GNAI1

Summary

GNAI1 (G protein subunit alpha i1, HGNC:4384) is a protein-coding gene on chromosome 7q21.11, encoding Guanine nucleotide-binding protein G(i) subunit alpha-1 (P63096). Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.

Guanine nucleotide binding proteins are heterotrimeric signal-transducing molecules consisting of alpha, beta, and gamma subunits. The alpha subunit binds guanine nucleotide, can hydrolyze GTP, and can interact with other proteins. The protein encoded by this gene represents the alpha subunit of an inhibitory complex. The encoded protein is part of a complex that responds to beta-adrenergic signals by inhibiting adenylate cyclase. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2770 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 149 total — 6 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 25
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002069

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4384
Approved symbol	GNAI1
Name	G protein subunit alpha i1
Location	7q21.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000127955
Ensembl biotype	protein_coding
OMIM	139310
Entrez	2770

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 25 protein_coding, 7 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay, 2 retained_intron

ENST00000351004, ENST00000418742, ENST00000442586, ENST00000457358, ENST00000490206, ENST00000647672, ENST00000647742, ENST00000648097, ENST00000648098, ENST00000648306, ENST00000648375, ENST00000648412, ENST00000648449, ENST00000648476, ENST00000648528, ENST00000648663, ENST00000648832, ENST00000648877, ENST00000648953, ENST00000649148, ENST00000649208, ENST00000649214, ENST00000649225, ENST00000649267, ENST00000649485, ENST00000649487, ENST00000649634, ENST00000649796, ENST00000649855, ENST00000649922, ENST00000650351, ENST00000650431, ENST00000897678, ENST00000897679, ENST00000897680, ENST00000939720, ENST00000959643, ENST00000959644, ENST00000959645

RefSeq mRNA: 2 — MANE Select: NM_002069 NM_001256414, NM_002069

CCDS: CCDS5595, CCDS59061

Canonical transcript exons

ENST00000649796 — 8 exons

Exon	Start	End
ENSE00000877050	80199225	80199382
ENSE00001129655	80189090	80189231
ENSE00001369917	80210969	80211098
ENSE00001371927	80134831	80135278
ENSE00001591517	80212716	80212869
ENSE00003623492	80188951	80188993
ENSE00003789917	80203704	80203832
ENSE00003836194	80217303	80226181

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 98.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.5768 / max 267.1069, expressed in 1459 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79249	11.3607	1378
79251	0.9703	492
79250	0.3956	150
79248	0.3758	192
79257	0.2720	78
79247	0.1024	43
79246	0.0541	11
79254	0.0286	6
79258	0.0110	3
79252	0.0063	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	98.91	gold quality
cortical plate	UBERON:0005343	98.87	gold quality
inferior vagus X ganglion	UBERON:0005363	98.47	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.97	gold quality
subthalamic nucleus	UBERON:0001906	97.90	gold quality
germinal epithelium of ovary	UBERON:0001304	97.85	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.67	gold quality
pons	UBERON:0000988	97.62	gold quality
oocyte	CL:0000023	97.57	gold quality
secondary oocyte	CL:0000655	97.41	gold quality
spinal cord	UBERON:0002240	97.40	gold quality
adrenal tissue	UBERON:0018303	97.39	gold quality
superior vestibular nucleus	UBERON:0007227	97.17	gold quality
lateral globus pallidus	UBERON:0002476	97.11	gold quality
substantia nigra pars compacta	UBERON:0001965	96.82	gold quality
upper leg skin	UBERON:0004262	96.76	gold quality
ganglionic eminence	UBERON:0004023	96.59	gold quality
ventral tegmental area	UBERON:0002691	96.48	gold quality
renal medulla	UBERON:0000362	96.17	gold quality
endothelial cell	CL:0000115	96.06	gold quality
prefrontal cortex	UBERON:0000451	96.03	gold quality
postcentral gyrus	UBERON:0002581	95.89	gold quality
adipose tissue	UBERON:0001013	95.85	gold quality
parietal lobe	UBERON:0001872	95.80	gold quality
globus pallidus	UBERON:0001875	95.75	gold quality
skin of hip	UBERON:0001554	95.64	gold quality
penis	UBERON:0000989	95.57	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.53	gold quality
primary visual cortex	UBERON:0002436	95.39	gold quality
superior frontal gyrus	UBERON:0002661	95.29	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	44.02
E-GEOD-83139	yes	9.26
E-CURD-112	yes	5.29
E-MTAB-6386	no	13.83
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HAND2, WT1

miRNA regulators (miRDB)

133 targeting GNAI1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3658	99.96	73.87	4379
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-23A-3P	99.95	74.24	3163

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Structural determinants for GoLoco-induced inhibition of nucleotide release by Galpha subunits (PMID:11976690)
• co-stimulation of G(12/13) and G(i) pathways is sufficient to activate GPIIb/IIIa in human platelets in a mechanism that involves intracellular calcium (PMID:12297512)
• An age-induced increase in G alpha i may have a role in depressing cardiac function in aged human atria. (PMID:14576516)
• region of the third cytoplasmic loop of Dopamine D2 receptor is crucial for determining G(i) protein coupling specificity. (PMID:14581469)
• Gi has a role in insulin attenuation of platelet functions by interfering with cAMP suppression along with IRS-1 (PMID:14602724)
• Gi, but not Gq or G12/13, signaling pathways are required for activation of Akt in platelets (PMID:14623889)
• Gi has a role in CXCL16 signaling that induces cell-cell adhesion and aortic smooth muscle cell proliferation (PMID:14625285)
• the G(alpha)o/i-coupled cannabinoid receptor, by regulating the proteasomal degradation of Rap1GAPII, activates Rap1 to induce neurite outgrowth. (PMID:15657046)
• G12, Rho, filamin-A, and the actin cytoskeleton are required for amino acid-stimulated Ca2+ oscillations produced by the Ca2+-sensing receptor (PMID:15837785)
• TPO integrates G(i), but not G(q), stimulation, supports integrin alpha(IIb)beta(3) activation platelet aggregation independently of phospholipase C but requires PI3-kinase and Rap1B (PMID:15863506)
• Gialpha and Gbeta subunits both define selectivity of G protein activation by alpha2-adrenergic receptors. (PMID:16371464)
• Nef protein of human immunodeficiency virus (HIV) reduces cell surface levels of eight different members of the CC- and CXC-family of Chemokine receptors (CKRs) by up to 92%. (PMID:16775006)
• autotaxin induces uPA expression via the Gi-PI3K-Akt-NF-kappaB signaling pathway that might be critical for autotaxin-induced tumor cell invasion and metastasis (PMID:17013094)
• These data revealed that PAR1 can be part of a preassembled complex with Galpha(i1) protein, resulting either from a direct interaction between these partners or from their colocalization in specific microdomains. (PMID:17267663)
• Data show that Gi and RGS proteins provide biochemical control of androgen receptor exclusion from the cell nucleus. (PMID:17416965)
• Selective induction of G alpha inhibiting subunit 1 (Gi alpha1) expression is a novel downstream event in hypertrophic signaling that may be a critical factor leading to cellular electrophysiological remodeling of the Ras transgenic mouse heart. (PMID:17646583)
• Heretotrimeric G protein subunit Galphai is associated with mitochondria. (PMID:18037379)
• The potency and efficacy of LPA-mediated inhibition of forskolin-stimulated adenylyl cyclase activity was enhanced in cells expressing RGSi G(i) (mutant) proteins as compared to RGSwt G(i). (PMID:18083345)
• MUPP1 binds to the G protein-coupled MT(1) melatonin receptor and directly regulates its G(i)-dependent signal transduction (PMID:18378672)
• analysis of structural determinants underlying the temperature-sensitive nature of a Galpha mutant (PMID:18519563)
• Galpha.GoLoco complexes have roles in mitotic spindle dynamics (PMID:18984596)
• Galpha(i1)(GDP) can bind a second Gbetagamma subunit with an affinity only 10-fold weaker than the primary site and close to the affinity between activated Galpha(i1) and Gbetagamma subunits. (PMID:19369247)
• differentialy expressed in dendritic cells upon stimulation of with with the major house dust mite allergen Der p 1 (PMID:19494521)
• A switch in G-protein coupling, in which glutamate775lysine loses G(o) subunit coupling but retains coupling to G(i), may explain the highly specialized metabotropic glutamate receptor mGlu6 phenotype. (PMID:19666700)
• The chemotaxis signal pathway induced by chemokines CKbeta8 and CKbeta8-1 is mediated via the Gi/Go protein, phospholipase C (PLC) and protein kinase C delta (PKC delta). (PMID:19951712)
• analysis of a novel Gi, P2Y-independent signaling pathway mediating Akt phosphorylation in response to thrombin receptors (PMID:20586915)
• Nucleobindin 1 is a calcium-regulated guanine nucleotide dissociation inhibitor of G{alpha}i1. (PMID:20679342)
• The RET combination analysis revealed that stimulation of the alpha(2A)-adrenergic receptor (alpha(2A)AR) leads to the recruitment of GRK2 at a receptor still associated with the Galpha(i1)beta(1)gamma(2) complex. (PMID:20696855)
• AGS3 receptor coupling to both Galphabetagamma and GPR-Galpha(i) offer additional flexibility for systems to respond and adapt to challenges and orchestrate complex behaviors (PMID:20716524)
• Data reveal a change in the repertoire of Galpha(i/o) subunits during T cell differentiation and suggest functional equivalence among Galpha(i/o) subunits irrespective of their relative abundance. (PMID:20829352)
• Galpha(o) protein contributes to maximally efficient mu-opioid receptor signaling and antinociception in Galpha(o) null transgenic mice. (PMID:21654736)
• RGS14 can form complexes with GPCRs in cells that are dependent on Galpha(i/o) and these RGS14.Galpha(i1).GPCR complexes may be substrates for other signaling partners such as Ric-8A (PMID:21880739)
• CXCL12 signaling via CXCR7 is Gialpha independent. (PMID:22070874)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• resistin contributes to the pro-inflammatory state of SMC by the up-regulation of CX3CL1 and CX3CR1 expression via a mechanism involving NF-kB, AP-1, and STAT1/3 transcription factors, (2) resistin employs TLR4 and Gi-protein signaling. (PMID:23086480)
• Data indicate that focal adhesion kinase (FAK) activation and cell migration require Src, Gi/Go, COX-2 and LOXs activities. (PMID:23179791)
• Data suggest that chemokine binding to CCX-CKR (a) recruits Gi proteins and beta-arrestin (beta-arr) with high affinity. (PMID:23341447)
• leucine can directly facilitate insulin signaling through a Galphai protein-dependent intracellular signaling pathway (PMID:23404499)
• This study support a role for RGS proteins as negative regulators of opioid supraspinal antinociception and also reveal a potential novel function of RGS proteins as positive regulators of opioid spinal antinociceptive pathways. (PMID:23467353)
• AC5, by binding active Galphai1, interferes with G-protein deactivation and reassembly and thereby might sensitize its own regulation. (PMID:23841650)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnai3	ENSDARG00000030644
mus_musculus	Gnai1	ENSMUSG00000057614
rattus_norvegicus	Gnai1	ENSRNOG00000057096
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), GNAI3 (ENSG00000065135), GNAO1 (ENSG00000087258), GNAS (ENSG00000087460), GNA11 (ENSG00000088256), GNAT1 (ENSG00000114349), GNAI2 (ENSG00000114353), GNA13 (ENSG00000120063), 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-1 — P63096 (reviewed: P63096)

Alternative names: Adenylate cyclase-inhibiting G alpha protein

All UniProt accessions (8): P63096, A0A3B3IRK0, A0A3B3IS42, A0A3B3ITG4, A0A3B3ITM0, A0A3B3ITX3, A0A3B3IU77, A0A3B3IUA8

UniProt curated annotations — full annotation on UniProt →

Function. 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 of ADCY1, ADCY5 and ADCY6, leading to decreased intracellular cAMP levels. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. Required for normal cytokinesis during mitosis. Required for cortical dynein-dynactin complex recruitment during metaphase.

Subunit / interactions. Heterotrimeric G proteins are composed of 3 units; alpha, beta and gamma. Part of a spindle orientation complex at least composed of GNAI1, GPSM2 and NUMA1. The alpha chain contains the guanine nucleotide binding site. Identified in complex with the beta subunit GNB1 and the gamma subunit GNG1. Identified in complex with the beta subunit GNB1 and the gamma subunit GNG2. Component of the TAS2R14-GNAI1 complex, consisting of TAS2R14, GNAI1, GNB1 and GNG2; within the complex interacts with TAS2R14; this complex plays a role in the perception of bitterness. GTP binding causes dissociation of the heterotrimer, liberating the individual subunits so that they can interact with downstream effector proteins. Interacts (GDP-bound form) with GPSM1; this inhibits guanine nucleotide exchange and GTP binding. Interacts (GDP-bound form) with GPSM2 (via GoLoco domains); this inhibits guanine nucleotide exchange. Interacts with RGS10; this strongly enhances GTP hydrolysis. Interacts with RGS1 and RGS16; this strongly enhances GTPase activity. Interacts with RGS4. Interacts with RGS12. Interacts (via active GTP- or inactive GDP-bound forms) with RGS14 (via RGS and GoLoco domains). Interacts with RGS3, RGS6, RGS7, RGS8, RGS17, RGS18 and RGS20 (in vitro). Interacts (GDP-bound form) with RIC8A (via C-terminus); promoting GNAI1 folding and association with the plasma membrane. Interacts (inactive GDP-bound form) with NUCB1 (via GBA motif); the interaction leads to activation of GNAI1. Interacts (inactive GDP-bound form) with CCDC88C/DAPLE (via GBA motif); the interaction leads to activation of GNAI1. Interacts (inactive GDP-bound form) with CCDC8A/GIV (via GBA motif). Interacts with GPR15. Interacts with FPR2. Component of a complex composed of FPR1 or FPR2 receptor and G(i) protein subunits GNAI1, GNB1 and GNG2; this complex is involved in innate recognition of N-formyl-methionyl peptides derived from invading microbes and host mitochondria as pathogen- and damage-associated molecular patterns (PAMPs and DAMPs). Interacts with GCGR. (Microbial infection) Interacts with human cytomegalovirus (HHV-5) US27; this interaction this interaction does not lead to the catalytic activation of Gi complex and probably interferes with the chemokine-Gi signaling. (Microbial infection) Interacts with human cytomegalovirus (HHV-5) US28; this interaction does not lead to the catalytic activation of Gi complex and probably interferes with the chemokine-Gi signaling.

Subcellular location. Nucleus. Cytoplasm. Cell membrane. Cytoskeleton. Microtubule organizing center. Centrosome. Cell cortex. Membrane.

Post-translational modifications. Myristoylation at Gly-2 is required for membrane anchoring before palmitoylation. Palmitoylation at Cys-3 varies with membrane lipid composition. (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. Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (NEDHISB) [MIM:619854] An autosomal dominant disorder characterized by global developmental delay, impaired intellectual development, delayed or absent speech, hypotonia, behavioral abnormalities, and epilepsy that ranges from self-limiting to intractable. More variable features include non-specific dysmorphic facial features, distal skeletal anomalies, and brain imaging abnormalities. 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.

Isoforms (2)

UniProt ID	Names	Canonical?
P63096-1	1	yes
P63096-2	2

RefSeq proteins (2): NP_001243343, NP_002060* (*=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

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (85 total): helix 21, sequence variant 16, strand 11, binding site 8, turn 6, region of interest 5, sequence conflict 5, mutagenesis site 4, modified residue 3, lipid moiety-binding region 2, initiator methionine 1, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

640 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6CRK	X-RAY DIFFRACTION	2
3UMR	X-RAY DIFFRACTION	2.04
9P7Z	ELECTRON MICROSCOPY	2.1
2OM2	X-RAY DIFFRACTION	2.2
8YN9	ELECTRON MICROSCOPY	2.3
9HYI	ELECTRON MICROSCOPY	2.3
9O36	ELECTRON MICROSCOPY	2.3
9P80	ELECTRON MICROSCOPY	2.3
8XXV	ELECTRON MICROSCOPY	2.33
3UMS	X-RAY DIFFRACTION	2.34
3ONW	X-RAY DIFFRACTION	2.38
20ZG	ELECTRON MICROSCOPY	2.4
20ZH	ELECTRON MICROSCOPY	2.4
7EJX	ELECTRON MICROSCOPY	2.4
7TRP	ELECTRON MICROSCOPY	2.4
8PJK	ELECTRON MICROSCOPY	2.4
9ODF	ELECTRON MICROSCOPY	2.4
9ODN	ELECTRON MICROSCOPY	2.4
9P82	ELECTRON MICROSCOPY	2.4
23IV	ELECTRON MICROSCOPY	2.42
23IW	ELECTRON MICROSCOPY	2.42
22ES	ELECTRON MICROSCOPY	2.43
7MBY	ELECTRON MICROSCOPY	2.44
8JIS	ELECTRON MICROSCOPY	2.46
9M0R	ELECTRON MICROSCOPY	2.47
8Y01	ELECTRON MICROSCOPY	2.48
8YKV	ELECTRON MICROSCOPY	2.48
9M1O	ELECTRON MICROSCOPY	2.49
1Y3A	X-RAY DIFFRACTION	2.5
7T2G	ELECTRON MICROSCOPY	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P63096-F1	93.92	0.87

Antibody-complex structures (SAbDab): 414 — 6CMO, 6CRK, 6DDE, 6KPF, 6KPG, 6LFM, 6LFO, 6LML, 6N4B, 6OMM, 6OS9, 6OT0, 6PB0, 6PB1, 6PT0, 6QNO, 6XBJ, 6XBK, 6XBL, 6XBM, 6XOX, 7CMU, 7CMV, 7DB6, 7DFL (+389 more)

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 (8): 151; 175–181; 181; 200–204; 269–272; 326; 43–48; 47

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

Mutagenesis-validated functional residues (4):

Position	Phenotype
42	abolishes switch to an activated conformation and dissociation from beta and gamma subunits upon gtp binding. abolishes
116	enhances interaction (inactive gdp-bound) with rgs14.
147	enhances interaction (inactive gdp-bound) with rgs14.
245	enhances interaction (inactive gdp-bound) with rgs14.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-170670	Adenylate cyclase inhibitory pathway
R-HSA-392170	ADP signalling through P2Y purinoceptor 12
R-HSA-400042	Adrenaline,noradrenaline inhibits insulin secretion
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-422356	Regulation of insulin secretion
R-HSA-9009391	Extra-nuclear estrogen signaling
R-HSA-9634597	GPER1 signaling
R-HSA-9660821	ADORA2B mediated anti-inflammatory cytokines production

MSigDB gene sets: 488 (showing top): PID_SHP2_PATHWAY, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, PID_S1P_S1P1_PATHWAY, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_RESPONSE_TO_PROSTAGLANDIN_E, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, REACTOME_ADRENALINE_NORADRENALINE_INHIBITS_INSULIN_SECRETION, GOCC_VACUOLAR_MEMBRANE, CROONQUIST_NRAS_SIGNALING_DN, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, REACTOME_G_ALPHA_Z_SIGNALLING_EVENTS

GO Biological Process (18): G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), adenylate cyclase-inhibiting serotonin receptor signaling pathway (GO:0007198), neuropeptide signaling pathway (GO:0007218), response to prostaglandin E (GO:0034695), response to peptide hormone (GO:0043434), positive regulation of cholesterol biosynthetic process (GO:0045542), negative regulation of insulin secretion (GO:0046676), cell division (GO:0051301), regulation of mitotic spindle organization (GO:0060236), chemokine-mediated signaling pathway (GO:0070098), T cell migration (GO:0072678), positive regulation of relaxation of smooth muscle (GO:1901082), cellular response to forskolin (GO:1904322), positive regulation of protein localization to cell cortex (GO:1904778), signal transduction (GO:0007165)

GO Molecular Function (16): magnesium ion binding (GO:0000287), G protein-coupled receptor binding (GO:0001664), GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), adenylate cyclase inhibitor activity (GO:0010855), GDP binding (GO:0019003), G-protein beta/gamma-subunit complex binding (GO:0031683), D2 dopamine receptor binding (GO:0031749), G protein-coupled serotonin receptor binding (GO:0031821), nucleotide binding (GO:0000166), protein binding (GO:0005515), adenylate cyclase regulator activity (GO:0010854), hydrolase activity (GO:0016787), guanyl nucleotide binding (GO:0019001), metal ion binding (GO:0046872)

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), cell cortex (GO:0005938), midbody (GO:0030496), centriolar satellite (GO:0034451), ciliary basal body (GO:0036064), extracellular exosome (GO:0070062), sperm principal piece (GO:0097228), nucleus (GO:0005634), cytoskeleton (GO:0005856), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
GPCR downstream signalling	3
G-protein mediated events	1
Activation of GABAB receptors	1
Signal amplification	1
Regulation of insulin secretion	1
Integration of energy metabolism	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	3
G protein-coupled receptor signaling pathway	3
cytoplasm	3
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	2
cellular process	2
guanyl ribonucleotide binding	2
nuclear lumen	2
intracellular membraneless organelle	2
intracellular membrane-bounded organelle	2
microtubule organizing center	2
cell periphery	2
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase activator activity	1
adenylate cyclase inhibitor activity	1
Gi/o-coupled serotonin receptor activity	1
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1
G protein-coupled serotonin receptor signaling pathway	1
response to prostaglandin	1
response to alcohol	1
response to ketone	1
response to hormone	1
response to nitrogen compound	1
response to oxygen-containing compound	1
cholesterol biosynthetic process	1
regulation of cholesterol biosynthetic process	1
positive regulation of cholesterol metabolic process	1
positive regulation of sterol biosynthetic process	1
positive regulation of alcohol biosynthetic process	1
insulin secretion	1
negative regulation of protein secretion	1
regulation of insulin secretion	1
negative regulation of peptide hormone secretion	1
mitotic spindle organization	1
regulation of spindle organization	1
cytokine-mediated signaling pathway	1
cellular response to chemokine	1
lymphocyte migration	1
relaxation of smooth muscle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

262 interactions, top by confidence:

A	B	Type	Score
GNG2	GNB1	psi-mi:“MI:0914”(association)	0.940
GPSM3	GNAI1	psi-mi:“MI:0915”(physical association)	0.830
GNAI1	GPSM3	psi-mi:“MI:0915”(physical association)	0.830
GNGT1	GNB1	psi-mi:“MI:0914”(association)	0.770
GNGT1	Ntsr1	psi-mi:“MI:0914”(association)	0.750
GNG5	GNB1	psi-mi:“MI:0914”(association)	0.740
CNR1	CNR1	psi-mi:“MI:2364”(proximity)	0.650
GNG7	GNB1	psi-mi:“MI:0914”(association)	0.640
GNG10	GNB1	psi-mi:“MI:0914”(association)	0.640
GNG12	GNB1	psi-mi:“MI:0914”(association)	0.640
GNG3	GNB1	psi-mi:“MI:0914”(association)	0.640
GNG5	GNB2	psi-mi:“MI:0914”(association)	0.640
GNG10	GNB2	psi-mi:“MI:0914”(association)	0.640
GNG3	GNAI1	psi-mi:“MI:0914”(association)	0.640
GNG4	GNAI1	psi-mi:“MI:0914”(association)	0.640
GNG5	GNAI1	psi-mi:“MI:0914”(association)	0.640
GNG7	GNAI1	psi-mi:“MI:0914”(association)	0.640
GNG8	GNAI1	psi-mi:“MI:0914”(association)	0.640
GNG10	GNAI1	psi-mi:“MI:0914”(association)	0.640
GNG8	GNB5	psi-mi:“MI:0914”(association)	0.640
PAK5	AURKA	psi-mi:“MI:0914”(association)	0.640
GNGT1	GNB2	psi-mi:“MI:0914”(association)	0.620
GNGT1	GNB3	psi-mi:“MI:0914”(association)	0.620
GNG5	GNB5	psi-mi:“MI:0914”(association)	0.620

BioGRID (271): RGS17 (Two-hybrid), GPSM3 (Two-hybrid), GNAI1 (FRET), GNAI1 (FRET), GNG4 (Affinity Capture-MS), GNAT3 (Affinity Capture-MS), GNAI3 (Affinity Capture-MS), GNAO1 (Affinity Capture-MS), RGS12 (Affinity Capture-MS), RIC8A (Affinity Capture-MS), RGS14 (Affinity Capture-MS), MTHFR (Affinity Capture-MS), GNG10 (Affinity Capture-MS), RAP1GDS1 (Affinity Capture-MS), GNA13 (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

172 interactions.

A	Effect	B	Mechanism
LPAR2	up-regulates	GNAI1	binding
F2RL3	up-regulates	GNAI1	binding
F2R	up-regulates	GNAI1	binding
SMO	up-regulates	GNAI1	binding
GPCR	“up-regulates activity”	GNAI1	binding
GNAI1	down-regulates	“3’,5’-cyclic AMP”
GPCR	up-regulates	GNAI1
GNAI1	“up-regulates activity”	TNFAIP8	binding
GNAI1	“down-regulates activity”	ADCY1	binding
ADORA3	“up-regulates activity”	GNAI1	binding
HRH4	“up-regulates activity”	GNAI1	binding
HTR1F	“up-regulates activity”	GNAI1	binding
LTB4R2	“up-regulates activity”	GNAI1	binding
NPBWR1	“up-regulates activity”	GNAI1	binding
S1PR5	“up-regulates activity”	GNAI1	binding
SSTR3	“up-regulates activity”	GNAI1	binding
FFAR3	“up-regulates activity”	GNAI1	binding
SSTR1	“up-regulates activity”	GNAI1	binding
SSTR4	“up-regulates activity”	GNAI1	binding
APLNR	“up-regulates activity”	GNAI1	binding
FPR1	“up-regulates activity”	GNAI1	binding
OPRD1	“up-regulates activity”	GNAI1	binding
SSTR2	“up-regulates activity”	GNAI1	binding
CHRM2	“up-regulates activity”	GNAI1	binding
CHRM4	“up-regulates activity”	GNAI1	binding
GALR1	“up-regulates activity”	GNAI1	binding
GPR34	“up-regulates activity”	GNAI1	binding
HRH3	“up-regulates activity”	GNAI1	binding
SSTR5	“up-regulates activity”	GNAI1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 99 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	16	145.0×	2e-32
Prostacyclin signalling through prostacyclin receptor	16	137.4×	7e-32
G beta:gamma signalling through PLC beta	16	130.5×	2e-31
G beta:gamma signalling through CDC42	16	130.5×	2e-31
ADP signalling through P2Y purinoceptor 12	18	127.7×	2e-34
Presynaptic function of Kainate receptors	16	124.3×	7e-31
G-protein activation	16	108.8×	2e-29
Thromboxane signalling through TP receptor	16	108.8×	2e-29

GO biological processes:

GO term	Partners	Fold	FDR
G protein-coupled receptor signaling pathway	24	11.2×	3e-16
mitotic cell cycle	6	10.3×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	13
Uncertain significance	93
Likely benign	14
Benign	6

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
1203197	NM_002069.6(GNAI1):c.671G>A (p.Cys224Tyr)	Pathogenic
1686915	NM_002069.6(GNAI1):c.995T>A (p.Val332Glu)	Pathogenic
1686919	NM_002069.6(GNAI1):c.809A>G (p.Lys270Arg)	Pathogenic
1686920	NM_002069.6(GNAI1):c.815A>G (p.Asp272Gly)	Pathogenic
2577995	NM_002069.6(GNAI1):c.118G>C (p.Gly40Arg)	Pathogenic
4819026	NM_002069.6(GNAI1):c.143C>T (p.Thr48Ile)	Pathogenic
1172689	NM_002069.6(GNAI1):c.142A>C (p.Thr48Pro)	Likely pathogenic
1685334	NM_002069.6(GNAI1):c.118G>T (p.Gly40Cys)	Likely pathogenic
2431632	NM_002069.6(GNAI1):c.611A>G (p.Gln204Arg)	Likely pathogenic
2498283	NM_002069.6(GNAI1):c.134G>A (p.Gly45Asp)	Likely pathogenic
3065594	NM_002069.6(GNAI1):c.170A>G (p.His57Arg)	Likely pathogenic
3362733	NM_002069.6(GNAI1):c.130T>G (p.Ser44Ala)	Likely pathogenic
3375466	NM_002069.6(GNAI1):c.670T>C (p.Cys224Arg)	Likely pathogenic
3775504	NM_002069.6(GNAI1):c.142A>G (p.Thr48Ala)	Likely pathogenic
4293365	NM_002069.6(GNAI1):c.814G>C (p.Asp272His)	Likely pathogenic
4537400	NM_002069.6(GNAI1):c.502_504del (p.Ile168del)	Likely pathogenic
4818886	NM_002069.6(GNAI1):c.995T>G (p.Val332Gly)	Likely pathogenic
984539	NM_002069.6(GNAI1):c.68_70del (p.Leu23del)	Likely pathogenic
987048	NM_002069.6(GNAI1):c.155A>C (p.Gln52Pro)	Likely pathogenic

SpliceAI

1283 predictions. Top by Δscore:

Variant	Effect	Δscore
7:80135274:GCTCG:G	donor_gain	1.0000
7:80135278:GGT:G	donor_loss	1.0000
7:80135279:G:GA	donor_loss	1.0000
7:80135279:G:GG	donor_gain	1.0000
7:80135280:T:A	donor_loss	1.0000
7:80188991:GAA:G	donor_gain	1.0000
7:80188994:G:GG	donor_gain	1.0000
7:80189079:T:TA	acceptor_gain	1.0000
7:80189087:TAG:T	acceptor_loss	1.0000
7:80189088:A:AG	acceptor_gain	1.0000
7:80189088:A:AT	acceptor_loss	1.0000
7:80189089:G:A	acceptor_loss	1.0000
7:80189089:G:GC	acceptor_gain	1.0000
7:80189089:GA:G	acceptor_gain	1.0000
7:80189089:GAAT:G	acceptor_gain	1.0000
7:80189089:GAATT:G	acceptor_gain	1.0000
7:80189227:GGGCG:G	donor_gain	1.0000
7:80189228:GGCG:G	donor_gain	1.0000
7:80189228:GGCGG:G	donor_gain	1.0000
7:80189229:GCG:G	donor_gain	1.0000
7:80189229:GCGG:G	donor_gain	1.0000
7:80189230:CGG:C	donor_loss	1.0000
7:80189232:G:GC	donor_loss	1.0000
7:80189232:G:GG	donor_gain	1.0000
7:80189233:TAAGT:T	donor_loss	1.0000
7:80189234:A:AG	donor_loss	1.0000
7:80199220:TTCA:T	acceptor_loss	1.0000
7:80199221:TCA:T	acceptor_loss	1.0000
7:80199222:CAG:C	acceptor_loss	1.0000
7:80199223:A:AG	acceptor_gain	1.0000

AlphaMissense

2373 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:80135228:T:C	L23P	1.000
7:80135267:T:C	L36P	1.000
7:80135270:T:A	L37Q	1.000
7:80135270:T:C	L37P	1.000
7:80135273:T:C	L38P	1.000
7:80135276:T:A	L39H	1.000
7:80135278:G:A	G40S	1.000
7:80135278:G:C	G40R	1.000
7:80135278:G:T	G40C	1.000
7:80188951:G:A	G40D	1.000
7:80188951:G:T	G40V	1.000
7:80188963:C:T	S44F	1.000
7:80188965:G:A	G45S	1.000
7:80188965:G:C	G45R	1.000
7:80188965:G:T	G45C	1.000
7:80188966:G:A	G45D	1.000
7:80188966:G:C	G45A	1.000
7:80188966:G:T	G45V	1.000
7:80188968:A:C	K46Q	1.000
7:80188969:A:T	K46I	1.000
7:80188970:A:C	K46N	1.000
7:80188970:A:T	K46N	1.000
7:80188971:A:C	S47R	1.000
7:80188971:A:T	S47C	1.000
7:80188972:G:T	S47I	1.000
7:80188973:T:A	S47R	1.000
7:80188973:T:G	S47R	1.000
7:80188975:C:A	T48K	1.000
7:80188975:C:T	T48I	1.000
7:80188985:G:C	K51N	1.000

dbSNP variants (sampled 300 via entrez): RS1000001132 (7:80134149 T>C), RS1000018215 (7:80173158 C>T), RS1000033771 (7:80133834 T>A,C), RS1000053883 (7:80153536 C>G,T), RS1000078722 (7:80211686 T>G), RS1000144909 (7:80224189 A>G,T), RS1000219069 (7:80186591 A>G), RS1000271970 (7:80153583 T>C), RS1000282795 (7:80139837 G>A), RS1000322378 (7:80221543 TGCAATCTCTAATC>T), RS1000354938 (7:80180868 C>G), RS1000364588 (7:80217746 G>A,T), RS1000366916 (7:80164689 T>G), RS1000374734 (7:80198010 A>C,G), RS1000398492 (7:80202947 C>T)

Disease associations

OMIM: gene MIM:139310 | disease phenotypes: MIM:619854

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	Autosomal dominant
neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (4): neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (MONDO:0859243), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000179	Thick lower lip vermilion
HP:0000219	Thin upper lip vermilion
HP:0000463	Anteverted nares
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001344	Absent speech
HP:0001513	Obesity
HP:0001847	Long hallux
HP:0002069	Bilateral tonic-clonic seizure
HP:0002121	Generalized non-motor (absence) seizure
HP:0002384	Focal impaired awareness seizure
HP:0003196	Short nose
HP:0010804	Tented upper lip vermilion
HP:0011968	Feeding difficulties
HP:0012171	Stereotypical hand wringing
HP:0025162	Severe temper tantrums
HP:0025336	Delayed ability to sit
HP:0031936	Delayed ability to walk

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003075_130	Cognitive decline rate in late mild cognitive impairment	1.000000e-06
GCST003075_95	Cognitive decline rate in late mild cognitive impairment	3.000000e-08
GCST003262_475	Post bronchodilator FEV1	2.000000e-06
GCST003542_206	Night sleep phenotypes	3.000000e-06
GCST008477_13	Emphysema annual change measurement in smokers (adjusted lung density)	5.000000e-06
GCST011754_2	Nicotine dependence	7.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0004314	forced expiratory volume
EFO:0007626	emphysema imaging measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3885584 (PROTEIN-PROTEIN INTERACTION), CHEMBL4741 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 110,358 (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
CHEMBL1590	PSEUDOEPHEDRINE	4	25,626
CHEMBL273575	NOMIFENSINE	4	7,327
CHEMBL932	DIPYRIDAMOLE	4	51,743
CHEMBL1255653	SEPIAPTERIN	3	676
CHEMBL51085	EBSELEN	3	13,237
CHEMBL19215	METERGOLINE	2	2,927
CHEMBL417799	SANGUINARIUM	2	8,822

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

ChEMBL bioactivities

34 potent at pChembl≥5 of 93 total, top 34 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.70	Potency	20	nM	CHEMBL1515691
6.15	Kd	710	nM	CHEMBL5408357
6.10	Potency	794.3	nM	CHEMBL338790
6.00	Potency	1000	nM	CHEMBL1356536
5.80	Potency	1585	nM	CHEMBL605003
5.70	Potency	1995	nM	CHEMBL1475433
5.60	Potency	2512	nM	TYRPHOSTIN 25
5.60	Potency	2512	nM	CHEMBL105739
5.50	Potency	3162	nM	SB-216763
5.40	Potency	3981	nM	TYRPHOSTIN A9
5.40	Potency	3981	nM	CHEMBL1363013
5.40	Potency	3981	nM	GW282974X
5.40	Potency	3981	nM	CHEMBL1591830
5.30	Kd	5000	nM	CHEMBL5408357
5.30	Potency	5012	nM	CHEMBL1448859
5.30	Potency	5012	nM	CHEMBL1316080
5.22	EC50	6000	nM	CHEMBL537414
5.20	Potency	6310	nM	CHEMBL397209
5.20	Potency	6310	nM	CHEMBL1222317
5.19	EC50	6400	nM	CHEMBL536499
5.19	EC50	6500	nM	CHEMBL536731
5.18	EC50	6600	nM	CHEMBL537413
5.10	Potency	7943	nM	CHEMBL72365
5.10	Potency	7943	nM	PSEUDOEPHEDRINE
5.07	EC50	8600	nM	CHEMBL536963
5.07	EC50	8600	nM	CHEMBL537639
5.00	Potency	1e+04	nM	CHEMBL56731
5.00	Potency	1e+04	nM	CHEMBL1257003
5.00	Potency	1e+04	nM	CHEMBL47940
5.00	Potency	1e+04	nM	CHEMBL293749
5.00	Potency	1e+04	nM	CHEMBL261557
5.00	Potency	1e+04	nM	MYRICETIN
5.00	Potency	1e+04	nM	CHEMBL258767
5.00	Potency	1e+04	nM	DIPYRIDAMOLE

PubChem BioAssay actives

8 with measured affinity, of 171 total; 7 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
(1S,7R,10R,16R,19S,22S,33R,36R,42R)-10-(4-aminobutyl)-36-benzyl-N-[(2S)-1,6-diamino-1-oxohexan-2-yl]-19-[(4-hydroxyphenyl)methyl]-33-(naphthalen-1-ylmethyl)-2,8,11,17,20,25,31,34,37,43,49-undecaoxo-3,9,12,18,21,24,32,35,38,44,48-undecazahexacyclo[26.16.5.126,30.03,7.012,16.038,42]pentaconta-26(50),27,29-triene-22-carboxamide	1971587: Binding affinity to N-terminal 6His-tagged GMPPNP-bound Galphai1 (unknown origin) expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by SPR analysis	kd	0.7100	uM
1-[4-(1-methylpiperidin-4-yl)piperidin-1-yl]pentadecan-1-one;hydrochloride	254628: Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i1	ec50	6.0000	uM
N-pentadecylpiperidine-4-carboxamide;hydrochloride	254628: Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i1	ec50	6.4000	uM
4-pentadecylpiperazin-1-amine;hydrochloride	254628: Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i1	ec50	6.5000	uM
1-[4-(2-piperidin-4-ylethyl)piperidin-1-yl]pentadecan-1-one;hydrochloride	254628: Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i1	ec50	6.6000	uM
1-(2-formamidoethyl)-N-pentadecylpiperidine-4-carboxamide;hydrochloride	254628: Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i1	ec50	8.6000	uM
1-(4-piperidin-4-ylpiperidin-1-yl)pentadecan-1-one;hydrochloride	254628: Concentration required to stimulate binding of [35S]GTP-gamma-S, with G alpha i1	ec50	8.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	4
Valproic Acid	affects expression, increases expression	4
bisphenol A	decreases expression, affects cotreatment, increases expression	2
sodium arsenite	affects cotreatment, increases expression, decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Smoke	decreases expression, increases abundance	2
Tetrachlorodibenzodioxin	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	decreases expression	2
bisphenol F	increases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, decreases expression	1
2,4,6-tribromophenol	decreases expression	1
decabromobiphenyl ether	decreases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	affects cotreatment, decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
periodate-oxidized adenosine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pinosylvin	decreases expression	1
perfluorooctane sulfonic acid	affects expression, affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
bisphenol B	increases expression	1
perfluorobutanesulfonic acid	affects cotreatment, decreases expression	1
asparanin A	decreases expression	1

ChEMBL screening assays

23 unique, capped per target: 14 functional, 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614085	Functional	PUBCHEM_BIOASSAY: qHTS Assay for Inhibitors of RGS12 GoLoco Motif Activity (Green Fluorophore). (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL1073356	Binding	Inhibition of Galphai-mediated LPA-stimulated cell invasion in human SKOV3 cells	Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2XT	Abcam HEK293T GNAI1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism