GNAI3

Summary

GNAI3 (G protein subunit alpha i3, HGNC:4387) is a protein-coding gene on chromosome 1p13.3, encoding Guanine nucleotide-binding protein G(i) subunit alpha-3 (P08754). Heterotrimeric guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.

Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling pathways. G proteins are composed of 3 units: alpha, beta and gamma. This gene encodes an alpha subunit and belongs to the G-alpha family. Mutation in this gene, resulting in a gly40-to-arg substitution, is associated with auriculocondylar syndrome, and shown to affect downstream targets in the G protein-coupled endothelin receptor pathway.

Source: NCBI Gene 2773 — RefSeq curated summary.

At a glance

• Gene–disease (curated): auriculocondylar syndrome 1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 105 total — 2 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 47
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006496

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4387
Approved symbol	GNAI3
Name	G protein subunit alpha i3
Location	1p13.3
Locus type	gene with protein product
Status	Approved
Aliases	87U6
Ensembl gene	ENSG00000065135
Ensembl biotype	protein_coding
OMIM	139370
Entrez	2773

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000369851, ENST00000879740, ENST00000879741, ENST00000879742, ENST00000879743, ENST00000920643, ENST00000920644

RefSeq mRNA: 1 — MANE Select: NM_006496 NM_006496

CCDS: CCDS802

Canonical transcript exons

ENST00000369851 — 9 exons

Exon	Start	End
ENSE00000783439	109573896	109574037
ENSE00000826739	109579204	109579361
ENSE00000826740	109582437	109582565
ENSE00000913041	109592043	109592255
ENSE00001342841	109592345	109600195
ENSE00001451089	109548615	109548838
ENSE00001740751	109586216	109586345
ENSE00001756567	109586729	109586882
ENSE00001781395	109573737	109573779

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 82.0806 / max 1790.5354, expressed in 1823 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4424	80.1408	1823
201606	1.9398	1031

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	99.33	gold quality
epithelium of esophagus	UBERON:0001976	98.93	gold quality
tongue squamous epithelium	UBERON:0006919	98.85	gold quality
squamous epithelium	UBERON:0006914	98.82	gold quality
gingival epithelium	UBERON:0001949	98.54	gold quality
gingiva	UBERON:0001828	98.43	gold quality
upper leg skin	UBERON:0004262	98.33	gold quality
parietal pleura	UBERON:0002400	97.98	gold quality
pleura	UBERON:0000977	97.76	gold quality
visceral pleura	UBERON:0002401	97.74	gold quality
hair follicle	UBERON:0002073	97.68	gold quality
skin of hip	UBERON:0001554	97.66	gold quality
tibia	UBERON:0000979	97.64	gold quality
cartilage tissue	UBERON:0002418	97.54	gold quality
oral cavity	UBERON:0000167	97.49	gold quality
upper arm skin	UBERON:0004263	97.43	gold quality
cervix epithelium	UBERON:0004801	97.43	gold quality
palpebral conjunctiva	UBERON:0001812	97.33	gold quality
mammalian vulva	UBERON:0000997	97.18	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.11	gold quality
secondary oocyte	CL:0000655	97.07	gold quality
cervix squamous epithelium	UBERON:0006922	97.05	gold quality
amniotic fluid	UBERON:0000173	96.90	gold quality
nephron tubule	UBERON:0001231	96.44	gold quality
colonic mucosa	UBERON:0000317	96.27	gold quality
penis	UBERON:0000989	96.25	gold quality
germinal epithelium of ovary	UBERON:0001304	96.24	gold quality
epithelium of nasopharynx	UBERON:0001951	95.96	gold quality
periodontal ligament	UBERON:0008266	95.70	gold quality
cranial nerve II	UBERON:0000941	95.68	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-75367	no	1080.00
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

205 targeting GNAI3, 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-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-3065-5P	99.97	71.56	3281

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 34)

• Overexpression of GIPN stimulates proteasome-dependent reduction of endogenous G alpha i3 in HEK293 cells and reduces the half-life of overexpressed G alpha i3-YFP. (PMID:12826607)
• diffraction data were collected to 2.5 A resolution at 100 K using synchrotron radiation at Pohang beamline 4A for human RGS10 complexed with Galphai3 [Galphai3] (PMID:16511171)
• x-ray crystallography of the complex of RGS5 and Galphai(3) proteins with GDP/Mg(2+)/AlF(4)(-) at 3.0 A resolution (PMID:17100651)
• The Galphai3-GIV switch serves to link direction sensing from different families of chemotactic receptors to formation of the leading edge during cell migration. (PMID:18663145)
• Insulin-like growth factor-binding protein-5 stimulates growth of human intestinal muscle cells by activation of Galphai3. (PMID:19808657)
• These data present AGS3, G-proteins, and mInsc as candidate proteins involved in regulating cellular stress associated with protein-processing pathologies. (PMID:20065032)
• we show that A3 adenosine receptor/Gi3 play important roles in human mast cells responses initiated on contact with activated T cells. (PMID:20190146)
• Data suggest that Galphai-TNFAIP8-mediated rescue of pre-oncogenic cells enhances progression to oncogenic transformation, providing a selective target to inhibit cellular transformation. (PMID:20607800)
• These results provide mechanistic insights into how reversible modulation of Galpha(i3) activity by AGS3 and GIV maintains the delicate equilibrium between promotion and inhibition of autophagy. (PMID:21209316)
• The mechanisms of regulation of GIRK by Galpha(i/o) using wild-type Galpha(i3) (Galpha(i3)WT) and Galpha(i3), were investigated. (PMID:21795707)
• These results identify the Oa1 transducer Galphai3 as the first downstream component in the Oa1 signaling pathway. (PMID:21931697)
• The phenotypic variability of auriculocondylar syndrome suggests that mutations in this pathway, especially those affecting core signaling molecules such as PLCB4 and GNAI3, should be considered as potential candidates for other ear and jaw malformations. (PMID:22560091)
• Data indicate that dynein- and astral microtubule-mediated transport of Galphai/LGN/nuclear mitotic apparatus (NuMA) complex from cell cortex to spindle poles. (PMID:23389635)
• We demonstrate that the GNAI3 variant is the likely cause of auriculocondylar syndrome in the original ACS1 family. (PMID:25026904)
• We observed increased expression of Galphai1/3 in wounded human skin and keloid skin tissues, suggesting the possible involvement of Galphai1/3 in wound healing and keloid formation. (PMID:25078664)
• Both SH2 and GEF domains of GIV are required for the formation of a ligand-activated ternary complex between GIV, Galphai3, and EGFR. (PMID:25187647)
• Low GNAI3 expression is associated with hepatocellular carcinoma. (PMID:25444921)
• transcriptional upregulation of Girdin expression and Girdin-Galphai3 signaling play crucial roles in regulating epithelial apicobasal polarity through the PAR complex. (PMID:25977476)
• In postmortem human prefrontal cortex, adenosine A1 receptor is coupled preferentially, if not exclusively, to Galphai-3. (PMID:26213104)
• GIV and its substrate Galphai3 are recruited to active integrin complexes (PMID:26391662)
• Data show that auriculo-condylar syndrome (ACS)-associated mutations in G protein subunit alpha i3 (GNAI3) produce dominant-negative Galpha(i3) mutant proteins that couple to endothelin type A receptor (ET(A)R). (PMID:27072656)
• GNAI3 is identified a second gene possibly responsible for X-linked ocular albinism. (PMID:27607449)
• These data indicate that, unlike in taste cells, TAS2Rs couple to the prevalent G proteins, Galphai1, Galphai2, and Galphai3, with no evidence for functional coupling to Galphagust. (PMID:28145731)
• magnetic field-dependent nuclear magnetic resonance relaxation analyses were used to investigate the structural and dynamic properties of GDP bound Galpha on a microsecond timescale. (PMID:28223697)
• Results show that Galphai3 nuclear translocation causes irradiation resistance in human glioma cells through its complexation with DNA-PKcs leading to DNA repair. (PMID:28456783)
• direct binding of GATA4 to the GNAI3 promoter, both in vitro and in vivo, is reported. (PMID:28484278)
• We found that the inhibitory Galphai3 protein selectively bound to the G-protein-binding domain on the C-terminus of PC1. The dissociation of Galphai3 upon cleavage of PC1 increased TRPC4 activity. (PMID:29472562)
• These results provide mechanistic insights into the critical role played by Galphai1/3 proteins in VEGF-induced VEGFR2 endocytosis, signaling and angiogenesis. (PMID:30279732)
• A highly conserved delta-opioid receptor region determines RGS4 interaction. (PMID:31386272)
• The CpG-SNP rs11810577 in GNAI3 in the gastric acid secretion pathway was significantly associated with susceptibility to gastric cancer. (PMID:32032744)
• A novel missense variant of the GNAI3 gene and recognisable morphological characteristics of the mandibula in ARCND1. (PMID:33723370)
• Galphai1/3 mediate Netrin-1-CD146-activated signaling and angiogenesis. (PMID:37153740)
• Integrins regulate hERG1 dynamics by girdin-dependent Galphai3: signaling and modeling in cancer cells. (PMID:37923359)
• GNAI3 mediated by Lin28A regulates lipopolysaccharide-induced inflammation and osteogenic differentiation in periodontal stem cells by mediating the NF-kappaB/NLRP3 inflammasome pathway. (PMID:38636252)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnai3	ENSDARG00000030644
mus_musculus	Gnai3	ENSMUSG00000000001
drosophila_melanogaster	Galphaf	FBGN0010223
caenorhabditis_elegans		WBGENE00001664
caenorhabditis_elegans		WBGENE00001665
caenorhabditis_elegans		WBGENE00001667
caenorhabditis_elegans		WBGENE00001668
caenorhabditis_elegans		WBGENE00001670
caenorhabditis_elegans		WBGENE00001671
caenorhabditis_elegans		WBGENE00001673
caenorhabditis_elegans		WBGENE00001675
caenorhabditis_elegans	gpa-14	WBGENE00001676
caenorhabditis_elegans	gsa-1	WBGENE00001745

Paralogs (15): GNA15 (ENSG00000060558), GNAO1 (ENSG00000087258), GNAS (ENSG00000087460), GNA11 (ENSG00000088256), GNAT1 (ENSG00000114349), GNAI2 (ENSG00000114353), GNA13 (ENSG00000120063), GNAI1 (ENSG00000127955), GNAZ (ENSG00000128266), GNAT2 (ENSG00000134183), GNAL (ENSG00000141404), GNA12 (ENSG00000146535), GNA14 (ENSG00000156049), GNAQ (ENSG00000156052), GNAT3 (ENSG00000214415)

Protein

Protein identifiers

Guanine nucleotide-binding protein G(i) subunit alpha-3 — P08754 (reviewed: P08754)

Alternative names: G(i) alpha-3

All UniProt accessions (1): P08754

UniProt curated annotations — full annotation on UniProt →

Function. Heterotrimeric guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal. Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins. Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels. Stimulates the activity of receptor-regulated K(+) channels. The active GTP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division. The active GTP-bound form activates the calcium permeant TRPC5 ion channels.

Subunit / interactions. Heterotrimeric G proteins are composed of 3 units; alpha, beta and gamma. The alpha subunit contains the guanine nucleotide binding site. GTP binding causes dissociation of the heterotrimer, liberating the individual subunits so that they can interact with downstream effector proteins. Forms a complex with CCDC88A/GIV and EGFR which leads to enhanced EGFR signaling and triggering of cell migration; ligand stimulation is required for recruitment of GNAI3 to the complex. Interacts (inactive GDP-bound form) with CCDC88A/GIV (via GBA motif); the interaction leads to activation of GNAI3. Interacts (inactive GDP-bound form) with CCDC88C/DAPLE (via GBA motif); the interaction leads to activation of GNAI3. Interacts (inactive GDP-bound form) with NUCB1 (via GBA motif) and NUCB2 (via GBA motif); the interaction leads to activation of GNAI3. Interacts (inactive GDP-bound form) with PLCD4 (via GBA motif); the interaction leads to activation of GNAI3. Interacts with INSR; the interaction is probably mediated by CCDC88A/GIV. Interacts with GPSM1. Interacts (GDP-bound form) with GPSM2 (via GoLoco domains). Does not interact with RGS2. Interacts with RGS8 and RGS10; this strongly enhances the intrinsic GTPase activity. Interacts with RGS16; this strongly enhances the intrinsic GTPase activity. Interacts with RGS12. Interacts (via active GTP- or inactive GDP-bound form) with RGS14. Interacts (via active GTP-bound form) with TRPC5 (via ANK repeats) in a homotetrameric ion channel; the interaction is direct and activates the channel activity.

Subcellular location. Cytoplasm. Cell membrane. Cytoskeleton. Microtubule organizing center. Centrosome.

Post-translational modifications. (Microbial infection) Deamidated at Gln-204 by Photorhabdus asymbiotica toxin PAU_02230, blocking GTP hydrolysis of heterotrimeric GNAQ or GNA11 and G-alphai (GNAI1, GNAI2 or GNAI3) proteins, thereby activating RhoA.

Disease relevance. Auriculocondylar syndrome 1 (ARCND1) [MIM:602483] An autosomal dominant form of auriculocondylar syndrome, a craniofacial malformation syndrome characterized by variable mandibular anomalies, including mild to severe micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic ear malformation that consists of separation of the lobule from the external ear, giving the appearance of a question mark (question-mark ear). Other frequently described features include prominent cheeks, cupped and posteriorly rotated ears, preauricular tags, and microstomia. Glossoptosis, masticatory abnormalities, orthodontic problems, and malocclusion occur in a majority of affected subjects. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the G-alpha family. G(i/o/t/z) subfamily.

RefSeq proteins (1): NP_006487* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001019	Gprotein_alpha_su	Family
IPR001408	Gprotein_alpha_I	Family
IPR011025	GproteinA_insert	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00503

UniProt features (113 total): binding site 43, helix 20, mutagenesis site 19, strand 11, region of interest 5, sequence variant 4, modified residue 3, turn 2, lipid moiety-binding region 2, initiator methionine 1, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

27 structures.

PDB	Method	Resolution (Å)
2ODE	X-RAY DIFFRACTION	1.9
8IKL	ELECTRON MICROSCOPY	2.33
8YK0	ELECTRON MICROSCOPY	2.4
7T10	ELECTRON MICROSCOPY	2.5
9VJ6	ELECTRON MICROSCOPY	2.62
7T11	ELECTRON MICROSCOPY	2.7
9VJF	ELECTRON MICROSCOPY	2.7
2IHB	X-RAY DIFFRACTION	2.71
2V4Z	X-RAY DIFFRACTION	2.8
7KH0	ELECTRON MICROSCOPY	2.8
4G5O	X-RAY DIFFRACTION	2.9
7RGP	ELECTRON MICROSCOPY	2.9
8K9L	ELECTRON MICROSCOPY	3.05
8SZH	ELECTRON MICROSCOPY	3.1
7RA3	ELECTRON MICROSCOPY	3.24
8GY7	ELECTRON MICROSCOPY	3.3
9WXM	ELECTRON MICROSCOPY	3.3
8OY1	X-RAY DIFFRACTION	3.34
8JD6	ELECTRON MICROSCOPY	3.4
4G5R	X-RAY DIFFRACTION	3.48
8SZI	ELECTRON MICROSCOPY	3.5
4G5S	X-RAY DIFFRACTION	3.62
8WGB	ELECTRON MICROSCOPY	3.7
9AVL	ELECTRON MICROSCOPY	3.8
8GVX	ELECTRON MICROSCOPY	3.91
7X6I	ELECTRON MICROSCOPY	3.93
7E9H	ELECTRON MICROSCOPY	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08754-F1	94.03	0.88

Antibody-complex structures (SAbDab): 10 — 7E9H, 7KH0, 7RA3, 7RGP, 7T10, 7T11, 8JD6, 8K9L, 9VJF, 9WXM

Functional residue map

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

Ligand- & substrate-binding residues (43): 43; 44; 44; 45; 45; 46; 46; 47; 47; 47; 48; 48 …

Post-translational modifications (5): 178, 204, 351, 2, 3

Mutagenesis-validated functional residues (19):

Position	Phenotype
35	decreased affinity for plcd4.
36	increased affinity for plcd4.
37	no effect on binding to plcd4.
39	decreased affinity for plcd4.
42	decreased affinity for plcd4.
184	no effect on binding to plcd4.
211	decreased affinity for ccdc88c and plcd4.
215	decreased affinity for ccdc88c and plcd4.
218	no effect on binding to plcd4.
248	no effect on binding to ccdc88c.
249	decreased affinity for plcd4.
249	no effect on binding to plcd4.
252	increased affinity for plcd4.
252	decreased affinity for plcd4.
256	decreased affinity for plcd4.
257	no effect on binding to plcd4.
258	increased affinity for plcd4. no effect on binding to ccdc88c.
259	no effect on binding to plcd4.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-170670	Adenylate cyclase inhibitory pathway
R-HSA-392170	ADP signalling through P2Y purinoceptor 12
R-HSA-418555	G alpha (s) signalling events
R-HSA-418594	G alpha (i) signalling events
R-HSA-418597	G alpha (z) signalling events
R-HSA-9009391	Extra-nuclear estrogen signaling
R-HSA-9634597	GPER1 signaling
R-HSA-9660821	ADORA2B mediated anti-inflammatory cytokines production

MSigDB gene sets: 386 (showing top): PID_SHP2_PATHWAY, SHEPARD_BMYB_MORPHOLINO_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_AUTOPHAGY, PID_S1P_S1P1_PATHWAY, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOCC_VACUOLAR_MEMBRANE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, REACTOME_G_ALPHA_Z_SIGNALLING_EVENTS, DITTMER_PTHLH_TARGETS_UP, KEGG_TIGHT_JUNCTION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, CTATGCA_MIR153, GOCC_MICROTUBULE_ORGANIZING_CENTER

GO Biological Process (8): adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), negative regulation of adenylate cyclase activity (GO:0007194), positive regulation of macroautophagy (GO:0016239), GTP metabolic process (GO:0046039), cell division (GO:0051301), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (9): G protein-coupled receptor binding (GO:0001664), GTPase activity (GO:0003924), GTP binding (GO:0005525), GDP binding (GO:0019003), G-protein beta/gamma-subunit complex binding (GO:0031683), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), guanyl nucleotide binding (GO:0019001)

GO Cellular Component (18): nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), Golgi apparatus (GO:0005794), centrosome (GO:0005813), cytosol (GO:0005829), heterotrimeric G-protein complex (GO:0005834), plasma membrane (GO:0005886), membrane (GO:0016020), midbody (GO:0030496), centriolar satellite (GO:0034451), ciliary basal body (GO:0036064), extracellular exosome (GO:0070062), sperm principal piece (GO:0097228), Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
GPCR downstream signalling	3
G-protein mediated events	1
Activation of GABAB receptors	1
Signal amplification	1
ESR-mediated signaling	1
G alpha (s) signalling events	1
Anti-inflammatory response favouring Leishmania parasite infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
adenylate cyclase activity	2
cellular process	2
guanyl ribonucleotide binding	2
nuclear lumen	2
intracellular membraneless organelle	2
cytoplasm	2
microtubule organizing center	2
G protein-coupled receptor signaling pathway	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
negative regulation of catalytic activity	1
regulation of adenylate cyclase activity	1
positive regulation of autophagy	1
macroautophagy	1
regulation of macroautophagy	1
purine ribonucleotide metabolic process	1
purine ribonucleoside triphosphate metabolic process	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
signaling receptor binding	1
ribonucleoside triphosphate phosphatase activity	1
purine ribonucleoside triphosphate binding	1
anion binding	1
protein-containing complex binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
purine nucleotide binding	1
intracellular anatomical structure	1
lysosome	1
lytic vacuole membrane	1
endomembrane system	1
intracellular membrane-bounded organelle	1
centriole	1

Protein interactions and networks

STRING

2422 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNAI3	RIC8A	Q9NPQ8	807
GNAI3	GNB2	P11016	794
GNAI3	PSMA5	P28066	762
GNAI3	GNG3	P29798	737
GNAI3	AMPD2	Q01433	726
GNAI3	RIC8B	Q9NVN3	694
GNAI3	GNB1	P04697	676
GNAI3	GPSM2	P81274	675
GNAI3	CCDC88B	A6NC98	655
GNAI3	CCDC88A	Q3V6T2	652
GNAI3	ADCY8	P40145	626
GNAI3	CCDC88C	Q9P219	622
GNAI3	WHRN	Q9P202	594
GNAI3	GPSM1	Q86YR5	591
GNAI3	EPS8	Q12929	588

IntAct

172 interactions, top by confidence:

A	B	Type	Score
RGS14	GNAI3	psi-mi:“MI:0915”(physical association)	0.800
GPSM3	GNAI3	psi-mi:“MI:0915”(physical association)	0.780
GNAI3	GPSM3	psi-mi:“MI:0915”(physical association)	0.780
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PCP2	GNAI3	psi-mi:“MI:0915”(physical association)	0.680
GNAI3	PCP2	psi-mi:“MI:0915”(physical association)	0.680
GNAI3	GPSM2	psi-mi:“MI:0915”(physical association)	0.670
GNAI3	RGS12	psi-mi:“MI:0914”(association)	0.640
PAK5	AURKA	psi-mi:“MI:0914”(association)	0.640
GNG8	GNB5	psi-mi:“MI:0914”(association)	0.640
GNG5	GNB5	psi-mi:“MI:0914”(association)	0.620
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
GNAI3		psi-mi:“MI:0915”(physical association)	0.560
RGS17	GNAI3	psi-mi:“MI:0915”(physical association)	0.560
	GNAI3	psi-mi:“MI:0915”(physical association)	0.560
GNAI3	RGS17	psi-mi:“MI:0915”(physical association)	0.560
CCDC88C	GNAI3	psi-mi:“MI:0915”(physical association)	0.560
GNAI3	PHF24	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (398): GNAI3 (Reconstituted Complex), RGS17 (Two-hybrid), GPSM3 (Two-hybrid), CCDC88C (Two-hybrid), GNAI3 (Affinity Capture-RNA), GNAI3 (Reconstituted Complex), GNAI3 (Reconstituted Complex), GPSM1 (Affinity Capture-Western), CCDC88A (Affinity Capture-Western), GNAI3 (Affinity Capture-MS), GNG4 (Affinity Capture-MS), RAP1GAP (Affinity Capture-MS), GNAI2 (Affinity Capture-MS), GNAO1 (Affinity Capture-MS), GNAT2 (Affinity Capture-MS)

ESM2 similar proteins: A8MTJ3, B2RSH2, G1XJZ0, O13055, O14438, O15976, P04695, P04696, P04897, P04899, P08752, P08753, P08754, P0C7Q4, P10824, P10825, P11488, P16894, P19087, P20353, P20612, P27044, P28052, P29348, P38400, P38401, P38402, P38403, P38407, P38408, P41776, P50146, P50147, P50149, P51876, P63096, P63097, P87034, P87383, Q18434

Diamond homologs: A2Y3B5, A8MTJ3, B0XRA0, B2RSH2, O04278, O04279, O13055, O13315, O14438, O15976, O42784, O74227, O74259, O95837, P04695, P04696, P04897, P04899, P08239, P08752, P08753, P08754, P09471, P0C7Q4, P0CN96, P0CN97, P10824, P10825, P11488, P16378, P16894, P18064, P18872, P19087, P20353, P20612, P26981, P27044, P27045, P28051

SIGNOR signaling

129 interactions.

A	Effect	B	Mechanism
SMO	up-regulates	GNAI3	binding
GNAI3	“up-regulates activity”	TNFAIP8	binding
GNAI3	“down-regulates activity”	ADCY1	binding
FPR2	“up-regulates activity”	GNAI3	binding
CYSLTR2	“up-regulates activity”	GNAI3	binding
ADORA3	“up-regulates activity”	GNAI3	binding
HRH4	“up-regulates activity”	GNAI3	binding
HTR1F	“up-regulates activity”	GNAI3	binding
LTB4R2	“up-regulates activity”	GNAI3	binding
NPBWR1	“up-regulates activity”	GNAI3	binding
S1PR5	“up-regulates activity”	GNAI3	binding
SSTR3	“up-regulates activity”	GNAI3	binding
FFAR3	“up-regulates activity”	GNAI3	binding
SSTR1	“up-regulates activity”	GNAI3	binding
SSTR4	“up-regulates activity”	GNAI3	binding
APLNR	“up-regulates activity”	GNAI3	binding
FPR1	“up-regulates activity”	GNAI3	binding
OPRD1	“up-regulates activity”	GNAI3	binding
SSTR2	“up-regulates activity”	GNAI3	binding
CHRM2	“up-regulates activity”	GNAI3	binding
CHRM4	“up-regulates activity”	GNAI3	binding
GALR1	“up-regulates activity”	GNAI3	binding
GPR34	“up-regulates activity”	GNAI3	binding
HRH3	“up-regulates activity”	GNAI3	binding
SSTR5	“up-regulates activity”	GNAI3	binding
LTB4R	“up-regulates activity”	GNAI3	binding
GPR17	“up-regulates activity”	GNAI3	binding
HTR1A	“up-regulates activity”	GNAI3	binding
PRLHR	“up-regulates activity”	GNAI3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 159 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
ADP signalling through P2Y purinoceptor 12	10	47.3×	2e-12
Prostacyclin signalling through prostacyclin receptor	8	45.8×	3e-10
G beta:gamma signalling through BTK	7	42.3×	1e-08
G beta:gamma signalling through PLC beta	7	38.1×	2e-08
G beta:gamma signalling through CDC42	7	38.1×	2e-08
Adrenaline,noradrenaline inhibits insulin secretion	10	37.5×	8e-12
Presynaptic function of Kainate receptors	7	36.2×	2e-08
G-protein activation	7	31.7×	6e-08

GO biological processes:

GO term	Partners	Fold	FDR
Ras protein signal transduction	8	12.5×	3e-04
protein autophosphorylation	8	8.8×	1e-03
G protein-coupled receptor signaling pathway	16	4.4×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	5
Uncertain significance	52
Likely benign	18
Benign	11

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
3391816	NM_006496.4(GNAI3):c.645dup (p.Glu216Ter)	Pathogenic
64691	NM_006496.4(GNAI3):c.141C>A (p.Ser47Arg)	Pathogenic
1809757	NM_006496.4(GNAI3):c.119G>T (p.Gly40Val)	Likely pathogenic
2663775	NM_006496.4(GNAI3):c.136A>G (p.Lys46Glu)	Likely pathogenic
3220872	NM_001377295.2(GNAT2):c.874+1G>T	Likely pathogenic
3900657	NM_006496.4(GNAI3):c.805A>T (p.Asn269Tyr)	Likely pathogenic
988478	NM_006496.4(GNAI3):c.143C>A (p.Thr48Asn)	Likely pathogenic

SpliceAI

1680 predictions. Top by Δscore:

Variant	Effect	Δscore
1:109548817:G:GT	donor_gain	1.0000
1:109573777:GAA:G	donor_gain	1.0000
1:109573778:AAGTA:A	donor_loss	1.0000
1:109573779:AGTA:A	donor_loss	1.0000
1:109573780:G:GG	donor_gain	1.0000
1:109573780:GTAA:G	donor_loss	1.0000
1:109573781:TAA:T	donor_loss	1.0000
1:109573891:TAAA:T	acceptor_loss	1.0000
1:109573892:A:AG	acceptor_gain	1.0000
1:109573893:A:G	acceptor_gain	1.0000
1:109573893:AAGA:A	acceptor_loss	1.0000
1:109573894:A:G	acceptor_gain	1.0000
1:109573894:AGAAT:A	acceptor_loss	1.0000
1:109573895:G:GA	acceptor_gain	1.0000
1:109573895:GA:G	acceptor_gain	1.0000
1:109573895:GAA:G	acceptor_gain	1.0000
1:109573895:GAAT:G	acceptor_gain	1.0000
1:109573895:GAATC:G	acceptor_gain	1.0000
1:109574023:G:GT	donor_gain	1.0000
1:109574023:G:T	donor_gain	1.0000
1:109574033:GGGCA:G	donor_gain	1.0000
1:109574034:GGCA:G	donor_gain	1.0000
1:109574034:GGCAG:G	donor_gain	1.0000
1:109574035:G:T	donor_gain	1.0000
1:109574035:GCA:G	donor_gain	1.0000
1:109574035:GCAG:G	donor_gain	1.0000
1:109574036:CA:C	donor_gain	1.0000
1:109574036:CAG:C	donor_loss	1.0000
1:109574037:AGT:A	donor_loss	1.0000
1:109574038:G:GG	donor_gain	1.0000

AlphaMissense

2353 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:109548830:T:A	L37Q	1.000
1:109548830:T:C	L37P	1.000
1:109548838:G:C	G40R	1.000
1:109548838:G:T	G40C	1.000
1:109573737:G:A	G40D	1.000
1:109573737:G:T	G40V	1.000
1:109573751:G:C	G45R	1.000
1:109573751:G:T	G45C	1.000
1:109573752:G:A	G45D	1.000
1:109573752:G:T	G45V	1.000
1:109573754:A:C	K46Q	1.000
1:109573755:A:T	K46I	1.000
1:109573756:A:C	K46N	1.000
1:109573756:A:T	K46N	1.000
1:109573757:A:C	S47R	1.000
1:109573757:A:T	S47C	1.000
1:109573759:C:A	S47R	1.000
1:109573759:C:G	S47R	1.000
1:109573774:G:C	Q52H	1.000
1:109573774:G:T	Q52H	1.000
1:109573962:T:A	N76K	1.000
1:109573962:T:G	N76K	1.000
1:109582496:T:A	V174D	1.000
1:109582499:T:A	L175H	1.000
1:109582499:T:C	L175P	1.000
1:109582502:G:C	R176P	1.000
1:109582517:C:T	T181I	1.000
1:109586223:G:C	D200H	1.000
1:109586224:A:G	D200G	1.000
1:109586229:G:C	G202R	1.000

dbSNP variants (sampled 300 via entrez): RS1000029335 (1:109575178 C>A,T), RS1000045319 (1:109555464 A>G), RS1000125903 (1:109588726 C>G,T), RS1000147976 (1:109581478 A>G), RS1000264192 (1:109562501 GT>G,GTT), RS1000270068 (1:109555286 T>G), RS1000315392 (1:109575091 TAAG>T), RS1000374690 (1:109568963 A>C,G), RS1000433676 (1:109570115 G>A), RS1000570975 (1:109548768 C>T), RS1000639648 (1:109576461 G>C,T), RS1000659961 (1:109555614 T>A), RS1000760959 (1:109582673 A>T), RS1000805828 (1:109597357 G>A,C), RS1000892924 (1:109549910 C>T)

Disease associations

OMIM: gene MIM:139370 | disease phenotypes: MIM:602483, MIM:613856

GenCC curated gene-disease

Disease	Classification	Inheritance
auriculocondylar syndrome 1	Definitive	Autosomal dominant
auriculocondylar syndrome	Supportive	Autosomal dominant

Mondo (3): auriculocondylar syndrome 1 (MONDO:0011234), achromatopsia 4 (MONDO:0013465), auriculocondylar syndrome (MONDO:0000107)

Orphanet (2): Auriculocondylar syndrome (Orphanet:137888), Achromatopsia (Orphanet:49382)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000160	Narrow mouth
HP:0000162	Glossoptosis
HP:0000171	Microglossia
HP:0000175	Cleft palate
HP:0000183	Tongue muscle weakness
HP:0000193	Bifid uvula
HP:0000256	Macrocephaly
HP:0000293	Full cheeks
HP:0000311	Round face
HP:0000324	Facial asymmetry
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000378	Cupped ear
HP:0000384	Preauricular skin tag
HP:0000402	Stenosis of the external auditory canal
HP:0000508	Ptosis
HP:0000678	Dental crowding
HP:0000689	Dental malocclusion
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0002098	Respiratory distress
HP:0002104	Apnea
HP:0002870	Obstructive sleep apnea
HP:0004451	Postauricular skin tag
HP:0004453	Overfolding of the superior helices
HP:0005216	Impaired mastication

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000578_3	Major depressive disorder	1.000000e-06
GCST90002409_14	Childhood body mass index	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C564206	Achromatopsia 4 (supp.)
C538270	Auriculo-condylar syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4221 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

9 potent at pChembl≥5 of 32 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.43	IC50	370	nM	MOLIBRESIB
6.41	Kd	387.9	nM	CHEMBL5653589
6.23	ED50	586.1	nM	CHEMBL5653589
5.23	EC50	5900	nM	CHEMBL536499
5.21	EC50	6100	nM	CHEMBL536732
5.20	EC50	6300	nM	CHEMBL537413
5.19	EC50	6500	nM	CHEMBL536731
5.03	EC50	9300	nM	CHEMBL536963
5.03	EC50	9300	nM	CHEMBL537639

PubChem BioAssay actives

8 with measured affinity, of 73 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178686: Inhibition of GNAI3 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.3700	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148442: Binding affinity to human GNAI3 incubated for 45 mins by Kinobead based pull down assay	kd	0.3879	uM
N-pentadecylpiperidine-4-carboxamide;hydrochloride	254629: Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i3	ec50	5.9000	uM
1-[4-[2-(1-methylpiperidin-4-yl)ethyl]piperidin-1-yl]pentadecan-1-one;hydrochloride	254629: Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i3	ec50	6.1000	uM
1-[4-(2-piperidin-4-ylethyl)piperidin-1-yl]pentadecan-1-one;hydrochloride	254629: Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i3	ec50	6.3000	uM
4-pentadecylpiperazin-1-amine;hydrochloride	254629: Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i3	ec50	6.5000	uM
1-(2-formamidoethyl)-N-pentadecylpiperidine-4-carboxamide;hydrochloride	254629: Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i3	ec50	9.3000	uM
1-(4-piperidin-4-ylpiperidin-1-yl)pentadecan-1-one;hydrochloride	254629: Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i3	ec50	9.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Particulate Matter	affects expression, affects methylation, increases abundance, decreases expression, increases methylation	3
Air Pollutants	affects expression, affects methylation, increases abundance, decreases expression	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	affects expression, decreases expression	2
Cyclosporine	increases expression	2
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
dicrotophos	decreases expression	1
beauvericin	affects cotreatment, increases expression	1
biochanin A	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sodium arsenate	decreases expression	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction, increases reaction	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	affects expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	affects expression, affects cotreatment	1
enniatins	affects cotreatment, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
ICG 001	decreases expression	1
perfluorobutanesulfonic acid	affects cotreatment, affects expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Bortezomib	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	increases expression	1

ChEMBL screening assays

11 unique, capped per target: 7 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651484	Binding	Binding affinity to human GNAI3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem
CHEMBL882871	Functional	Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i3	Design, synthesis, and preliminary pharmacological evaluation of a set of small molecules that directly activate gi proteins. — J Med Chem

Clinical trials (associated diseases)

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