GABRR1

Summary

GABRR1 (gamma-aminobutyric acid type A receptor subunit rho1, HGNC:4090) is a protein-coding gene on chromosome 6q15, encoding Gamma-aminobutyric acid receptor subunit rho-1 (P24046). Rho subunit of the pentameric ligand-gated chloride channels responsible for mediating the effects of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain.

GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA receptors, which are ligand-gated chloride channels. GABRR1 is a member of the rho subunit family. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2569 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 71 total
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002042

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4090
Approved symbol	GABRR1
Name	gamma-aminobutyric acid type A receptor subunit rho1
Location	6q15
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000146276
Ensembl biotype	protein_coding
OMIM	137161
Entrez	2569

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000369451, ENST00000435811, ENST00000454853, ENST00000457434, ENST00000481493, ENST00000964580

RefSeq mRNA: 4 — MANE Select: NM_002042 NM_001256703, NM_001256704, NM_001267582, NM_002042

CCDS: CCDS5019, CCDS59028, CCDS59029

Canonical transcript exons

ENST00000454853 — 10 exons

Exon	Start	End
ENSE00001819226	89217201	89217358
ENSE00001910453	89177504	89179063
ENSE00003505712	89181905	89182057
ENSE00003541008	89185310	89185450
ENSE00003550436	89201159	89201265
ENSE00003564212	89198020	89198243
ENSE00003566199	89190165	89190247
ENSE00003576598	89203435	89203485
ENSE00003639301	89199362	89199429
ENSE00003649796	89180292	89180488

Expression profiles

Bgee: expression breadth broad, 64 present calls, max score 87.30.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0587 / max 17.0287, expressed in 25 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74683	0.0481	21
74684	0.0106	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.30	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.90	gold quality
descending thoracic aorta	UBERON:0002345	72.02	gold quality
thoracic aorta	UBERON:0001515	63.07	gold quality
ascending aorta	UBERON:0001496	62.48	gold quality
pancreatic ductal cell	CL:0002079	57.00	gold quality
decidua	UBERON:0002450	56.55	gold quality
aorta	UBERON:0000947	54.83	gold quality
lower esophagus mucosa	UBERON:0035834	54.75	gold quality
tibialis anterior	UBERON:0001385	53.61	silver quality
hair follicle	UBERON:0002073	52.43	gold quality
ileal mucosa	UBERON:0000331	51.90	silver quality
epithelial cell of pancreas	CL:0000083	50.68	silver quality
deltoid	UBERON:0001476	49.52	silver quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
quadriceps femoris	UBERON:0001377	49.04	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
tibial artery	UBERON:0007610	48.88	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
popliteal artery	UBERON:0002250	48.79	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
vastus lateralis	UBERON:0001379	48.25	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

85 targeting GABRR1, 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-3162-3P	100.00	65.37	363
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699

Literature-anchored findings (GeneRIF, showing 23)

• examination of receptor modulation by divalent cations (PMID:11862606)
• Tyr-102 is a component of the GABA binding domain and it might be important for coupling agonist binding to channel opening (PMID:12226075)
• a single amino acid change within the ion-channel domain of the gamma-aminobutyric acid rho1 receptor accelerates desensitization and increases taurine agonism (PMID:15163459)
• a complete model of the GABA(C) receptor binding pocket was proposed and discussed in comparison with the GABA(A) receptor binding pocket (PMID:15548535)
• GABA receptor subunit rho-1 effectively altered gene expression through its interaction with the cellular retinoic acid binding protein pathway (PMID:16198491)
• Charge selectivity of the anionic rho1 GABA receptor can be influenced by the introduction of glutamates, one at a time, over an 8-amino acid stretch (-2’ to 5’) in the proposed intracellular end of TM2 and the TM1-TM2 intracellular linker. (PMID:18079559)
• Results imply that the M3M4 loop is not essential for GABA rho1 receptor assembly and function and suggest that the cytoplasmic domain may fold as an independent module from the transmembrane and extracellular domains. (PMID:18227272)
• Structural determinants for antagonists that distinguish the GABRR1 receptor from GABA-A receptors are reported. (PMID:18599601)
• These functional data support negative cross-talk between P2X(4) and rho1 receptors. (PMID:18675255)
• GABRR1 and GABRR2 encode the GABA-A receptor subunits rho1 and rho2 and are associated with alcohol dependence (PMID:19536785)
• Nonsense mutations of GABA(A) receptor are associated with genetic epilepsies. (PMID:19717338)
• Data show that GABArho1 can tolerate removal of several residues that form the fourth transmembrane segment up to a critical point, signaled by W475, beyond which the mutant protein is translated but does not form functional receptors. (PMID:20056107)
• GABRR1 is associated with susceptibility to bipolar disorder with schizophrenia-like psychotic features (PMID:20583128)
• found no significant differences in either the frequencies of the GABRR1-M26V, GABRR1- H27R, GABRR2-T455M, and GABRR3-Y205X genotypes or in the frequencies of the allelic variants of these polymorphisms in patients with essential tremor (PMID:20820800)
• evidence supporta the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorder. (PMID:22169095)
• The function of GABA(C) receptors can be enhanced by nitric oxide acting at the extracellular Cys-loop. (PMID:22747884)
• Data indicate that all compounds from the study exhibited increased selectivity for GABAC. (PMID:23755849)
• Both GABAAalpha1 and GABAArho1 mRNAs and proteins were identified in cultured retinal pigment epithelial cells; antibody staining was mainly localized to the cell membrane and was also present in the cytoplasm but not in the nucleus. (PMID:26321868)
• Thr244 of rho1 GABAC Receptors is an important residue for channel activation as it forms a H-bond with agonists, initiating the conformational changes required for priming of the receptor and stabilizes the open conformation (review). (PMID:27244450)
• Study determined that levels of GABAA receptors rho1 and rho2 are not altered in the cerebellum of WT and rho1 knockin mice. In addition, findings show that mutation of the inhibitory ethanol site in rho1 does not alter normal channel function, but is important for the development of acute tolerance to ethanol-induced motor impairment. (PMID:28623169)
• GABAergic genes interacting with parenting in adolescent depressive symptoms: GABRR1 X perceived parental support interaction. (PMID:28660714)
• The most common polymorphisms in the GABRR genes seemed to be not associated with the risk for migraine in Caucasian Spanish people, although one of them (GABRR1 rs1186902) shows a statistically significant association with the age of onset of migraine. (PMID:28699326)
• Divergent mechanisms of steroid inhibition in the human rho1 GABAA receptor. (PMID:39242530)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gabrr1	ENSDARG00000043902
danio_rerio	GABRR1	ENSDARG00000098081
mus_musculus	Gabrr1	ENSMUSG00000028280
rattus_norvegicus	Gabrr1	ENSRNOG00000007603

Paralogs (45): GABRA3 (ENSG00000011677), GABRA1 (ENSG00000022355), CHRNA3 (ENSG00000080644), GABRP (ENSG00000094755), CHRNA4 (ENSG00000101204), GLRA2 (ENSG00000101958), GABRE (ENSG00000102287), CHRNE (ENSG00000108556), GABRA4 (ENSG00000109158), GLRB (ENSG00000109738), GABRR2 (ENSG00000111886), GABRG2 (ENSG00000113327), CHRNB4 (ENSG00000117971), CHRNA2 (ENSG00000120903), CHRNA10 (ENSG00000129749), CHRND (ENSG00000135902), CHRNA1 (ENSG00000138435), GLRA3 (ENSG00000145451), GABRA6 (ENSG00000145863), GABRB2 (ENSG00000145864), GLRA1 (ENSG00000145888), CHRNB3 (ENSG00000147432), CHRNA6 (ENSG00000147434), HTR3B (ENSG00000149305), GABRA2 (ENSG00000151834), CHRNB2 (ENSG00000160716), GABRG1 (ENSG00000163285), GABRB1 (ENSG00000163288), GABRB3 (ENSG00000166206), CHRFAM7A (ENSG00000166664), HTR3A (ENSG00000166736), CHRNA5 (ENSG00000169684), CHRNB1 (ENSG00000170175), CHRNA9 (ENSG00000174343), CHRNA7 (ENSG00000175344), HTR3C (ENSG00000178084), GABRG3 (ENSG00000182256), GABRR3 (ENSG00000183185), HTR3E (ENSG00000186038), HTR3D (ENSG00000186090)

Protein

Protein identifiers

Gamma-aminobutyric acid receptor subunit rho-1 — P24046 (reviewed: P24046)

Alternative names: GABA(A) receptor subunit rho-1, GABA(C) receptor

All UniProt accessions (2): P24046, F8WB88

UniProt curated annotations — full annotation on UniProt →

Function. Rho subunit of the pentameric ligand-gated chloride channels responsible for mediating the effects of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. Rho-containing GABA-gated chloride channels are a subclass of GABA(A) receptors (GABAARs) entirely composed of rho subunits, where GABA molecules bind at the rho intersubunit interfaces. When activated by GABA, rho-GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient. Rho-1 subunits are primarily expressed in retina where rho-1-containing GABAARs may play a role in retinal neurotransmission. Rho-1 GABAARs are also involved in neuronal tonic (extrasynaptic) and phasic (synaptic) transmission in the Purkinje neurons of the cerebellum. Rho-1 GABAARs may also contribute to the regulation of glial development in the cerebellum by controlling extrasynaptic transmission.

Subunit / interactions. Three rho subunits (rho-1/GBRR1, rho-2/GBRR2 and rho-3/GBRR3) coassemble either to form functional homopentamers or heteropentamers. Rho-1/GBRR1 subunits can also associate with alpha-1/GBRA1 subunits to form a functional GABAAR. Interacts with SQSTM1.

Subcellular location. Postsynaptic cell membrane. Cell membrane.

Tissue specificity. Highly expressed in the retina. Expressed in a lesser extent in brain, lung and thymus.

Activity regulation. Inhibited by TPMPA, a rho-specific antagonist, when forming a homopentamer. In contrast with other GABAARs, rho-1 GABAAR is not inhibited by bicuculline, when forming a homopentamer.

Domain organisation. GABAARs subunits share a common topological structure: a peptide sequence made up of a long extracellular N-terminal, four transmembrane domains, intracellular or cytoplasmic domain located between the third and the fourth transmembrane domains.

Similarity. Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRR1 sub-subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P24046-1	1	yes
P24046-2	2
P24046-3	3

RefSeq proteins (4): NP_001243632, NP_001243633, NP_001254511, NP_002033* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006028	GABAA/Glycine_rcpt	Family
IPR006029	Neurotrans-gated_channel_TM	Domain
IPR006201	Neur_channel	Family
IPR006202	Neur_chan_lig-bd	Domain
IPR008057	GABAAa_rho_rcpt	Family
IPR008058	GABAAa_rho1_rcpt	Family
IPR018000	Neurotransmitter_ion_chnl_CS	Conserved_site
IPR036719	Neuro-gated_channel_TM_sf	Homologous_superfamily
IPR036734	Neur_chan_lig-bd_sf	Homologous_superfamily
IPR038050	Neuro_actylchol_rec	Homologous_superfamily

Pfam: PF02931, PF02932

Catalyzed reactions (Rhea), 1 shown:

• chloride(in) = chloride(out) (RHEA:29823)

UniProt features (55 total): strand 13, helix 10, turn 6, topological domain 5, transmembrane region 4, binding site 3, glycosylation site 3, splice variant 2, sequence variant 2, sequence conflict 2, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1, disulfide bond 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
9FRB	ELECTRON MICROSCOPY	2.05
9G7A	ELECTRON MICROSCOPY	2.12
9FRH	ELECTRON MICROSCOPY	2.14
9FRI	ELECTRON MICROSCOPY	2.14
9G7B	ELECTRON MICROSCOPY	2.18
9FRE	ELECTRON MICROSCOPY	2.19
8OQ7	ELECTRON MICROSCOPY	2.2
9FRF	ELECTRON MICROSCOPY	2.41
9FRG	ELECTRON MICROSCOPY	2.41
9G57	ELECTRON MICROSCOPY	2.48
8RH4	ELECTRON MICROSCOPY	2.52
9G5Q	ELECTRON MICROSCOPY	2.61
8RH8	ELECTRON MICROSCOPY	2.66
8RH7	ELECTRON MICROSCOPY	2.78
8OQ8	ELECTRON MICROSCOPY	2.9
8OQA	ELECTRON MICROSCOPY	2.9
8RHG	ELECTRON MICROSCOPY	3.01
9G55	ELECTRON MICROSCOPY	3.04
9G78	ELECTRON MICROSCOPY	3.11
9G70	ELECTRON MICROSCOPY	3.13
8OQ6	ELECTRON MICROSCOPY	3.21
8RH9	ELECTRON MICROSCOPY	3.21
9G5R	ELECTRON MICROSCOPY	3.28
9G62	ELECTRON MICROSCOPY	3.32
8OP9	ELECTRON MICROSCOPY	3.36
9G60	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P24046-F1	74.22	0.48

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 (3): 125 (in chain a); 189 (in chain a); 217 (in chain b)

Disulfide bonds (1): 198–212

Glycosylation sites (3): 140, 234, 274

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-977443	GABA receptor activation

MSigDB gene sets: 131 (showing top): chr6q15, GSE45365_NK_CELL_VS_CD11B_DC_UP, MODULE_64, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_GAMMA_AMINOBUTYRIC_ACID_SIGNALING_PATHWAY, GOBP_CELL_CELL_SIGNALING, GOBP_CHLORIDE_TRANSPORT, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, TGACATY_UNKNOWN, GOBP_SYNAPTIC_SIGNALING, FREAC4_01, KANG_IMMORTALIZED_BY_TERT_DN, REACTOME_TRANSMISSION_ACROSS_CHEMICAL_SYNAPSES, GOBP_TRANSMEMBRANE_TRANSPORT, TGGAAA_NFAT_Q4_01

GO Biological Process (9): gamma-aminobutyric acid signaling pathway (GO:0007214), chemical synaptic transmission (GO:0007268), modulation of chemical synaptic transmission (GO:0050804), synaptic transmission, GABAergic (GO:0051932), chloride transmembrane transport (GO:1902476), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), monoatomic ion transmembrane transport (GO:0034220), regulation of presynaptic membrane potential (GO:0099505)

GO Molecular Function (11): GABA-A receptor activity (GO:0004890), protein domain specific binding (GO:0019904), GABA-gated chloride ion channel activity (GO:0022851), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential (GO:0099507), transmembrane signaling receptor activity (GO:0004888), monoatomic ion channel activity (GO:0005216), extracellular ligand-gated monoatomic ion channel activity (GO:0005230), chloride channel activity (GO:0005254), GABA receptor activity (GO:0016917)

GO Cellular Component (10): plasma membrane (GO:0005886), chloride channel complex (GO:0034707), presynaptic membrane (GO:0042734), postsynaptic membrane (GO:0045211), intracellular vesicle (GO:0097708), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), GABA-A receptor complex (GO:1902711), membrane (GO:0016020), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Neurotransmitter receptors and postsynaptic signal transmission	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
GABA receptor activity	2
chemical synaptic transmission	2
protein binding	2
ligand-gated monoatomic ion channel activity	2
synaptic membrane	2
synapse	2
cell-cell signaling	1
anterograde trans-synaptic signaling	1
regulation of trans-synaptic signaling	1
chloride transport	1
monoatomic anion transmembrane transport	1
transport	1
monoatomic anion transport	1
inorganic anion transport	1
monoatomic ion transport	1
transmembrane transport	1
regulation of membrane potential	1
chloride channel activity	1
transmitter-gated monoatomic ion channel activity	1
ligand-gated monoatomic anion channel activity	1
binding	1
presynaptic membrane	1
regulation of presynaptic membrane potential	1
signaling receptor activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
transmembrane signaling receptor activity	1
membrane	1
cell periphery	1
monoatomic ion channel complex	1
presynapse	1
postsynapse	1
intracellular anatomical structure	1
vesicle	1
intracellular membrane-bounded organelle	1
GABA receptor complex	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

834 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GABRR1	EYS	Q5T1H1	571
GABRR1	GRM5	P41594	511
GABRR1	GNB3	P16520	509
GABRR1	GABBR2	O75899	447
GABRR1	KCNE2	Q9Y6J6	445
GABRR1	KIAA1671	Q9BY89	413
GABRR1	C6orf52	Q5T4I8	411
GABRR1	PDE10A	Q9Y233	409
GABRR1	RGS7	P49802	398
GABRR1	CCDC102A	Q96A19	395
GABRR1	C5AR1	P21730	391
GABRR1	GNAS	Q5JWF2	379
GABRR1	MTNR1B	P49286	377
GABRR1	ABCB4	P21439	353
GABRR1	BRS3	P32247	339

IntAct

2 interactions, top by confidence:

A	B	Type	Score
MYC		psi-mi:“MI:0914”(association)	0.350

BioGRID (13): GABRR1 (Biochemical Activity), GABRR1 (Biochemical Activity), GABRR1 (Biochemical Activity), GABRR1 (Biochemical Activity), GABRR1 (Biochemical Activity), GABRR1 (Biochemical Activity), TAX1BP1 (Affinity Capture-MS), GABRR1 (Affinity Capture-MS), BCR (Affinity Capture-MS), DNM1L (Affinity Capture-MS), IP6K2 (Affinity Capture-MS), FEZF1 (Affinity Capture-MS), TAX1BP1 (Affinity Capture-Western)

ESM2 similar proteins: A8MPY1, F1R8P4, O75311, O93430, P02713, P02714, P02715, P02716, P02717, P02718, P04759, P05376, P09628, P09660, P09690, P20782, P22770, P22771, P23415, P23416, P24046, P24524, P25110, P26714, P28476, P43144, P47742, P49580, P49582, P50572, P50573, P54244, P56475, P56476, P57695, Q05941, Q07001, Q08832, Q0II76, Q24352

Diamond homologs: A8MPY1, D1LYT2, F1R8P4, G5EBR3, O00591, O09028, O14764, O18276, O75311, O93430, P07727, P08219, P08220, P0C2W5, P10063, P10064, P14867, P15431, P16305, P18505, P18506, P18507, P18508, P19019, P19150, P19969, P20236, P20237, P20781, P21548, P22300, P22723, P22771, P22933, P23415, P23416, P23574, P23576, P24045, P24046

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
MAPK1	unknown	GABRR1	phosphorylation
PRKACA	unknown	GABRR1	phosphorylation
PRKCA	unknown	GABRR1	phosphorylation
PRKG1	unknown	GABRR1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1305 predictions. Top by Δscore:

Variant	Effect	Δscore
6:89179059:GGAAG:G	acceptor_gain	1.0000
6:89179060:GAAG:G	acceptor_gain	1.0000
6:89179061:AAG:A	acceptor_gain	1.0000
6:89179062:AG:A	acceptor_gain	1.0000
6:89179063:GC:G	acceptor_loss	1.0000
6:89179064:C:CC	acceptor_gain	1.0000
6:89179065:T:C	acceptor_loss	1.0000
6:89179071:CAG:C	acceptor_gain	1.0000
6:89180288:TCACC:T	donor_loss	1.0000
6:89180289:CA:C	donor_loss	1.0000
6:89180291:CCTT:C	donor_gain	1.0000
6:89180294:T:A	donor_gain	1.0000
6:89180315:T:TA	donor_gain	1.0000
6:89180320:T:A	donor_gain	1.0000
6:89180356:TCCAG:T	donor_gain	1.0000
6:89180357:CCAGC:C	donor_gain	1.0000
6:89180484:GATAC:G	acceptor_gain	1.0000
6:89180485:ATAC:A	acceptor_gain	1.0000
6:89180486:TAC:T	acceptor_gain	1.0000
6:89180486:TACC:T	acceptor_loss	1.0000
6:89180487:AC:A	acceptor_gain	1.0000
6:89180487:ACC:A	acceptor_loss	1.0000
6:89180488:CC:C	acceptor_gain	1.0000
6:89180489:C:CC	acceptor_gain	1.0000
6:89180496:C:CT	acceptor_gain	1.0000
6:89181900:CTTA:C	donor_loss	1.0000
6:89181903:ACC:A	donor_loss	1.0000
6:89181904:C:G	donor_loss	1.0000
6:89182053:CCAGC:C	acceptor_gain	1.0000
6:89182054:CAGCC:C	acceptor_gain	1.0000

AlphaMissense

3201 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:89180385:G:C	S351R	1.000
6:89180385:G:T	S351R	1.000
6:89180387:T:G	S351R	1.000
6:89182042:A:G	L271P	1.000
6:89185416:C:A	W230C	1.000
6:89185416:C:G	W230C	1.000
6:89185417:C:G	W230S	1.000
6:89185418:A:G	W230R	1.000
6:89185418:A:T	W230R	1.000
6:89185429:A:G	L226P	1.000
6:89190166:G:C	S218R	1.000
6:89190166:G:T	S218R	1.000
6:89190168:T:G	S218R	1.000
6:89190179:A:G	L214P	1.000
6:89190184:G:C	C212W	1.000
6:89190185:C:G	C212S	1.000
6:89190185:C:T	C212Y	1.000
6:89190186:A:G	C212R	1.000
6:89190186:A:T	C212S	1.000
6:89190226:G:C	C198W	1.000
6:89190227:C:G	C198S	1.000
6:89190227:C:T	C198Y	1.000
6:89190228:A:G	C198R	1.000
6:89190228:A:T	C198S	1.000
6:89198020:C:A	R191M	1.000
6:89198020:C:G	R191T	1.000
6:89198025:A:C	S189R	1.000
6:89198025:A:T	S189R	1.000
6:89198027:T:G	S189R	1.000
6:89198032:A:G	L187P	1.000

dbSNP variants (sampled 300 via entrez): RS1000056677 (6:89194749 C>T), RS1000326427 (6:89215301 T>C), RS1000371102 (6:89203401 C>T), RS1000464533 (6:89207281 ACCT>A), RS1000472963 (6:89191125 A>G), RS1000482937 (6:89201127 A>C), RS1000577611 (6:89190029 G>A,C), RS1000614788 (6:89212484 G>A), RS1000619246 (6:89184408 G>C), RS1000768262 (6:89207477 G>A), RS1000877647 (6:89185095 G>T), RS1000922321 (6:89226171 T>C), RS1000941045 (6:89207680 A>G), RS1001027163 (6:89213341 G>A,C), RS1001061931 (6:89196185 T>C)

Disease associations

OMIM: gene MIM:137161 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000821_30	Bipolar disorder and schizophrenia	4.000000e-08
GCST003455_15	Spherical equivalent (joint analysis main effects and education interaction)	4.000000e-08
GCST005889_1	Early diabetic kidney disease in type 2 diabetes	5.000000e-08
GCST005895_2	Diabetic kidney disease in type 2 diabetes	4.000000e-07
GCST009441_4	Age-related cognitive decline (memory) (slope of z-scores)	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment
EFO:0007710	cognitive decline measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2109242 (PROTEIN COMPLEX GROUP), CHEMBL3561 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 303,493 (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
CHEMBL15891	LINDANE	4	83,653
CHEMBL601	AMINOLEVULINIC ACID	4	53,584
CHEMBL112797	SGS-742	2	309
CHEMBL96	GAMMA-AMINOBUTYRIC ACID	1	160,188
CHEMBL273481	MUSCIMOL	1	5,759

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — GABA_A receptors

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
CACA	Agonist	4.13	pEC50

ChEMBL bioactivities

59 potent at pChembl≥5 of 87 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.04	IC50	91	nM	LINDANE
6.57	EC50	269.1	nM	GAMMA-AMINOBUTYRIC ACID
6.57	EC50	270	nM	GAMMA-AMINOBUTYRIC ACID
6.47	EC50	340	nM	GAMMA-AMINOBUTYRIC ACID
6.47	EC50	338.8	nM	GAMMA-AMINOBUTYRIC ACID
6.40	EC50	400	nM	t-4-AMINOCROTONIC ACID (TACA)
6.36	EC50	440	nM	t-4-AMINOCROTONIC ACID (TACA)
6.22	Kd	600	nM	t-4-AMINOCROTONIC ACID (TACA)
6.22	EC50	600	nM	t-4-AMINOCROTONIC ACID (TACA)
6.16	EC50	691.8	nM	MUSCIMOL
6.16	EC50	700	nM	MUSCIMOL
6.10	IC50	800	nM	ALPHA-ENDOSULFAN
6.10	EC50	800	nM	GAMMA-AMINOBUTYRIC ACID
6.00	EC50	1000	nM	GAMMA-AMINOBUTYRIC ACID
5.92	EC50	1200	nM	CHEMBL4464494
5.92	EC50	1202	nM	CHEMBL4464494
5.92	EC50	1190	nM	GAMMA-AMINOBUTYRIC ACID
5.91	EC50	1230	nM	CHEMBL3322882
5.85	EC50	1400	nM	MUSCIMOL
5.80	EC50	1585	nM	CHEMBL3322886
5.80	EC50	1600	nM	CHEMBL4442696
5.80	EC50	1585	nM	CHEMBL4442696
5.77	Kd	1700	nM	GAMMA-AMINOBUTYRIC ACID
5.65	IC50	2220	nM	CHEMBL397209
5.64	EC50	2300	nM	MUSCIMOL
5.64	EC50	2300	nM	CHEMBL3322882
5.64	Kd	2300	nM	MUSCIMOL
5.61	EC50	2430	nM	CHEMBL33186
5.56	EC50	2754	nM	CHEMBL4458674
5.55	EC50	2800	nM	CHEMBL4458674
5.51	EC50	3090	nM	CHEMBL2315213
5.51	EC50	3100	nM	CHEMBL2315213
5.43	EC50	3700	nM	CHEMBL4554798
5.43	EC50	3715	nM	CHEMBL4554798
5.42	EC50	3800	nM	CHEMBL4526098
5.41	EC50	3890	nM	CHEMBL4526098
5.34	EC50	4600	nM	IMIDAZOLE ACETIC ACID
5.34	EC50	4571	nM	IMIDAZOLE ACETIC ACID
5.34	EC50	4600	nM	HOMOHYPOTAURINE
5.27	EC50	5400	nM	CHEMBL4547372
5.27	EC50	5370	nM	CHEMBL4547372
5.27	IC50	5400	nM	CHEMBL113348
5.26	IC50	5500	nM	CHEMBL109375
5.19	EC50	6500	nM	CHEMBL79325
5.19	EC50	6457	nM	CHEMBL79325
5.18	IC50	6600	nM	CHEMBL2398121
5.13	EC50	7400	nM	CHEMBL4464494
5.13	EC50	7413	nM	CHEMBL4464494
5.09	EC50	8100	nM	CHEMBL3322886
5.08	EC50	8400	nM	CHEMBL1788265

PubChem BioAssay actives

61 with measured affinity, of 241 total; 28 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
6-aminopyridine-3-carboxylic acid	1184362: Agonist activity at human GABAA rho1 expressed in tsA-201cells by FLIPR membrane potential blue assay	ec50	<0.0001	uM
6-amino-2-methylpyridine-3-carboxylic acid	1184362: Agonist activity at human GABAA rho1 expressed in tsA-201cells by FLIPR membrane potential blue assay	ec50	<0.0001	uM
piperidine-4-carboxylic acid	1184362: Agonist activity at human GABAA rho1 expressed in tsA-201cells by FLIPR membrane potential blue assay	ec50	<0.0001	uM
6-amino-4-methylpyridine-3-carboxylic acid	1184362: Agonist activity at human GABAA rho1 expressed in tsA-201cells by FLIPR membrane potential blue assay	ec50	<0.0001	uM
.gamma.-aminobutyric acid	1184362: Agonist activity at human GABAA rho1 expressed in tsA-201cells by FLIPR membrane potential blue assay	ec50	0.2692	uM
(E)-4-aminobut-2-enoic acid	406570: Agonist activity at human GABAc Rho1 receptor expressed in Xenopus oocytes assessed as whole cell current production by two electrode voltage clamp method	ec50	0.4000	uM
5-(aminomethyl)-1,2-oxazol-3-one	1184362: Agonist activity at human GABAA rho1 expressed in tsA-201cells by FLIPR membrane potential blue assay	ec50	0.6918	uM
2-(2-amino-4,5-dihydro-1,3-thiazol-4-yl)propanoic acid	1599026: Agonist activity at recombinant human GABA-A rho-1 receptor transiently expressed in human tsA201 cells incubated for 30 mins and measured up to 90 secs by FMP dye based FLIPR membrane potential blue assay	ec50	1.2000	uM
6-amino-2,3,4,5-tetrahydropyridine-3-carboxylic acid	1184362: Agonist activity at human GABAA rho1 expressed in tsA-201cells by FLIPR membrane potential blue assay	ec50	1.2303	uM
2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid	1184362: Agonist activity at human GABAA rho1 expressed in tsA-201cells by FLIPR membrane potential blue assay	ec50	1.5849	uM
(2R)-2-[(4R)-2-amino-4,5-dihydro-1,3-thiazol-4-yl]propanoic acid	1599026: Agonist activity at recombinant human GABA-A rho-1 receptor transiently expressed in human tsA201 cells incubated for 30 mins and measured up to 90 secs by FMP dye based FLIPR membrane potential blue assay	ec50	1.5849	uM
methyl(1,2,3,6-tetrahydropyridin-4-yl)phosphinic acid	569661: Antagonist activity at human recombinant GABAc rho-1 receptor expressed in Xenopus laevis oocytes assessed as inhibition of GABA-induced current by two electrode voltage clamp technique	ic50	2.2200	uM
(Z)-4-amino-2-fluorobut-2-enoic acid	71533: Partial agonist activity against rho-1 subunit GABA-C receptor expressed in Xenopus oocytes	ec50	2.4300	uM
2-(4,5-dihydro-1H-imidazol-5-yl)acetic acid	1599026: Agonist activity at recombinant human GABA-A rho-1 receptor transiently expressed in human tsA201 cells incubated for 30 mins and measured up to 90 secs by FMP dye based FLIPR membrane potential blue assay	ec50	2.7542	uM
(1-hydroxypyrazol-4-yl)methanamine	724585: Agonist activity at human GABAA rho1 receptor expressed in TSA201 cells after 1 min by FLIPR assay	ec50	3.0903	uM
2-[(4S)-2-amino-4,5-dihydro-1,3-thiazol-4-yl]acetic acid	1599026: Agonist activity at recombinant human GABA-A rho-1 receptor transiently expressed in human tsA201 cells incubated for 30 mins and measured up to 90 secs by FMP dye based FLIPR membrane potential blue assay	ec50	3.7000	uM
2-(2-amino-4,5-dihydro-1H-imidazol-5-yl)acetic acid	1599026: Agonist activity at recombinant human GABA-A rho-1 receptor transiently expressed in human tsA201 cells incubated for 30 mins and measured up to 90 secs by FMP dye based FLIPR membrane potential blue assay	ec50	3.8000	uM
2-(1H-imidazol-5-yl)acetic acid	1599026: Agonist activity at recombinant human GABA-A rho-1 receptor transiently expressed in human tsA201 cells incubated for 30 mins and measured up to 90 secs by FMP dye based FLIPR membrane potential blue assay	ec50	4.5709	uM
3-aminopropane-1-sulfinic acid	71411: Partial agonist activity against human rho1 subunit GABA-C receptor expressed in Xenopus oocytes	ec50	4.6000	uM
2-[(4R)-2-amino-4,5-dihydro-1,3-thiazol-4-yl]acetic acid	1599026: Agonist activity at recombinant human GABA-A rho-1 receptor transiently expressed in human tsA201 cells incubated for 30 mins and measured up to 90 secs by FMP dye based FLIPR membrane potential blue assay	ec50	5.3703	uM
[(2R)-3-amino-2-hydroxypropyl]-methylphosphinic acid	321739: Antagonist activity at human recombinant GABAc rho1 receptor expressed in Xenopus laevis oocytes at -60mV by two-electrode voltage clamp method	ic50	5.4000	uM
[(E)-3-aminoprop-1-enyl]-methylphosphinic acid	406571: Antagonist activity at human GABAc Rho1 receptor expressed in Xenopus oocytes assessed as whole cell current production by two electrode voltage clamp method	ic50	5.5000	uM
2-(2-amino-4,5-dihydro-1,3-thiazol-4-yl)acetic acid	1599026: Agonist activity at recombinant human GABA-A rho-1 receptor transiently expressed in human tsA201 cells incubated for 30 mins and measured up to 90 secs by FMP dye based FLIPR membrane potential blue assay	ec50	6.4565	uM
4-aminocyclopentene-1-carboxylic acid	756695: Antagonist activity at human recombinant GABAA rho1 receptor expressed in Xenopus laevis assessed as inhibition of GABA-induced chloride current production after 2 to 5 days by two-electrode voltage-clamp electrophysiological assay	ic50	6.6000	uM
2-[(3R)-pyrrolidin-3-yl]acetic acid	1599026: Agonist activity at recombinant human GABA-A rho-1 receptor transiently expressed in human tsA201 cells incubated for 30 mins and measured up to 90 secs by FMP dye based FLIPR membrane potential blue assay	ec50	8.3176	uM
cis-(1R,2R)-2-(aminomethyl)cyclopropane-1-carboxylic acid	406570: Agonist activity at human GABAc Rho1 receptor expressed in Xenopus oocytes assessed as whole cell current production by two electrode voltage clamp method	ec50	9.0000	uM
4-aminocyclopentene-1-carboxamide	756695: Antagonist activity at human recombinant GABAA rho1 receptor expressed in Xenopus laevis assessed as inhibition of GABA-induced chloride current production after 2 to 5 days by two-electrode voltage-clamp electrophysiological assay	ic50	9.6000	uM
[(4S)-4-aminocyclopenten-1-yl]-butylphosphinic acid	733879: Antagonist activity at human GABAC rho1 receptor expressed in Xenopus laevis oocytes assessed as inhibition of GABA-induced current by two electrode voltage clamp assay	ic50	9.7600	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
6-methoxyflavone	increases activity, increases reaction	1
6-methoxyflavanone	increases activity, increases reaction	1
bisphenol A	increases expression	1
trichostatin A	decreases expression	1
gaboxadol	decreases reaction, increases activity	1
benzo(e)pyrene	decreases methylation	1
triadimefon	increases expression	1
12-ketoendrin	affects binding	1
1-(4-ethynylphenyl)-4-propyl-2,6,7-trioxabicyclo(2.2.2)octane	affects binding	1
CGP 52608	affects binding, increases reaction	1
(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid	increases activity, decreases reaction	1
theaflavin-3,3’-digallate	affects expression	1
Arsenic Trioxide	decreases expression	1
Hexachlorocyclohexane	affects binding	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Diazepam	increases activity, increases reaction	1
Dieldrin	affects binding	1
Endosulfan	affects binding	1
gamma-Aminobutyric Acid	decreases reaction, increases activity, increases reaction	1
Methapyrilene	decreases methylation	1
Sarin	decreases expression	1
Thimerosal	increases expression	1
Tretinoin	increases expression	1
Raloxifene Hydrochloride	affects reaction, increases expression, affects expression	1

ChEMBL screening assays

55 unique, capped per target: 29 binding, 26 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL679661	Functional	Agonist activity against Gamma-aminobutyric acid C (GABA-C) receptor derived from bovine retinal RNA expressed in Xenopus oocytes	GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology. — J Med Chem
CHEMBL2317987	Binding	Agonist activity at human GABAA rho1 receptor expressed in TSA201 cells after 1 min by FLIPR assay relative to GABA	Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as γ-aminobutyric acid(a) receptor agonists. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_YA50	IDG-HEK293T-GABRR1-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

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