucleotide-binding protein subunit beta-5 (O14775). Enhances GTPase-activating protein (GAP) activity of regulator of G protein signaling (RGS) proteins, such as RGS7 and RGS9, hence involved in the termination of the signaling initiated by the G protein coupled receptors (GPCRs) by accelerating the GTP hydrolysis on the G-alpha….

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. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. Alternatively spliced transcript variants encoding different isoforms exist.

Source: NCBI Gene 10681 — RefSeq curated summary.

At a glance

• Gene–disease (curated): language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 210 total — 18 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 29
• MANE Select transcript: NM_016194

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4401
Approved symbol	GNB5
Name	G protein subunit beta 5
Location	15q21.2
Locus type	gene with protein product
Status	Approved
Aliases	GB5
Ensembl gene	ENSG00000069966
Ensembl biotype	protein_coding
OMIM	604447
Entrez	10681

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 4 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000261837, ENST00000358784, ENST00000396335, ENST00000557936, ENST00000558122, ENST00000558519, ENST00000559348, ENST00000559541, ENST00000560075, ENST00000560085, ENST00000560116, ENST00000561313

RefSeq mRNA: 3 — MANE Select: NM_016194 NM_001379343, NM_006578, NM_016194

CCDS: CCDS10149, CCDS45261

Canonical transcript exons

ENST00000261837 — 13 exons

Exon	Start	End
ENSE00000688926	52147459	52147535
ENSE00001281225	52191322	52191392
ENSE00001856378	52115100	52122768
ENSE00003467009	52179768	52179879
ENSE00003475633	52141140	52141272
ENSE00003477167	52125948	52126044
ENSE00003509061	52153940	52154076
ENSE00003595923	52135613	52135756
ENSE00003613960	52184551	52184694
ENSE00003617131	52128196	52128244
ENSE00003626241	52124473	52124639
ENSE00003628758	52149884	52149925
ENSE00003652392	52133378	52133469

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 97.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.5769 / max 241.9268, expressed in 1742 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149978	17.2731	1742
149979	0.2289	56
149982	0.0338	7
149980	0.0334	6
149981	0.0077	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	97.01	gold quality
endothelial cell	CL:0000115	96.24	gold quality
cerebellar hemisphere	UBERON:0002245	95.84	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.82	gold quality
cerebellar cortex	UBERON:0002129	95.81	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.46	gold quality
cerebellum	UBERON:0002037	95.19	gold quality
left ovary	UBERON:0002119	94.71	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.69	gold quality
primary visual cortex	UBERON:0002436	94.33	gold quality
pons	UBERON:0000988	94.02	gold quality
nephron tubule	UBERON:0001231	93.51	gold quality
stromal cell of endometrium	CL:0002255	93.22	gold quality
right ovary	UBERON:0002118	93.19	gold quality
occipital lobe	UBERON:0002021	92.85	gold quality
prefrontal cortex	UBERON:0000451	92.47	gold quality
right frontal lobe	UBERON:0002810	92.41	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.36	gold quality
nucleus accumbens	UBERON:0001882	92.30	gold quality
ovary	UBERON:0000992	92.21	gold quality
putamen	UBERON:0001874	92.12	gold quality
substantia nigra pars compacta	UBERON:0001965	92.11	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.10	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.04	gold quality
cortical plate	UBERON:0005343	91.97	gold quality
lateral globus pallidus	UBERON:0002476	91.70	gold quality
caudate nucleus	UBERON:0001873	91.56	gold quality
cerebellar vermis	UBERON:0004720	91.50	gold quality
body of uterus	UBERON:0009853	91.42	gold quality
frontal cortex	UBERON:0001870	91.34	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.57
E-HCAD-10	yes	4.19
E-MTAB-6524	no	102.78

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 23)

• under certain conditions, RGS9 and Gbeta5 may possibly function as betagamma dimer (PMID:15474482)
• From yeast two hybrid screening with HBX as bait, human guanine nucleotide binding protein beta subunit 5L (GNbeta5) was isolated from the cDNA library constructed in this study as a new hepatitis b X protein-interacting protein. (PMID:16135253)
• cytoplasmic RGS7*Gbeta5*R7BP heterotrimers and RGS7*Gbeta5 heterodimers are equivalently inefficient regulators of G protein-coupled receptor signaling relative to plasma membrane-bound heterotrimers bearing palmitoylated R7BP. (PMID:16867977)
• G-protein beta5 short splice variant isoform is indispensable for outer plexiform layer integrity and normal light responses of the retina in transgenic mice. (PMID:18094259)
• cytosolic chaperonin complex-dependent mechanism exists for Gbeta5-RGS7 assembly that utilizes the co-chaperone activity of PhLP1 in a unique way. (PMID:19376773)
• Gbeta5’s function in vision is reviewed. (PMID:20374718)
• Type 5 G protein beta subunit (Gbeta5) controls the interaction of regulator of G protein signaling 9 (RGS9) with membrane anchors (PMID:21511947)
• The intrinsic resistance to TRAIL-triggered apoptosis of colon cancer cells is overcome by antagonization of Gbeta5. (PMID:25043307)
• Results suggest that D2R can interact with and stabilize the Gb5 protein, independently of R7 G protein signaling (RGS) proteins. (PMID:25162404)
• individuals with loss-of-function GNB5 alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype (PMID:27523599)
• Data mapped differences in deuterium exchange between the regulator of G protein signaling 7 (RGS7)-Gbeta5 protein(Gbeta5)-RGS7 family binding protein (R7BP) trimer and the RGS7-Gbeta5 dimer. (PMID:30540250)
• GNB5 overexpression contributes to cetuximab resistance in colorectal cancer. (PMID:30719834)
• The PSD-95 GK domain binds to Gnb5, and this interaction is triggered by CRIPT-derived PDZ3 ligands binding to the third PDZ domain of PSD-95, unraveling a hierarchical binding mechanism of PSD-95 complex formation. (PMID:30864948)
• provide mechanistic insights and proof of principle for potential therapy in patients carrying GNB5 mutations (PMID:31208990)
• GNB5 developmental and epileptic encephalopathy is characterized by epileptic spasms, focal seizures, and profound impairment. (PMID:31631344)
• IDDCA syndrome in a Chinese infant due to GNB5 biallelic mutations. (PMID:32203251)
• [Intellectual developmental disorder with cardiac arrhythmia syndrome in a family caused by GNB5 variation and literature review]. (PMID:32987464)
• Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome. (PMID:33172956)
• Extended Phenotyping and Functional Validation Facilitate Diagnosis of a Complex Patient Harboring Genetic Variants in MCCC1 and GNB5 Causing Overlapping Phenotypes. (PMID:34573334)
• Cryo-EM structure of human GPR158 receptor coupled to the RGS7-Gbeta5 signaling complex. (PMID:34793198)
• Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gbeta5. (PMID:34815401)
• Inheritance of c.628-6G>A GNB5 hypomorphic allele uncovers another challenge in the pathogenic prediction of genomic variants. (PMID:37994112)
• The association of GNB5 with Alzheimer disease revealed by genomic analysis restricted to variants impacting gene function. (PMID:38354736)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnb5b	ENSDARG00000055377
danio_rerio	gnb5a	ENSDARG00000099685
mus_musculus	Gnb5	ENSMUSG00000032192
rattus_norvegicus	Gnb5	ENSRNOG00000047799
drosophila_melanogaster	Gbeta5	FBGN0030011
caenorhabditis_elegans	gpb-2	WBGENE00001680

Paralogs (4): GNB1 (ENSG00000078369), GNB3 (ENSG00000111664), GNB4 (ENSG00000114450), GNB2 (ENSG00000172354)

Protein

Protein identifiers

Guanine nucleotide-binding protein subunit beta-5 — O14775 (reviewed: O14775)

Alternative names: Gbeta5, Transducin beta chain 5

All UniProt accessions (4): O14775, H0YLU1, H0YNW7, Q96F32

UniProt curated annotations — full annotation on UniProt →

Function. Enhances GTPase-activating protein (GAP) activity of regulator of G protein signaling (RGS) proteins, such as RGS7 and RGS9, hence involved in the termination of the signaling initiated by the G protein coupled receptors (GPCRs) by accelerating the GTP hydrolysis on the G-alpha subunits, thereby promoting their inactivation. Increases RGS7 GTPase-activating protein (GAP) activity, thereby regulating mood and cognition. Increases RGS9 GTPase-activating protein (GAP) activity, hence contributes to the deactivation of G protein signaling initiated by D(2) dopamine receptors. May play an important role in neuronal signaling, including in the parasympathetic, but not sympathetic, control of heart rate.

Subunit / interactions. Component of a complex composed of RGS9 (isoform RGS9-1), GNB5 and RGS9BP; within this complex, the presence of GNB5 stabilizes both itself and RGS9 and increases RGS9 GTPase-activating protein (GAP) activity. Interacts with RGS7, forming the RGS7-GNB5 complex; within this complex, the presence of GNB5 increases RGS7 GTPase-activating protein (GAP) activity. Interacts with GPR158; promotes the GTPase activator activity of the RGS7-GNB5 complex in absence of glycine, in contrast GTPase activator activity of the RGS7-GNB5 complex is inhibited in presence of glycine. Interacts with RGS6.

Subcellular location. Membrane.

Tissue specificity. Widely expressed.

Disease relevance. Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmia (LDMLS1) [MIM:617173] An autosomal recessive multisystem disorder characterized by delayed psychomotor development, severe intellectual disability with poor or absent speech, and bradycardia and/or cardiac sinus arrhythmias. Additional features include visual abnormalities, seizures, hypotonia, and gastric reflux. The disease is caused by variants affecting the gene represented in this entry. Lodder-Merla syndrome, type 2, with developmental delay and with or without cardiac arrhythmia (LDMLS2) [MIM:617182] An autosomal recessive neurodevelopmental disorder characterized by speech impairment and variable expressivity of attention deficit-hyperactivity disorder. Some patients manifest developmental and motor delay, hypotonia, and sinus-node dysfunction. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (3)

UniProt ID	Names	Canonical?
O14775-1	1, Long, Beta-5L	yes
O14775-2	2
O14775-3	3

RefSeq proteins (3): NP_001366272, NP_006569, NP_057278* (*=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 (49 total): strand 29, repeat 7, turn 6, sequence variant 2, splice variant 2, chain 1, sequence conflict 1, helix 1

Structure

Experimental structures (PDB)

32 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8SH9	ELECTRON MICROSCOPY	2.7
8SHE	ELECTRON MICROSCOPY	2.8
8SHG	ELECTRON MICROSCOPY	2.8
8SHN	ELECTRON MICROSCOPY	2.8
8SG9	ELECTRON MICROSCOPY	2.9
8SGC	ELECTRON MICROSCOPY	2.9
8SGL	ELECTRON MICROSCOPY	2.9
8SHD	ELECTRON MICROSCOPY	2.9
8SHQ	ELECTRON MICROSCOPY	2.9
9NOQ	ELECTRON MICROSCOPY	2.9
9NRH	ELECTRON MICROSCOPY	2.9
8SG8	ELECTRON MICROSCOPY	3
8SHA	ELECTRON MICROSCOPY	3
8SHF	ELECTRON MICROSCOPY	3
8SHL	ELECTRON MICROSCOPY	3
8SHO	ELECTRON MICROSCOPY	3
8SHP	ELECTRON MICROSCOPY	3
8SHT	ELECTRON MICROSCOPY	3
9NPW	ELECTRON MICROSCOPY	3
9NQ1	ELECTRON MICROSCOPY	3
9NRG	ELECTRON MICROSCOPY	3
9NOO	ELECTRON MICROSCOPY	3.1
9NOP	ELECTRON MICROSCOPY	3.1
9NQ6	ELECTRON MICROSCOPY	3.1
9NRE	ELECTRON MICROSCOPY	3.1
9NRF	ELECTRON MICROSCOPY	3.1
9NOC	ELECTRON MICROSCOPY	3.17
9NR1	ELECTRON MICROSCOPY	3.2
9NR4	ELECTRON MICROSCOPY	3.2
9NRD	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14775-F1	93.92	0.83

Function

Pathways and Gene Ontology

Reactome pathways

29 pathways

ID	Pathway
R-HSA-1296041	Activation of G protein gated Potassium channels
R-HSA-202040	G-protein activation
R-HSA-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
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-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells
R-HSA-997272	Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits
R-HSA-2514859	Inactivation, recovery and regulation of the phototransduction cascade

MSigDB gene sets: 340 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_GLUCAGON_TYPE_LIGAND_RECEPTORS, REACTOME_ADRENALINE_NORADRENALINE_INHIBITS_INSULIN_SECRETION, REACTOME_POTASSIUM_CHANNELS, REACTOME_INWARDLY_RECTIFYING_K_CHANNELS, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, REACTOME_G_ALPHA_Z_SIGNALLING_EVENTS, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, PID_CONE_PATHWAY, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, DOANE_RESPONSE_TO_ANDROGEN_DN

GO Biological Process (7): signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), G protein-coupled dopamine receptor signaling pathway (GO:0007212), light adaption (GO:0036367), dark adaptation (GO:1990603), positive regulation of GTPase activity (GO:0043547), negative regulation of voltage-gated calcium channel activity (GO:1901386)

GO Molecular Function (6): GTPase activity (GO:0003924), GTPase activator activity (GO:0005096), signaling receptor complex adaptor activity (GO:0030159), G-protein gamma-subunit binding (GO:0031682), protein-folding chaperone binding (GO:0051087), protein binding (GO:0005515)

GO Cellular Component (14): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), heterotrimeric G-protein complex (GO:0005834), dendrite (GO:0030425), presynaptic membrane (GO:0042734), postsynaptic membrane (GO:0045211), cell tip (GO:0051286), parallel fiber to Purkinje cell synapse (GO:0098688), GTPase activator complex (GO:1902773), plasma membrane (GO:0005886), membrane (GO:0016020), synapse (GO:0045202), presynapse (GO:0098793)

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
Opioid Signalling	1
Platelet homeostasis	1
Beta-catenin independent WNT signaling	1
Class B/2 (Secretin family receptors)	1
Aquaporin-mediated transport	1
Platelet activation, signaling and aggregation	1
Activation of kainate receptors upon glutamate binding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
GTPase activity	2
protein binding	2
synaptic membrane	2
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
synaptic transmission, dopaminergic	1
G protein-coupled receptor signaling pathway	1
cellular response to dopamine	1
response to light intensity	1
cellular response to absence of light	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
voltage-gated calcium channel activity	1
negative regulation of calcium ion transmembrane transporter activity	1
regulation of voltage-gated calcium channel activity	1
ribonucleoside triphosphate phosphatase activity	1
enzyme activator activity	1
GTPase regulator activity	1
signaling receptor binding	1
signaling adaptor activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
extrinsic component of cytoplasmic side of plasma membrane	1
plasma membrane protein complex	1
GTPase complex	1
neuron projection	1
dendritic tree	1
presynapse	1
postsynapse	1
cell pole	1
excitatory synapse	1
enzyme activator complex	1

Protein interactions and networks

STRING

2835 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNB5	RGS7	P49802	999
GNB5	RGS9BP	Q6ZS82	999
GNB5	RGS11	O94810	998
GNB5	RGS6	P49758	998
GNB5	RGS7BP	Q6MZT1	990
GNB5	RGS9	O75916	973
GNB5	GGT5	P36269	967
GNB5	RGS4	P49798	884
GNB5	RGS21	Q2M5E4	882
GNB5	RGS8	P57771	880
GNB5	RGS17	Q9UGC6	878
GNB5	RGS13	O14921	878
GNB5	RGS10	O43665	878
GNB5	RGS20	O76081	878
GNB5	RGS12	O14924	876
GNB5	RGS18	Q9NS28	876

IntAct

63 interactions, top by confidence:

A	B	Type	Score
GNG8	GNB5	psi-mi:“MI:0914”(association)	0.640
GNG5	GNB5	psi-mi:“MI:0914”(association)	0.620
GNG5	GNB5	psi-mi:“MI:0915”(physical association)	0.620
GNG7	GNB5	psi-mi:“MI:0914”(association)	0.600
GNB5	GNG7	psi-mi:“MI:0915”(physical association)	0.600
GNG7	GNB5	psi-mi:“MI:2364”(proximity)	0.600
GNB5	PFDN5	psi-mi:“MI:0915”(physical association)	0.560
GNG2	GNB5	psi-mi:“MI:0914”(association)	0.530
GNG3	GNB5	psi-mi:“MI:0914”(association)	0.500
GNG4	GNB5	psi-mi:“MI:0914”(association)	0.500
GNG3	GNB5	psi-mi:“MI:0915”(physical association)	0.500
GNG4	GNB5	psi-mi:“MI:0915”(physical association)	0.500
RGS6	GNB5	psi-mi:“MI:0915”(physical association)	0.500
RGS9	GNB5	psi-mi:“MI:0914”(association)	0.500
RGS9	GNB5	psi-mi:“MI:0915”(physical association)	0.500
POLR2A	GNB5	psi-mi:“MI:0915”(physical association)	0.400
GNB5	MLF1	psi-mi:“MI:0915”(physical association)	0.400
MLF2	GNB5	psi-mi:“MI:0915”(physical association)	0.400
HSP90AB1	GNB5	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (89): GNB5 (Affinity Capture-MS), CCT6B (Affinity Capture-MS), CCT3 (Affinity Capture-MS), TCP1 (Affinity Capture-MS), PDCL (Affinity Capture-MS), PFDN5 (Affinity Capture-MS), COPS5 (Affinity Capture-MS), RGS7 (Affinity Capture-MS), GNB5 (Co-localization), GNB5 (Affinity Capture-Western), DRD2 (Co-localization), DRD2 (PCA), GNB5 (Affinity Capture-MS), RGS7 (Affinity Capture-MS), GNB5 (Affinity Capture-MS)

ESM2 similar proteins: A0A223GEB2, A1L271, G4MQX3, O14435, O14775, O24456, O35353, O45040, P11017, P16520, P17343, P23232, P26308, P29387, P29829, P36408, P52287, P54311, P54313, P62871, P62872, P62873, P62874, P62879, P62880, P62881, P62882, P79147, P79959, P93339, P93397, P93398, P93563, Q08706, Q20636, Q39336, Q39836, Q40507, Q5GIS3, Q5R5W8

Diamond homologs: A0A223GEB2, A1L271, A2QPZ4, A4R3M4, A6H603, A6RRD4, B2VWG7, B3MHX6, B3MJV8, B4GT01, B4JPT9, B5DG67, B8N9H4, C0S902, C1GB49, C4R6H3, C4YPI7, C5GVJ9, C5JD40, E3LB80, G0S8H7, G1SJB4, G4MQX3, O14775, O18640, O24076, O24456, O42248, O42249, O94527, P0CS34, P0CS35, P25382, P25387, P38011, P40968, P46800, P49026, P49027, P52287

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
DRD2	“up-regulates activity”	GNB5	binding
DRD3	“up-regulates activity”	GNB5	binding
DRD4	“up-regulates activity”	GNB5	binding
GNB5	“down-regulates activity”	ADCY1	binding
GNB5	“down-regulates activity”	ADCY5	binding
“GABA-B receptor”	“up-regulates activity”	GNB5	binding
GNB5	“down-regulates activity”	Adenylate_cyclase	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 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
G beta:gamma signalling through BTK	8	158.6×	1e-14
Prostacyclin signalling through prostacyclin receptor	8	150.3×	1e-14
G beta:gamma signalling through PLC beta	8	142.8×	1e-14
G beta:gamma signalling through CDC42	8	142.8×	1e-14
Presynaptic function of Kainate receptors	8	135.9×	2e-14
ADP signalling through P2Y purinoceptor 12	8	124.1×	3e-14
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	13	122.1×	7e-23
G-protein activation	8	119.0×	4e-14

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	8	20.2×	1e-06
G protein-coupled receptor signaling pathway	10	8.8×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	11
Uncertain significance	77
Likely benign	39
Benign	46

Top pathogenic / likely-pathogenic (29)

Variant ID	HGVS	Classification
1210290	NM_016194.4(GNB5):c.262del (p.Glu88fs)	Pathogenic
146334	GRCh38/hg38 15q21.1-21.2(chr15:47460844-52494222)x1	Pathogenic
1685857	NM_016194.4(GNB5):c.1160G>C (p.Trp387Ser)	Pathogenic
1694471	NM_016194.4(GNB5):c.239-2A>C	Pathogenic
2322088	NM_016194.4(GNB5):c.666G>A (p.Trp222Ter)	Pathogenic
254029	NM_016194.4(GNB5):c.368C>T (p.Ser123Leu)	Pathogenic
2575916	NM_016194.4(GNB5):c.368C>A (p.Ser123Ter)	Pathogenic
2575917	NM_016194.4(GNB5):c.458G>A (p.Cys153Tyr)	Pathogenic
2575919	NM_016194.4(GNB5):c.481del (p.Ala161fs)	Pathogenic
268098	NM_016194.4(GNB5):c.375G>A (p.Gln125=)	Pathogenic
268100	NM_016194.4(GNB5):c.375+1G>T	Pathogenic
268102	NM_016194.4(GNB5):c.1032C>G (p.Tyr344Ter)	Pathogenic
3337152	NM_016194.4(GNB5):c.500del (p.Leu167fs)	Pathogenic
3337676	NM_016194.4(GNB5):c.841_851del (p.Glu281fs)	Pathogenic
4073558	NM_016194.4(GNB5):c.514del (p.Ser172fs)	Pathogenic
4081908	NM_016194.4(GNB5):c.640_641delinsC (p.Ser214fs)	Pathogenic
426541	NM_016194.4(GNB5):c.348_352del (p.Asp116fs)	Pathogenic
4291728	NM_016194.4(GNB5):c.627+1G>A	Pathogenic
1723418	NM_016194.4(GNB5):c.494+1G>T	Likely pathogenic
268099	NM_016194.4(GNB5):c.1120C>T (p.Arg374Ter)	Likely pathogenic
2692565	NM_016194.4(GNB5):c.375+1G>A	Likely pathogenic
3256586	NM_016194.4(GNB5):c.819C>A (p.Cys273Ter)	Likely pathogenic
3385342	NM_016194.4(GNB5):c.1009+1G>C	Likely pathogenic
3895326	NM_016194.4(GNB5):c.154G>T (p.Glu52Ter)	Likely pathogenic
3902534	NM_016194.4(GNB5):c.375+1G>C	Likely pathogenic
4073556	NM_016194.4(GNB5):c.628-6G>A	Likely pathogenic
4081431	NM_016194.4(GNB5):c.864-1G>T	Likely pathogenic
817365	NM_016194.4(GNB5):c.1092del (p.Phe364fs)	Likely pathogenic
977622	NM_016194.4(GNB5):c.368C>G (p.Ser123Trp)	Likely pathogenic

SpliceAI

2265 predictions. Top by Δscore:

Variant	Effect	Δscore
15:52124471:A:AC	donor_gain	1.0000
15:52124472:C:CC	donor_gain	1.0000
15:52124472:CT:C	donor_gain	1.0000
15:52126043:CA:C	acceptor_gain	1.0000
15:52133372:A:AC	donor_gain	1.0000
15:52133373:C:CT	donor_gain	1.0000
15:52133373:CTGA:C	donor_gain	1.0000
15:52133465:CATCC:C	acceptor_gain	1.0000
15:52133467:TCC:T	acceptor_gain	1.0000
15:52133468:CC:C	acceptor_gain	1.0000
15:52133468:CCC:C	acceptor_gain	1.0000
15:52133468:CCCT:C	acceptor_loss	1.0000
15:52133469:CC:C	acceptor_gain	1.0000
15:52133470:C:A	acceptor_loss	1.0000
15:52135631:T:TA	donor_gain	1.0000
15:52135762:C:CT	acceptor_gain	1.0000
15:52141268:AACCA:A	acceptor_gain	1.0000
15:52141270:CCA:C	acceptor_gain	1.0000
15:52141271:CA:C	acceptor_gain	1.0000
15:52141271:CAC:C	acceptor_gain	1.0000
15:52141273:C:CC	acceptor_gain	1.0000
15:52141278:A:C	acceptor_gain	1.0000
15:52154072:GTGCA:G	acceptor_gain	1.0000
15:52154074:GCA:G	acceptor_gain	1.0000
15:52154075:CAC:C	acceptor_gain	1.0000
15:52154077:C:CC	acceptor_gain	1.0000
15:52154077:CTGGA:C	acceptor_loss	1.0000
15:52154078:T:A	acceptor_loss	1.0000
15:52179767:CG:C	donor_gain	1.0000
15:52122045:T:A	donor_gain	0.9900

AlphaMissense

2602 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:52124486:T:A	D388V	1.000
15:52124486:T:G	D388A	1.000
15:52124487:C:G	D388H	1.000
15:52124488:C:A	W387C	1.000
15:52124488:C:G	W387C	1.000
15:52124489:C:A	W387L	1.000
15:52124490:A:G	W387R	1.000
15:52124490:A:T	W387R	1.000
15:52124493:A:G	S386P	1.000
15:52124495:C:T	G385E	1.000
15:52124496:C:G	G385R	1.000
15:52124496:C:T	G385R	1.000
15:52124514:C:A	G379W	1.000
15:52124536:G:C	S371R	1.000
15:52124536:G:T	S371R	1.000
15:52124538:T:G	S371R	1.000
15:52124540:A:T	V370D	1.000
15:52124544:G:T	R369S	1.000
15:52124591:T:A	D353V	1.000
15:52124595:A:G	W352R	1.000
15:52124595:A:T	W352R	1.000
15:52124613:C:G	D346H	1.000
15:52124621:C:T	G343E	1.000
15:52124622:C:G	G343R	1.000
15:52124622:C:T	G343R	1.000
15:52124639:C:A	G337V	1.000
15:52124639:C:T	G337D	1.000
15:52125979:A:C	F326L	1.000
15:52125979:A:T	F326L	1.000
15:52125981:A:G	F326L	1.000

dbSNP variants (sampled 300 via entrez): RS1000031073 (15:52159248 G>A,C), RS1000038303 (15:52175773 A>G), RS1000105596 (15:52152442 G>C), RS1000133840 (15:52116824 G>A), RS1000139192 (15:52167736 A>C), RS1000170355 (15:52127940 A>G), RS1000177233 (15:52120911 A>G), RS1000285126 (15:52131854 T>G), RS1000336977 (15:52132126 T>C), RS1000379295 (15:52140373 C>A,T), RS1000440768 (15:52164431 A>C), RS1000466726 (15:52134183 T>C), RS1000535187 (15:52180254 C>A), RS1000551742 (15:52150964 T>A), RS1000564465 (15:52136565 G>A)

Disease associations

OMIM: gene MIM:604447 | disease phenotypes: MIM:617173, MIM:617182, MIM:617667

GenCC curated gene-disease

Disease	Classification	Inheritance
language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia	Strong	Autosomal recessive
gnb5-related intellectual disability-cardiac arrhythmia syndrome	Strong	Autosomal recessive
schizophrenia	No Known Disease Relationship	Unknown

Mondo (6): gnb5-related intellectual disability-cardiac arrhythmia syndrome (MONDO:0014953), congenital nervous system disorder (MONDO:0002320), language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia (MONDO:0014957), attention deficit-hyperactivity disorder (MONDO:0007743), Fraser syndrome 3 (MONDO:0054739), schizophrenia (MONDO:0005090)

Orphanet (1): GNB5-related intellectual disability-cardiac arrhythmia syndrome (Orphanet:542306)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000512	Abnormal electroretinogram
HP:0000546	Retinal degeneration
HP:0000563	Keratoconus
HP:0000639	Nystagmus
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000817	Reduced eye contact
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001344	Absent speech
HP:0001626	Abnormality of the cardiovascular system
HP:0001655	Patent foramen ovale
HP:0001662	Bradycardia
HP:0002020	Gastroesophageal reflux
HP:0002421	Poor head control
HP:0002521	Hypsarrhythmia
HP:0003593	Infantile onset
HP:0005155	Ventricular escape rhythm
HP:0007010	Poor fine motor coordination
HP:0007018	Attention deficit hyperactivity disorder
HP:0010864	Severe intellectual disability
HP:0011675	Arrhythmia
HP:0011704	Sick sinus syndrome
HP:0012248	Prolonged PR interval

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002591_17	Lewy body disease	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006799	Lewy body dementia measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	4
trichostatin A	affects cotreatment, decreases expression	2
Arsenic	decreases methylation, increases abundance, increases expression	2
N(6)-(delta(2)-isopentenyl)adenine	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation, affects cotreatment	1
sodium arsenite	increases abundance, increases expression	1
cobaltous chloride	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Arsenates	affects cotreatment, increases expression	1
Atrazine	affects cotreatment, increases expression	1
Barium	affects binding, decreases reaction, increases transport	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cadmium	increases abundance, increases expression	1
Carbamazepine	affects expression	1
Chelating Agents	affects binding, increases expression	1
Cisplatin	increases expression	1
Copper	affects binding, increases expression	1
Diclofenac	affects expression	1
Hydrogen Peroxide	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Rotenone	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Metals, Heavy	increases abundance, decreases methylation	1

Cellosaurus cell lines

3 cell lines: 2 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8LY	Ubigene HCT 116 GNB5 KO	Cancer cell line	Male
CVCL_XI71	CSSi009-A	Induced pluripotent stem cell	Male
CVCL_XI72	CSSi010-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety