GABRA5

Summary

GABRA5 (gamma-aminobutyric acid type A receptor subunit alpha5, HGNC:4079) is a protein-coding gene on chromosome 15q12, encoding Gamma-aminobutyric acid receptor subunit alpha-5 (P31644). Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.

GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. Transcript variants utilizing three different alternative non-coding first exons have been described.

Source: NCBI Gene 2558 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 79 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 162 total — 8 pathogenic, 1 likely-pathogenic
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈22% of expected missense variation)
• GTEx eGene: eQTL in 14 tissues, sQTL in 2 (q < 0.05)
• Phenotypes (HPO): 60
• Drug target: yes — 1 via a complex or family; 27 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs acting on a complex or family including it: 1 — Zopiclone (GABA-A receptor; agonist GABA site)
• Constraint (gnomAD): pLI 0.79 (intermediate), LOEUF 0.56 (moderately constrained)
• MANE Select transcript: NM_000810

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4079
Approved symbol	GABRA5
Name	gamma-aminobutyric acid type A receptor subunit alpha5
Location	15q12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000186297
Ensembl biotype	protein_coding
OMIM	137142
Entrez	2558

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 13 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

MANE Select: ENST00000335625

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 3: 2, TSL 4: 3, TSL 5: 4

ENST00000335625, ENST00000355395, ENST00000400081, ENST00000554038, ENST00000554083, ENST00000554596, ENST00000554599, ENST00000555060, ENST00000555182, ENST00000557449, ENST00000557484, ENST00000879566, ENST00000951856, ENST00001061909, ENST00001061910, ENST00001101702, ENST00001132991

RefSeq mRNA: 2 — MANE Select: NM_000810 NM_000810, NM_001165037

CCDS: CCDS45194

Canonical transcript exons

ENST00000335625 — 11 exons

Exon	Start	End
ENSE00001333513	26937185	26937328
ENSE00001372316	26914803	26914885
ENSE00001387903	26868729	26868793
ENSE00001430185	26883166	26883233
ENSE00001783227	26939925	26940077
ENSE00002440125	26867062	26867111
ENSE00002493541	26943215	26943426
ENSE00003566900	26869175	26869334
ENSE00003631305	26880846	26880967
ENSE00003784216	26883337	26883557
ENSE00004781803	26947934	26949208

Expression profiles

Bgee: expression breadth ubiquitous, 141 present calls, max score 95.91.

FANTOM5 (CAGE): breadth broad, TPM avg 2.6591 / max 243.8537, expressed in 308 samples.

Highest expression (Bgee): nucleus accumbens, prefrontal cortex, Brodmann (1909) area 10, cingulate cortex, anterior cingulate cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

GABRA5 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 14 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

16 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Muscularis	eqtl	4.7e-81	-0.78	15:26871798:G:T
Thyroid	eqtl	8.3e-42	+0.74	15:26831275:C:G
Esophagus Gastroesophageal Junction	eqtl	3.9e-40	-0.62	15:26871798:G:T
Esophagus Mucosa	eqtl	1.2e-36	-0.62	15:26871798:G:T
Testis	eqtl	6.1e-22	-0.65	15:26826920:T:C
Pancreas	eqtl	6.8e-16	+0.70	15:26831275:C:G
Colon Sigmoid	eqtl	1.8e-15	-0.58	15:26873655:C:T
Prostate	eqtl	1.6e-10	+0.75	15:26864893:T:C
Stomach	eqtl	1.8e-08	+0.29	15:26833716:AT:A
Esophagus Muscularis	sqtl	1.0e-05	+0.42	15:26943188:T:A
Cells Cultured fibroblasts	eqtl	5.6e-05	+0.24	15:26866979:G:C
Kidney Cortex	eqtl	2.7e-03	+0.90	15:26855798:T:A
Pituitary	eqtl	2.3e-02	+0.24	15:26831638:A:G
Brain Caudate basal ganglia	eqtl	3.8e-02	+0.33	15:27369877:G:A
Brain Cortex	sqtl	3.9e-02	+0.47	15:26944984:C:T
Brain Hypothalamus	eqtl	5.0e-02	+0.44	15:26819234:A:T

FANTOM5 promoters

showing 10 of 15 alternative TSS:

Promoter ID	TPM avg	Samples expressed
145575	0.8893	199
145578	0.4155	89
145584	0.2520	61
145580	0.2466	58
145573	0.1970	88
145579	0.1147	48
145576	0.1115	60
207444	0.0943	42
145583	0.0669	38
145574	0.0665	32

Top tissues by expression

showing 100 of 271 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	95.91	gold quality
prefrontal cortex	UBERON:0000451	93.91	gold quality
Brodmann (1909) area 10	UBERON:0013541	93.09	gold quality
cingulate cortex	UBERON:0003027	92.99	gold quality
anterior cingulate cortex	UBERON:0009835	92.95	gold quality
orbitofrontal cortex	UBERON:0004167	92.38	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.95	gold quality
Ammon’s horn	UBERON:0001954	91.40	gold quality
frontal cortex	UBERON:0001870	91.17	gold quality
CA1 field of hippocampus	UBERON:0003881	90.70	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.69	gold quality
frontal pole	UBERON:0002795	90.56	gold quality
caudate nucleus	UBERON:0001873	90.54	gold quality
neocortex	UBERON:0001950	90.42	gold quality
cerebral cortex	UBERON:0000956	90.20	gold quality
cortical plate	UBERON:0005343	89.78	gold quality
telencephalon	UBERON:0001893	89.46	gold quality
right frontal lobe	UBERON:0002810	89.37	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.75	gold quality
amygdala	UBERON:0001876	88.29	gold quality
Brodmann (1909) area 46	UBERON:0006483	87.58	gold quality
putamen	UBERON:0001874	87.40	gold quality
temporal lobe	UBERON:0001871	87.39	gold quality
entorhinal cortex	UBERON:0002728	86.65	gold quality
superior frontal gyrus	UBERON:0002661	86.17	gold quality
forebrain	UBERON:0001890	85.10	gold quality
postcentral gyrus	UBERON:0002581	82.11	gold quality
parietal lobe	UBERON:0001872	81.56	gold quality
hypothalamus	UBERON:0001898	80.61	gold quality
middle frontal gyrus	UBERON:0002702	80.32	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.02	gold quality
lower esophagus muscularis layer	UBERON:0035833	79.02	gold quality
brain	UBERON:0000955	78.96	gold quality
lower esophagus	UBERON:0013473	78.91	gold quality
central nervous system	UBERON:0001017	78.16	gold quality
middle temporal gyrus	UBERON:0002771	77.03	gold quality
Brodmann (1909) area 23	UBERON:0013554	72.99	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	72.50	gold quality
endothelial cell	CL:0000115	71.11	silver quality
occipital lobe	UBERON:0002021	71.10	gold quality
primary visual cortex	UBERON:0002436	69.97	gold quality
lateral globus pallidus	UBERON:0002476	67.72	silver quality
lower lobe of lung	UBERON:0008949	66.90	silver quality
mucosa of stomach	UBERON:0001199	66.67	gold quality
pancreatic ductal cell	CL:0002079	64.44	silver quality
dorsal plus ventral thalamus	UBERON:0001897	64.17	gold quality
ganglionic eminence	UBERON:0004023	63.98	gold quality
ventricular zone	UBERON:0003053	63.63	gold quality
corpus callosum	UBERON:0002336	62.21	gold quality
substantia nigra	UBERON:0002038	62.09	gold quality
midbrain	UBERON:0001891	60.78	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	60.04	gold quality
ileal mucosa	UBERON:0000331	59.84	silver quality
gall bladder	UBERON:0002110	59.35	gold quality
esophagus	UBERON:0001043	58.31	gold quality
adult organism	UBERON:0007023	57.81	gold quality
embryo	UBERON:0000922	57.60	gold quality
sural nerve	UBERON:0015488	56.64	gold quality
stromal cell of endometrium	CL:0002255	56.55	gold quality
decidua	UBERON:0002450	56.55	gold quality
ventral tegmental area	UBERON:0002691	56.23	silver quality
right atrium auricular region	UBERON:0006631	55.87	gold quality
cardiac atrium	UBERON:0002081	55.36	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	54.32	gold quality
tibialis anterior	UBERON:0001385	53.47	silver quality
spinal cord	UBERON:0002240	53.20	gold quality
deltoid	UBERON:0001476	53.04	gold quality
islet of Langerhans	UBERON:0000006	52.86	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
apex of heart	UBERON:0002098	52.23	gold quality
epithelial cell of pancreas	CL:0000083	51.97	gold quality
biceps brachii	UBERON:0001507	51.39	gold quality
quadriceps femoris	UBERON:0001377	50.94	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
globus pallidus	UBERON:0001875	50.14	silver quality
vastus lateralis	UBERON:0001379	50.00	gold quality
cranial nerve II	UBERON:0000941	49.65	silver quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
oviduct epithelium	UBERON:0004804	48.21	gold quality
fundus of stomach	UBERON:0001160	48.12	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
medial globus pallidus	UBERON:0002477	48.03	silver quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
stomach	UBERON:0000945	47.85	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
lower esophagus mucosa	UBERON:0035834	47.80	gold quality
upper leg skin	UBERON:0004262	47.78	silver quality
metanephric glomerulus	UBERON:0004736	47.74	gold quality
nasal cavity epithelium	UBERON:0005384	47.70	gold quality
body of stomach	UBERON:0001161	47.61	gold quality
renal glomerulus	UBERON:0000074	47.60	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.43

HPA expression

RNA tissue specificity: Tissue enriched

53 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Hippocampus	tissue	198.8
Nucleus accumbens	tissue	191.6
Hippocampal formation	tissue	106.8
Postcentral gyrus	tissue	74.5
Thalamus	tissue	74.2
Prefrontal cortex	tissue	66.5
Cerebral cortex	tissue	66.5
Motor cortex	tissue	61.5
Retrosplenial and cingulate cortex	tissue	55.7
Basal ganglia	tissue	54.3
Frontal cortex	tissue	53.4
Ventral forebrain	tissue	53.1
Retrosplenial cortex	tissue	51.0
Amygdala	tissue	49.2
Temporal cortex	tissue	47.9
Insular cortex	tissue	46.3
Entorhinal cortex	tissue	45.7
Somatosensory cortex	tissue	45.2
Septum	tissue	44.5
Superior colliculi	tissue	41.6
Putamen	tissue	39.4
Midbrain	tissue	36.4
Occipital cortex	tissue	35.7
Caudate putamen	tissue	34.7
Olfactory bulb	tissue	32.9
Pons	tissue	29.6
Hypothalamus	tissue	17.1
Locus coeruleus	tissue	9.2
Thymus	tissue	8.4
Periaqueductal gray	tissue	8.3
Corpus callosum	tissue	7.7
Spinal cord	tissue	5.9
Medulla oblongata	tissue	5.3
Substantia nigra	tissue	4.0
Choroid plexus	tissue	3.3
Retina	tissue	1.5
Esophagus	tissue	1.5
Gallbladder	tissue	0.7
Testis	tissue	0.6
Parathyroid gland	tissue	0.6
Smooth muscle	tissue	0.5
Pituitary gland	tissue	0.4
Stomach 1	tissue	0.3
Tonsil	tissue	0.3
Prostate	tissue	0.2
Heart muscle	tissue	0.1
Ovary	tissue	0.1
Seminal vesicle	tissue	0.1
Tongue	tissue	0.1
Cerebellum	tissue	0.1
Thyroid gland	tissue	0.1
Kidney	tissue	0.1
Appendix	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 188; highest nTPM — Hippocampus, CA1 (279.2), Posterior cingulate cortex (255.7), Hippocampus, CA3 (227.4), Olfactory area (221.8), Dentate gyrus (214.9).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting GABRA5 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 131 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
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-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-141-3P	99.94	72.79	2421

Functional genomics

gnomAD constraint: pLI 0.794, LOEUF 0.56, missense Z 3.26 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000335625 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈22% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
15:26,869,249–26,939,961	216 / 335.3	0.64	no
15:26,939,962–26,943,406	43 / 133.7	0.32	yes (p 4.3e-15)
15:26,943,407–26,948,230	106 / 130.3	0.81	no

Literature-anchored findings (GeneRIF, showing 26)

• extracellular domain models show subunit arrangement of GABA-A receptors (PMID:15033447)
• These results suggest that the GABRA5 gene may confer susceptibility to bipolar I disorder. (PMID:15882799)
• GABA(A) receptor alpha5 subunit as a candidate gene for autism and bipolar disorder; observations suggest parent-of-origin and gain-of-function effects (PMID:17353214)
• The ratios of beta(3)/beta(2) and alpha(5)/alpha(1) subunit protein expression in Angelman syndrome cortex were significantly decreased when compared with controls. (PMID:20692323)
• In subjects with schizophrenia, mean GABA (A) alpha5 rerceptor subunit mRNA expression is 15% lower in layer 4 of the dorsolateral prefrontal cortex. (PMID:20843900)
• Data indicate the selectivity of some selected compounds were assessed in recombinant alpha(1)beta(2)gamma(2)L, alpha(2)beta(1)gamma(2)L, and alpha(5)beta(2)gamma(2)L GABA(A) receptors. (PMID:21751815)
• These results provide initial evidence of a GABAA alpha5 deficit in autism spectrum disorder and support further investigations of the GABA system in this disorder. (PMID:22546616)
• The alpha5 nicotinic receptor GABAergic neurons form a link from the medial habenula to the serotonergic brain centers. (PMID:24227714)
• Findings provide genetic evidence for the involvement of the genes GABRB3 and GABRA5 in the susceptibility to panic disorder (PMID:24755890)
• 1,2-dichlorohexafluorocyclobutane enhancement of GABRA5 activity is abolished by GABRB3 mutations. (PMID:25211390)
• This study showed that in male groups, the expression of GABRA5 was generally lower in schizophrenia cases compared to the control. (PMID:25660468)
• Study found that a significant portion of GABAergic postsynaptic compartments contain the alpha5 GABAAR subunit, both in vitro and in vivo (PMID:25663431)
• Report benzodiazepine derivative as GABA-site inhibitor of extra-synaptic GABAA alpha5 receptors. (PMID:26169564)
• Study found a significant reduction in [(11)C]Ro15 4513 binding in the nucleus accumbens in an opiate-dependent compared with the healthy control group. Study suggests that reduced GABA A receptor alpha5 levels in the nucleus accumbens are associated with addiction. (PMID:26876472)
• GABAA receptor gene polymorphisms can predict symptom-based and developmental deficits in autistic spectrum disorders individuals. (PMID:28607477)
• Meta-analysis showed that GABRA5 polymorphisms are not significantly associated with autism. (PMID:29725984)
• Low GABRA5 expression typified hyperproliferative tumors, and loss of taurine signaling correlated with reduced patient survival, suggesting this tumor suppressive mechanism operates in vivo. (PMID:29787571)
• The GABRA5 p.V294L variant produced receptors that were 10-times more sensitive to GABA but had reduced maximal GABA-evoked current due to increased receptor desensitization. (PMID:29961870)
• cryo-EM structure of the human alpha5beta3 GABAA receptor (PMID:30140029)
• both total GABAA and GABAA alpha5 receptor availability in two positron emission tomography imaging studies, are reported. (PMID:30282698)
• study identified GABRA5 as a causative gene for early onset epileptic encephalopathy and expands the mutant GABRA1 phenotypic spectrum, supporting growing evidence that defects in GABAergic neurotransmission contribute to early onset epileptic encephalopathy phenotypes. (PMID:31056671)
• Sex Differences in the Expression of the alpha5 Subunit of the GABAA Receptor in Alcoholics with and without Cirrhosis of the Liver. (PMID:31840824)
• An association study in the Taiwan Biobank elicits the GABAA receptor genes GABRB3, GABRA5, and GABRG3 as candidate loci for sleep duration in the Taiwanese population. (PMID:34530807)
• GABA Receptor SNPs and Elevated Plasma GABA Levels Affect the Severity of the Indian ASD Probands. (PMID:35562522)
• Effects of alpha5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer’s disease. (PMID:35822698)
• Novel variants in GABAA receptor subunits: A possible association with benzodiazepine resistance in patients with drug-resistant epilepsy. (PMID:36469977)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gabra5	ENSDARG00000070730
mus_musculus	Gabra5	ENSMUSG00000055078
rattus_norvegicus	Gabra5	ENSRNOG00000010803

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), GABRR1 (ENSG00000146276), 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), ZACN (ENSG00000186919), GABRD (ENSG00000187730), CHRNG (ENSG00000196811), GABRQ (ENSG00000268089)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:95617) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 29 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal spatial learning	2
abnormal cochlea morphology	1
abnormal heart morphology	1
enlarged heart	1
abnormal spleen morphology	1
small spleen	1
abnormal thymus morphology	1
enlarged thymus	1
abnormal testis morphology	1
small testis	1
abnormal contextual conditioning behavior	1
abnormal long-term potentiation	1
cochlear ganglion degeneration	1
abnormal inhibitory postsynaptic currents	1
abnormal GABA-mediated receptor currents	1
cochlear inner hair cell degeneration	1
cochlear outer hair cell degeneration	1
type IV spiral ligament fibrocyte degeneration	1
abnormal cochlear OHC efferent innervation pattern	1
abnormal distortion product otoacoustic emission	1
sensorineural hearing loss	1
abnormal hippocampus CA1 region morphology	1
decreased prepulse inhibition	1
enhanced cued conditioning behavior	1
abnormal behavioral response to xenobiotic	1

+4 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca mulatta	D1LYT2	100.0%	Diamond
Drosophila melanogaster	P25123	99.8%	Diamond
Bos taurus	P57695	99.8%	Diamond
Macaca fascicularis	Q4R534	99.8%	Diamond
Pongo abelii	Q5RCC5	99.8%	Diamond
Drosophila simulans	Q9BLY8	99.8%	Diamond
Gallus gallus	P19150	96.9%	Diamond
Musca domestica	Q75NA5	84.3%	Diamond
Haemonchus contortus	P91730	81.4%	Diamond
Caenorhabditis elegans	Q17328	81.4%	Diamond
Lymnaea stagnalis	P26714	58.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
GABRG3	protein-coding	2567
GABRB3	protein-coding	2562
LINC02248	ncRNA	107984780
GABRG3-AS1	ncRNA	101928869
OCA2	protein-coding	4948
HERC2	protein-coding	8924

Protein

Protein identifiers

Gamma-aminobutyric acid receptor subunit alpha-5 — P31644 (reviewed: P31644)

Alternative names: GABA(A) receptor subunit alpha-5

All UniProt accessions (7): P31644, G3V296, G3V2G8, G3V2K2, G3V2Q9, G3V2Y5, G3V408

UniProt curated annotations — full annotation on UniProt →

Function. Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain. GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s). When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient. GABAARs containing alpha-5/GABRA5 subunits are mainly extrasynaptic and contribute to the tonic GABAergic inhibition in the hippocampus. Extrasynaptic alpha-5-containing GABAARs in CA1 pyramidal neurons play a role in learning and memory processes.

Subunit / interactions. Heteropentamer, formed by a combination of alpha (GABRA1-6), beta (GABRB1-3), gamma (GABRG1-3), delta (GABRD), epsilon (GABRE), rho (GABRR1-3), pi (GABRP) and theta (GABRQ) chains, each subunit exhibiting distinct physiological and pharmacological properties.

Subcellular location. Postsynaptic cell membrane. Cell membrane.

Disease relevance. Developmental and epileptic encephalopathy 79 (DEE79) [MIM:618559] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE79 is an autosomal dominant form characterized by onset of refractory seizures in the first months of life. Brain imaging may show hypomyelination, cerebral atrophy and thinning of the corpus callosum. The disease is caused by variants affecting the gene represented in this entry.

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. GABRA5 sub-subfamily.

RefSeq proteins (2): NP_000801, NP_001158509 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001390	GABAAa_rcpt	Family
IPR005435	GABBAa5_rcpt	Family
IPR006028	GABAA/Glycine_rcpt	Family
IPR006029	Neurotrans-gated_channel_TM	Domain
IPR006201	Neur_channel	Family
IPR006202	Neur_chan_lig-bd	Domain
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
IPR047024	Gabra-1-6_TM	Domain

Pfam: PF02931, PF02932

Catalyzed reactions (Rhea)

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

UniProt features (54 total): strand 15, helix 9, turn 7, topological domain 5, glycosylation site 4, transmembrane region 4, sequence variant 3, binding site 2, signal peptide 1, chain 1, region of interest 1, disulfide bond 1, cross-link 1

Structure

Experimental structures (PDB)

23 structures by resolution:

PDB	Title	Method	Resolution (Å)
8BHG	GABA-A receptor a5 heteromer - a5V2 - Bretazenil	X-RAY DIFFRACTION	2.39
8BHB	GABA-A receptor a5 homomer - a5V3 - RO154513	ELECTRON MICROSCOPY	2.54
8BGI	GABA-A receptor a5 homomer - a5V1 - Flumazenil	X-RAY DIFFRACTION	2.56
8BHA	GABA-A receptor a5 homomer - a5V3 - Basmisanil - HR	ELECTRON MICROSCOPY	2.67
8BHI	GABA-A receptor a5 homomer - a5V3 - RO5211223	ELECTRON MICROSCOPY	2.67
8BHO	GABA-A receptor a5 homomer - a5V3 - L655708	ELECTRON MICROSCOPY	2.93
8BHM	GABA-A receptor a5 homomer - a5V3 - DMCM	ELECTRON MICROSCOPY	2.95
9HNS	a5b3 GABAAR bound to GABA and Mb25 in a desensitized state in saposin nanodiscs after …	ELECTRON MICROSCOPY	3.1
9RL5	a5b3 GABAAR bound to Topiramate, GABA, and Mb25 in a desensitized state in saposin …	ELECTRON MICROSCOPY	3.1
9RPB	a5b3 GABAAR bound to GABA, and Mb25 in a desensitized state in saposin nanodiscs …	ELECTRON MICROSCOPY	3.1
9HAA	a5b3 GABAA Receptor resting state	ELECTRON MICROSCOPY	3.14
9HNR	a5b3 GABAA Receptor in 1 a5 to 4 b3 stoichiometry in desensitized state	ELECTRON MICROSCOPY	3.17
5O8F	Structure of a chimaeric beta3-alpha5 GABAA receptor in complex with nanobody Nb25 and …	X-RAY DIFFRACTION	3.2
8BEJ	GABA-A receptor a5 homomer - a5V3 - APO	ELECTRON MICROSCOPY	3.24
8BHS	GABA-A receptor a5 homomer - a5V3 - RO4938581	ELECTRON MICROSCOPY	3.24
5OJM	Structure of a chimaeric beta3-alpha5 GABAA receptor in complex with nanobody Nb25	X-RAY DIFFRACTION	3.3
8BHK	GABA-A receptor a5 homomer - a5V3 - Diazepam	ELECTRON MICROSCOPY	3.3
8BHQ	GABA-A receptor a5 homomer - a5V3 - RO7172670	ELECTRON MICROSCOPY	3.3
9HNT	a5b3 GABAAR bound to Etomidate, GABA, and Mb25 in a desensitized state in saposin …	ELECTRON MICROSCOPY	3.32
9HUM	a5b3 GABAAR bound to GABA and Mb25 in a desensitized state in saposin nanodiscs after …	ELECTRON MICROSCOPY	3.35
8BHR	GABA-A receptor a5 homomer - a5V3 - RO7015738	ELECTRON MICROSCOPY	3.38
6A96	Cryo-EM structure of the human alpha5beta3 GABAA receptor in complex with GABA and Nb25	ELECTRON MICROSCOPY	3.51
9HNQ	a5b3 GABAA Receptor bound to GABA and Mb25 in desensitized state in detergent micelles	ELECTRON MICROSCOPY	3.81

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31644-F1	81.67	0.61

Antibody-complex structures (SAbDab)

3 antibodies co-crystallized with this protein: 5O8F, 5OJM, 6A96

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Predicted membrane proteins, Predicted intracellular proteins, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes, Epilepsy

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane; actin filaments; cytosol; nucleoplasm

Antibody reliability (HPA): IF supported

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 (2)

Position	Role
101	4-aminobutanoate
164	4-aminobutanoate

Post-translational modifications (1)

Type	Positions
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	355

Disulfide bonds (1)

Type	Positions
Disulfide bond	173–187

Glycosylation sites (4)

Type	Positions
N-linked (glcnac…) asparagine	45, 145, 207, 236

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-977443	GABA receptor activation	electronic
R-HSA-112316	Neuronal System	—
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission	—
R-HSA-112315	Transmission across Chemical Synapses	—

MSigDB gene sets: 274 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_EPITHELIUM_DEVELOPMENT, TAATAAT_MIR126, GOBP_COGNITION, MODULE_274, GOBP_BEHAVIOR, GOBP_SYNAPSE_ASSEMBLY, GOBP_ASSOCIATIVE_LEARNING, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_GAMMA_AMINOBUTYRIC_ACID_SIGNALING_PATHWAY, GOBP_NEUROGENESIS, GOBP_MULTICELLULAR_ORGANISMAL_RESPONSE_TO_STRESS, GOBP_CELL_CELL_SIGNALING, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_CELL_JUNCTION_ORGANIZATION

GO Biological Process (15): signal transduction (GO:0007165), gamma-aminobutyric acid signaling pathway (GO:0007214), synaptic transmission, GABAergic (GO:0051932), inner ear receptor cell development (GO:0060119), innervation (GO:0060384), cochlea development (GO:0090102), chloride transmembrane transport (GO:1902476), inhibitory synapse assembly (GO:1904862), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), chemical synaptic transmission (GO:0007268), monoatomic ion transmembrane transport (GO:0034220), neuron development (GO:0048666), regulation of postsynaptic membrane potential (GO:0060078), regulation of presynaptic membrane potential (GO:0099505)

GO Molecular Function (10): GABA-A receptor activity (GO:0004890), GABA-gated chloride ion channel activity (GO:0022851), signaling receptor activity (GO:0038023), GABA receptor binding (GO:0050811), ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential (GO:0099507), transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential (GO:1904315), 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)

GO Cellular Component (14): plasma membrane (GO:0005886), dendrite membrane (GO:0032590), neuronal cell body membrane (GO:0032809), chloride channel complex (GO:0034707), presynaptic membrane (GO:0042734), postsynapse (GO:0098794), GABA-ergic synapse (GO:0098982), postsynaptic specialization membrane (GO:0099634), GABA-A receptor complex (GO:1902711), membrane (GO:0016020), dendrite (GO:0030425), signaling receptor complex (GO:0043235), cell body (GO:0044297), postsynaptic membrane (GO:0045211)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Neurotransmitter receptors and postsynaptic signal transmission	1
Transmission across Chemical Synapses	1
Neuronal System	1

GO top-level categories

58 GO namespaces:

Category	Terms
synaptic membrane	3
cellular anatomical structure	3
GABA receptor activity	2
regulation of membrane potential	2
transmitter-gated monoatomic ion channel activity	2
ligand-gated monoatomic ion channel activity	2
synapse	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell-cell signaling	1
chemical synaptic transmission	1
neuron development	1
inner ear receptor cell differentiation	1
nerve development	1
multicellular organismal process	1
inner ear development	1
animal gross anatomical part developmental process	1
chloride transport	1
monoatomic anion transmembrane transport	1
synapse assembly	1
transport	1
monoatomic anion transport	1
inorganic anion transport	1
anterograde trans-synaptic signaling	1
monoatomic ion transport	1
transmembrane transport	1
neuron differentiation	1
cell development	1
chloride channel activity	1
ligand-gated monoatomic anion channel activity	1
molecular transducer activity	1
signaling receptor binding	1
presynaptic membrane	1
regulation of presynaptic membrane potential	1
regulation of postsynaptic 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
membrane	1
cell periphery	1
dendrite	1
neuron projection membrane	1
neuronal cell body	1
cell body membrane	1
monoatomic ion channel complex	1
presynapse	1
postsynaptic membrane	1
postsynaptic specialization	1
GABA receptor complex	1
neuron projection	1
dendritic tree	1
protein-containing complex	1
postsynapse	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 2 of 39 annotations. The rest are phylogenetic / computational / electronic (IEA).

2 experimentally-supported GO terms:

GO term	NS	Evidence
plasma membrane	CC	direct assay
ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,272 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GABRA5	SLC6A1	P30531	852
GABRA5	SLC6A13	Q9NSD5	799
GABRA5	SLC6A11	P48066	742
GABRA5	UBE3A	P78355	711
GABRA5	GABRB3	P28472	690
GABRA5	GABRG3	Q99928	648
GABRA5	ATP10A	O60312	593
GABRA5	GABBR2	O75899	579
GABRA5	CFAP74	Q9C0B2	547
GABRA5	SNRPN	P14648	540
GABRA5	MAGEL2	Q9UJ55	539
GABRA5	NIPA1	Q7RTP0	528
GABRA5	MECP2	P51608	528
GABRA5	MKRN3	Q13064	527
GABRA5	GRIA3	P42263	517

IntAct

Human interaction partners of GABRA5 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
GABRB3	direct interaction	0.360	1

BioGRID (9 interactions; top human partners by supporting records): GABRA3 (Affinity Capture-MS; 2 records), SQSTM1 (Affinity Capture-MS), TNKS (Proximity Label-MS)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
GABRA5	“form complex”	“GABA-A (a5-b1-g2) receptor”	binding
PCDH19	“up-regulates quantity by stabilization”	GABRA5	binding

Ligand–receptor pairs (CellPhoneDB) (1)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

1 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
GABRA5;GABRB3;GABRG2		Signaling by GABA

Disease & clinical

Genetic variants

Variant evidence for GABRA5: 162 ClinVar records (9 pathogenic / likely pathogenic); 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	1
Uncertain significance	85
Likely benign	45
Benign	11

Top pathogenic / likely-pathogenic (9)

Showing all 9 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1207653	NM_000810.4(GABRA5):c.871G>C (p.Val291Leu)	Likely pathogenic	criteria provided, single submitter	1
625713	GRCh37/hg19 15q11.2-13.1(chr15:22770994-29050198)	Pathogenic	criteria provided, single submitter	1
1012382	GRCh37/hg19 15q11.2-12(chr15:22833525-27193380)x4	Pathogenic	criteria provided, single submitter	1
1456510	NC_000015.9:g.(?26792940)(28544682_?)del	Pathogenic	criteria provided, single submitter	1
689391	NM_000810.4(GABRA5):c.880G>C (p.Val294Leu)	Pathogenic	no assertion criteria provided	1
689393	NM_000810.4(GABRA5):c.1238C>T (p.Ser413Phe)	Pathogenic	no assertion criteria provided	1
395546	GRCh37/hg19 15q11.2-13.1(chr15:23707452-28406650)x1	Pathogenic	no assertion criteria provided	1
441588	GRCh37/hg19 15q11.2-13.1(chr15:22770421-29062203)x1	Pathogenic	no assertion criteria provided	1
443863	GRCh37/hg19 15q11.2-13.1(chr15:23615769-28561097)x3	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore GABRA5’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 37 predictions of 1,090):

Position(s)	Effect	Δscore	Sites
15:26869260	donor_gain	1.0000
15:26880842–26880844	acceptor_gain	1.0000	3
15:26880844–26880845	acceptor_loss	1.0000	5
15:26880968–26880969	donor_loss	1.0000	5
15:26883333	acceptor_gain	1.0000
15:26883335–26883336	acceptor_loss	1.0000	5
15:26883558–26883559	donor_loss	1.0000	5
15:26937183–26937184	acceptor_loss	1.0000	6
15:26937329–26937330	donor_loss	1.0000	5
15:26943199	acceptor_gain	1.0000

AlphaMissense

1,727 missense substitutions predicted likely pathogenic (of 3,066 scored), across 320 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M92	9	0.981	1.000
M300	9	0.957	0.999
M270	9	0.937	1.000
M165	9	0.932	0.995
M175	9	0.926	0.999
M320	9	0.923	0.996
M182	9	0.903	0.997
D321	8	1.000	1.000
D106	8	0.999	1.000
H144	8	0.999	1.000
D183	8	0.999	1.000
D97	8	0.998	0.999
D132	8	0.998	1.000
D426	8	0.998	1.000
D61	8	0.997	1.000
F279	8	0.997	1.000
F433	8	0.992	1.000
F332	8	0.991	0.999
F100	8	0.989	0.999
F135	8	0.989	0.999

HPA cancer prognostics

RNA cancer specificity: Group enriched (Glioblastoma Multiforme, Lung Squamous Cell Carcinoma, Skin Cutaneous Melanoma, Testicular Germ Cell Tumor)

Disease associations

OMIM: gene MIM:137142 | disease phenotypes: MIM:618559

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
developmental and epileptic encephalopathy, 79	Strong	Autosomal dominant	3
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Early onset or syndromic epilepsy	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (2): developmental and epileptic encephalopathy, 79 (MONDO:0032813), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

HPO phenotypes

60 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001270	Motor delay
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001315	Diminished deep tendon reflex
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001508	Failure to thrive
HP:0001558	Decreased fetal movement
HP:0002020	Gastroesophageal reflux
HP:0002059	Cerebral atrophy
HP:0002063	Rigidity
HP:0002079	Hypoplasia of the corpus callosum
HP:0002120	Cerebral cortical atrophy
HP:0002133	Status epilepticus
HP:0002317	Unsteady gait
HP:0002376	Developmental regression
HP:0002421	Poor head control
HP:0002509	Limb hypertonia
HP:0002521	Hypsarrhythmia
HP:0003429	CNS hypomyelination
HP:0004305	Involuntary movements
HP:0004322	Short stature
HP:0005484	Secondary microcephaly
HP:0006892	Frontotemporal cerebral atrophy
HP:0007018	Attention deficit hyperactivity disorder
HP:0010844	EEG with multifocal slow activity
HP:0010864	Severe intellectual disability
HP:0011443	Abnormality of coordination
HP:0011968	Feeding difficulties
HP:0012444	Brain atrophy
HP:0012447	Abnormal myelination
HP:0012547	Abnormal involuntary eye movements
HP:0025190	Bilateral tonic-clonic seizure with generalized onset
HP:0032786	Migrating focal seizure
HP:0032792	Tonic seizure
HP:0032794	Myoclonic seizure
HP:0100660	Dyskinesia
HP:0100710	Impulsivity

GWAS associations

4 associations:

Study	Trait	p-value
GCST004904_93	Body mass index	3e-8
GCST008170_3	Thyroglobulin plasma levels	2e-6
GCST010577_16	Crohn’s disease	3e-6
GCST009391_1978	Metabolite levels	6e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0010050	thyroglobulin measurement
EFO:0010372	phosphatidylcholine 32:0 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (9): CHEMBL2093872 (PROTEIN COMPLEX GROUP), CHEMBL2094122 (PROTEIN COMPLEX), CHEMBL2109243 (PROTEIN COMPLEX GROUP), CHEMBL2109244 (PROTEIN COMPLEX GROUP), CHEMBL3885576 (PROTEIN COMPLEX), CHEMBL3885577 (PROTEIN COMPLEX), CHEMBL4296057 (PROTEIN COMPLEX), CHEMBL4523641 (PROTEIN COMPLEX), CHEMBL5112 (SINGLE PROTEIN)

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes GABRA5 — the drug acts on the assembly or class, not necessarily on this subunit alone.

1 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
ZOPICLONE	GABA-A receptor; agonist GABA site	9	4

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 417,751 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

27 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL661	ALPRAZOLAM	4	131,051
CHEMBL3183409	APALUTAMIDE	4	4,347
CHEMBL207538	BREXANOLONE	4	1,647
CHEMBL451	CHLORDIAZEPOXIDE	4	36,835
CHEMBL452	CLONAZEPAM	4	33,611
CHEMBL12	DIAZEPAM	4	92,923
CHEMBL1082407	ENZALUTAMIDE	4	10,210
CHEMBL407	FLUMAZENIL	4	7,208
CHEMBL13280	FLUNITRAZEPAM	4	11,627
CHEMBL1568698	GANAXOLONE	4	1,695
CHEMBL1544	LIOTHYRONINE	4	23,991
CHEMBL526	PROPOFOL	4	29,086
CHEMBL646	TRIAZOLAM	4	21,762
CHEMBL454095	ABECARNIL	2	566
CHEMBL1783282	AZD7325	2	80
CHEMBL8260	BAICALEIN	2	8,718
CHEMBL3681419	BASMISANIL	2	107
CHEMBL366947	BRETAZENIL	2	825
CHEMBL3647536	DARIGABAT	2	147
CHEMBL268254	DELORAZEPAM	2	1,315
CHEMBL275638	FLAVONE	2
CHEMBL200177	MK-0777	2
CHEMBL287631	PROGABIDE	2
CHEMBL73416	SARIPIDEM	2
CHEMBL1783256	AZD6280	1
CHEMBL96	GAMMA-AMINOBUTYRIC ACID	1
CHEMBL273481	MUSCIMOL	1

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — GABA_A receptors

Most potent curated ligand interactions (10 total), top 10:

Ligand	Action	Affinity	Parameter
CGS8216	Inverse agonist	9.6	pKi
flumazenil	Allosteric modulator	9.22	pKi
[3H]RY80	Binding	9.2	pKd
ZK93423	Partial agonist	8.4	pKi
triazolam	Positive	8.4	pKd
compound 20 [PMID: 35584373]	Negative	8.39	pKd
basmisanil	Negative	8.33	pKi
flunitrazepam	Positive	8.26	pKi
ONO-8590580	Negative	8.1	pKi
alprazolam	Positive	8.0	pEC50

Binding affinities (BindingDB)

2181 measured of 2279 human assays (2286 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-(4-Ethynyl-phenyl)-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one	KI	0.03 nM
PHENAZEPAM	KI	0.05 nM
8-Ethynyl-2-phenyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one	KI	0.06 nM
2-Phenyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one (CGS 8216)	KI	0.08 nM
8-Bromo-2-phenyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one	KI	0.08 nM
6-[2-[[3-(5-chloro-2-pyridinyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-2-hydroxyethyl]pyridine-3-carboxamide	KI	0.1 nM	US-8846719: Isoxazolo-pyridine derivatives
2’-fluoro-5’-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-1,1’-biphenyl-2-carbonitrile	KI	0.1 nM
CHEMBL5280240	KI	0.1 nM
2-(4-Methoxy-phenyl)-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one (CGS 9895)	KD	0.1 nM
PW-007A	KI	0.1 nM
CHEMBL4476044	KI	0.12 nM
8-Hydroxy-5-methyl-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid tert-butyl ester	KI	0.14 nM
4-(2-fluoro-5-(7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyrimidin-3-yl)phenyl)nicotinonitrile	KI	0.14 nM
3-Phenyl-6-(pyridazin-3-ylmethoxy)-[1,2,4]triazolo[3,4-a]phthalazine	KI	0.15 nM
5’-(7-ethyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-2’,4-difluoro-1,1’-biphenyl-2-carbonitrile	KI	0.15 nM
8-Chloro-2-phenyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one	KI	0.17 nM
2’,6-difluoro-5’-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-1,1’-biphenyl-2-carbonitrile	KI	0.19 nM
6-[[3-(5-chloro-2-pyridinyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-N-(oxan-4-yl)pyridine-3-carboxamide	KI	0.2 nM	US-20240279218: ISOXAZOLYL ETHER DERIVATIVES AS GABA A ALPHA5 PAM
6-[1-[[3-(5-chloro-2-pyridinyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-2,2,2-trifluoroethyl]pyridine-3-carboxamide	KI	0.2 nM	US-8846719: Isoxazolo-pyridine derivatives
ethyl 3-fluoro-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine-10-carboxylate	KI	0.2 nM
3-(3-fluoro-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepin-10-yl)-5-methyl-1,2,4-oxadiazole	KI	0.2 nM
CHEMBL566181	KI	0.2 nM
CHEMBL567243	KI	0.2 nM
CHEMBL571466	KI	0.2 nM
CHEMBL566189	KI	0.2 nM
2-(4-Bromo-phenyl)-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one	KI	0.21 nM
3’-(7-trifluoromethyl-imidazo[1,2-a]pyrimidin-3-yl)-biphenyl-2-carbonitrile	KI	0.21 nM
CHEMBL4303594	KI	0.23 nM
5,2-difluoro-5-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile	KI	0.26 nM
CHEMBL3274851	KI	0.26 nM
4-(6-((1-(4-(Difluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridazin-3-yl)-5,6-dihydropyridin-2(1H)-one	KI	0.27 nM	US-20250136581: SUBSTITUTED TRIAZOLE DERIVATIVE, PREPARATION METHOD THEREFOR, PHARMACEUTICAL COMPOSITION THEREOF, AND USE THEREOF
8-Methoxy-5-methyl-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid tert-butyl ester	KI	0.29 nM
6-[[3-(5-fluoro-2-pyridinyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-N-(2,2,2-trifluoroethyl)pyridine-3-carboxamide	KI	0.3 nM	US-8846719: Isoxazolo-pyridine derivatives
6-[[3-(5-chloro-2-pyridinyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-N-propan-2-ylpyridine-3-carboxamide	KI	0.3 nM	US-8846719: Isoxazolo-pyridine derivatives
6-[[3-(5-chloro-2-pyridinyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-N-cyclopropylpyridine-3-carboxamide	KI	0.3 nM	US-8846719: Isoxazolo-pyridine derivatives
6-[[3-(5-fluoropiperidin-2-yl)-5-methyl-1,2-oxazol-4-yl]methoxy]-N-propan-2-ylpyridine-3-carboxamide	KI	0.3 nM	US-8846719: Isoxazolo-pyridine derivatives
6-[[3-(5-chloro-2-pyridinyl)-5-methyl-1,2-oxazol-4-yl]methoxy-cyclopropylmethyl]pyridine-3-carboxamide	KI	0.3 nM	US-8846719: Isoxazolo-pyridine derivatives
7-tert-butyl-6-((2-ethyl-2H-1,2,4-triazol-3-yl)methoxy)-3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine	KI	0.3 nM
3-(2,6-difluorophenyl)-5-[4-fluoro-3-(3-fluoropyridin-2-yl)-phenyl]pyridazine	KI	0.3 nM
10-chloro-3-fluoro-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine	KI	0.3 nM
10-chloro-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine	KI	0.3 nM
CHEMBL565560	KI	0.3 nM
CHEMBL1783282	KI	0.309 nM
2-(3-(4-fluoro-3-(pyridin-4-yl)phenyl)imidazo[1,2-a]pyrimidin-7-yl)propan-2-ol	KI	0.31 nM
8-Chloro-2-(4-methoxy-phenyl)-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one	KI	0.32 nM
3-(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl) methoxy)pyridazin-3-yl)-5,6-dihydro- 8H-[1,2,4]triazolo[3,4-c][1,4]oxazine	KI	0.32 nM	US-20250215016: ISOXAZOLE-HETEROCYCLIC DERIVATIVE, PHARMACEUTICAL COMPOSITION AND USE
2’,4-difluoro-5’-(7-methyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)-1,1’-biphenyl-2-carbonitrile	KI	0.39 nM
6-[[3-(5-fluoro-2-pyridinyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-N-(2-hydroxyethyl)pyridine-3-carboxamide	KI	0.4 nM	US-8846719: Isoxazolo-pyridine derivatives
6-[[3-(5-fluoropiperidin-2-yl)-5-methyl-1,2-oxazol-4-yl]methoxy]-N-(oxan-4-yl)pyridine-3-carboxamide	KI	0.4 nM	US-8846719: Isoxazolo-pyridine derivatives
N-(cyclopropylmethyl)-6-[[3-(5-fluoropiperidin-2-yl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridine-3-carboxamide	KI	0.4 nM	US-8846719: Isoxazolo-pyridine derivatives

ChEMBL bioactivities

1961 potent at pChembl≥5 of 2018 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.10	Ki	0.08	nM	CHEMBL3144696
10.00	IC50	0.1	nM	CHEMBL454349
10.00	Ki	0.1	nM	CHEMBL436768
10.00	Ki	0.1	nM	CHEMBL202696
10.00	Ki	0.1	nM	CHEMBL3681588
9.92	Ki	0.12	nM	CHEMBL199957
9.92	Ki	0.12	nM	CHEMBL4476044
9.92	Ki	0.12	nM	CHEMBL4243764
9.85	Ki	0.14	nM	CHEMBL383677
9.85	Ki	0.14	nM	CHEMBL130609
9.82	Ki	0.15	nM	CHEMBL206587
9.82	Ki	0.15	nM	CHEMBL300615
9.80	IC50	0.16	nM	CHEMBL309517
9.77	Ki	0.17	nM	CHEMBL3144849
9.77	Ki	0.17	nM	CHEMBL299210
9.72	Ki	0.19	nM	CHEMBL361129
9.72	Ki	0.19	nM	CHEMBL206380
9.70	Ki	0.2	nM	CHEMBL178677
9.70	Ki	0.2	nM	MK-0777
9.70	Ki	0.2	nM	CHEMBL381380
9.70	Ki	0.2	nM	CHEMBL3681586
9.70	IC50	0.2	nM	CHEMBL4747460
9.70	Ki	0.2	nM	CHEMBL566181
9.70	Ki	0.2	nM	CHEMBL567243
9.70	Ki	0.2	nM	CHEMBL571466
9.70	Ki	0.2	nM	CHEMBL566189
9.70	Ki	0.2	nM	CHEMBL1079870
9.70	Ki	0.2	nM	CHEMBL1078299
9.70	Ki	0.2	nM	CHEMBL3144841
9.68	Ki	0.21	nM	CHEMBL361114
9.68	Ki	0.21	nM	CHEMBL199689
9.64	Ki	0.23	nM	CHEMBL4303594
9.62	IC50	0.24	nM	CHEMBL79037
9.60	Ki	0.25	nM	CGS-8216
9.59	Ki	0.26	nM	CHEMBL362282
9.59	Ki	0.26	nM	CHEMBL202768
9.59	Ki	0.26	nM	CHEMBL3274851
9.57	Ki	0.27	nM	Ro-154513
9.54	Ki	0.29	nM	CHEMBL360122
9.54	Ki	0.29	nM	CHEMBL133049
9.53	Ki	0.293	nM	CHEMBL133049
9.52	Ki	0.3	nM	CHEMBL203286
9.52	Ki	0.3	nM	CHEMBL3676421
9.52	Ki	0.3	nM	CHEMBL3676424
9.52	Ki	0.3	nM	CHEMBL3676425
9.52	Ki	0.3	nM	CHEMBL3676426
9.52	Ki	0.3	nM	CHEMBL3676436
9.52	Ki	0.3	nM	CHEMBL3681585
9.52	Ki	0.3	nM	CHEMBL4060185
9.52	Ki	0.3	nM	CHEMBL5268764

PubChem BioAssay actives

1492 with measured affinity, of 2743 total; 50 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-(4-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-3-one	40988: Inhibition on Benzodiazepine receptor	ic50	0.0001	uM
5-fluoro-2-[2-fluoro-5-[7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]benzonitrile	259132: Displacement of [3H]Ro-151788 from human recombinant GABAA alpha5 in combination with beta3gamma2 expressed in L(tk-) cells	ki	0.0001	uM
tert-butyl 8-hydroxy-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate	73523: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-5-beta-3-gamma-2	ki	0.0001	uM
3-phenyl-6-(pyridazin-3-ylmethoxy)-[1,2,4]triazolo[3,4-a]phthalazine	72625: Binding affinity for human GABA-A receptor alpha-5-beta-3-gamma-2 subunits in L(tk-) cells	ki	0.0001	uM
2-[5-(7-ethyl-8-oxoimidazo[1,2-a]pyrazin-3-yl)-2-fluorophenyl]-5-fluorobenzonitrile	262297: Displacement of [3H]Ro-151788 from human recombinant GABA-Aalpha5 receptor plus beta3gamma2	ki	0.0001	uM
8-ethynyl-2-phenyl-1H-pyrazolo[4,3-c]quinolin-3-one	73523: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-5-beta-3-gamma-2	ki	0.0001	uM
2-[3-[5-(2-hydroxypropan-2-yl)benzimidazol-1-yl]phenyl]benzonitrile	1604549: Displacement of [3H]-Ro15-1788 from human GABAA alpha5beta3gamma2 expressed in HEK293 cell membranes incubated for 40 or 90 mins by liquid scintillation counting method	ki	0.0001	uM
8-bromo-2-phenyl-1H-pyrazolo[4,3-c]quinolin-3-one	73523: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-5-beta-3-gamma-2	ki	0.0001	uM
4-[2-fluoro-5-[7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]pyridine-3-carbonitrile	262147: Displacement of [3H]Ro 15-1788 from recombinant human GABA-Aalpha5 receptor plus beta-3-gamma-2 expressed in L(tk-) cells	ki	0.0001	uM
2-[3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl]benzonitrile	259132: Displacement of [3H]Ro-151788 from human recombinant GABAA alpha5 in combination with beta3gamma2 expressed in L(tk-) cells	ki	0.0001	uM
2-[2-fluoro-5-(7-methyl-8-oxoimidazo[1,2-a]pyrazin-3-yl)phenyl]benzonitrile	262297: Displacement of [3H]Ro-151788 from human recombinant GABA-Aalpha5 receptor plus beta3gamma2	ki	0.0001	uM
8-methoxy-2-phenyl-1H-pyrazolo[4,3-c]quinolin-3-one	73523: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-5-beta-3-gamma-2	ki	0.0002	uM
2-(4-ethynylphenyl)-1H-pyrazolo[4,3-c]quinolin-3-one	73523: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-5-beta-3-gamma-2	ki	0.0002	uM
6-phenyl-9-[(2-propyl-1,2,4-triazol-3-yl)methoxy]-4,5,7,8-tetrazatetracyclo[9.2.2.02,10.03,7]pentadeca-2(10),3,5,8-tetraene	239566: Inhibition of [3H]Ro-151788 binding to recombinant human gamma-aminobutyric-acid A receptor alpha-5-beta-3-gamma-2 subtype expressed in L (tk-) cells	ki	0.0002	uM
9-[(1-benzylimidazol-2-yl)methoxy]-6-phenyl-4,5,7,8-tetrazatetracyclo[9.2.2.02,10.03,7]pentadeca-2(10),3,5,8-tetraene	239566: Inhibition of [3H]Ro-151788 binding to recombinant human gamma-aminobutyric-acid A receptor alpha-5-beta-3-gamma-2 subtype expressed in L (tk-) cells	ki	0.0002	uM
6-[(1-methylimidazol-2-yl)methoxy]-3-phenyl-[1,2,4]triazolo[3,4-a]phthalazine	72625: Binding affinity for human GABA-A receptor alpha-5-beta-3-gamma-2 subunits in L(tk-) cells	ki	0.0002	uM
9-[(3,5-dimethyl-2-pyridinyl)methoxy]-6-phenyl-4,5,7,8-tetrazatetracyclo[9.2.2.02,10.03,7]pentadeca-2(10),3,5,8-tetraene	239566: Inhibition of [3H]Ro-151788 binding to recombinant human gamma-aminobutyric-acid A receptor alpha-5-beta-3-gamma-2 subtype expressed in L (tk-) cells	ki	0.0002	uM
ethyl 15-methoxy-2,4,8,9,11-pentazatetracyclo[11.4.0.02,6.08,12]heptadeca-1(13),3,5,9,11,14,16-heptaene-5-carboxylate	448426: Binding affinity to GABAA alpha-5-beta-3-gamma-2 receptor	ki	0.0002	uM
ethyl 4-(methoxymethyl)-5-phenylmethoxy-9H-pyrido[3,4-b]indole-3-carboxylate	1932290: Displacement of [3H]flunitrazepam from GABAA (unknown origin ) receptor by radioligand binding assay	ic50	0.0002	uM
3-(15-fluoro-2,4,8,9,11-pentazatetracyclo[11.4.0.02,6.08,12]heptadeca-1(13),3,5,9,11,14,16-heptaen-5-yl)-5-methyl-1,2,4-oxadiazole	468635: Displacement of [3H]Flumazenil from cloned human GABA alpha-5-beta-3-gamma-2 receptor expressed in HEK293 cells	ki	0.0002	uM
ethyl 2,4,8,9,11-pentazatetracyclo[11.4.0.02,6.08,12]heptadeca-1(17),3,5,9,11,13,15-heptaene-5-carboxylate	448426: Binding affinity to GABAA alpha-5-beta-3-gamma-2 receptor	ki	0.0002	uM
ethyl 15-chloro-2,4,8,9,11-pentazatetracyclo[11.4.0.02,6.08,12]heptadeca-1(13),3,5,9,11,14,16-heptaene-5-carboxylate	448426: Binding affinity to GABAA alpha-5-beta-3-gamma-2 receptor	ki	0.0002	uM
ethyl 15-fluoro-2,4,8,9,11-pentazatetracyclo[11.4.0.02,6.08,12]heptadeca-1(13),3,5,9,11,14,16-heptaene-5-carboxylate	468641: Displacement of [3H]Flumazenil from human GABA alpha-5-beta-3-gamma-2 receptor expressed in insect SF9 cells	ki	0.0002	uM
7-cyclobutyl-3-(2,6-difluorophenyl)-6-[(2-methyl-1,2,4-triazol-3-yl)methoxy]-[1,2,4]triazolo[4,3-b]pyridazine	1604541: Displacement of [3H]-flumazenil from human GABAA alpha5beta3gamma2 expressed in Ltk cells	ki	0.0002	uM
3-fluoro-2-[2-fluoro-5-(7-methyl-8-oxoimidazo[1,2-a]pyrazin-3-yl)phenyl]benzonitrile	262297: Displacement of [3H]Ro-151788 from human recombinant GABA-Aalpha5 receptor plus beta3gamma2	ki	0.0002	uM
5-ethoxy-2,4,8,9-tetrazatetracyclo[11.4.0.02,6.08,12]heptadeca-1(17),3,5,9,11,13,15-heptaene	448426: Binding affinity to GABAA alpha-5-beta-3-gamma-2 receptor	ki	0.0002	uM
7-tert-butyl-6-[(2-ethyl-1,2,4-triazol-3-yl)methoxy]-3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine	259132: Displacement of [3H]Ro-151788 from human recombinant GABAA alpha5 in combination with beta3gamma2 expressed in L(tk-) cells	ki	0.0002	uM
2-[3-[7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]benzonitrile	259132: Displacement of [3H]Ro-151788 from human recombinant GABAA alpha5 in combination with beta3gamma2 expressed in L(tk-) cells	ki	0.0002	uM
2-[2-fluoro-5-[7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]benzonitrile	259132: Displacement of [3H]Ro-151788 from human recombinant GABAA alpha5 in combination with beta3gamma2 expressed in L(tk-) cells	ki	0.0002	uM
4-[2-fluoro-5-[3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]phenyl]pyridine-3-carbonitrile	262147: Displacement of [3H]Ro 15-1788 from recombinant human GABA-Aalpha5 receptor plus beta-3-gamma-2 expressed in L(tk-) cells	ki	0.0003	uM
4-fluoro-2-[2-fluoro-5-[7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]phenyl]benzonitrile	259132: Displacement of [3H]Ro-151788 from human recombinant GABAA alpha5 in combination with beta3gamma2 expressed in L(tk-) cells	ki	0.0003	uM
2-[3-(4-fluoro-3-pyridin-4-ylphenyl)imidazo[1,2-a]pyrimidin-7-yl]propan-2-ol	262147: Displacement of [3H]Ro 15-1788 from recombinant human GABA-Aalpha5 receptor plus beta-3-gamma-2 expressed in L(tk-) cells	ki	0.0003	uM
tert-butyl 8-azido-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate	73523: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-5-beta-3-gamma-2	ki	0.0003	uM
8-chloro-2-(4-methoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-3-one	1388021: Displacement of [3H]Ro15-1788 from human GABAA receptor alpha5beta3gamma2 expressed in LTK cells preincubated for 30 secs measured every 15 mins at -60 mV holding potential by two-electrode voltage clamp assay	ki	0.0003	uM
ethyl (7S)-14-bromo-11-oxo-2,4,10-triazatetracyclo[10.4.0.02,6.07,10]hexadeca-1(16),3,5,12,14-pentaene-5-carboxylate	73523: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-5-beta-3-gamma-2	ki	0.0003	uM
tert-butyl 8-methoxy-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate	73523: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-5-beta-3-gamma-2	ki	0.0003	uM
3-phenyl-6-(pyridin-4-ylmethoxy)-[1,2,4]triazolo[3,4-a]phthalazine	72625: Binding affinity for human GABA-A receptor alpha-5-beta-3-gamma-2 subunits in L(tk-) cells	ki	0.0003	uM
9-[(3,5-dimethylpyrazol-1-yl)methoxy]-6-phenyl-4,5,7,8-tetrazatetracyclo[9.2.2.02,10.03,7]pentadeca-2(10),3,5,8-tetraene	239566: Inhibition of [3H]Ro-151788 binding to recombinant human gamma-aminobutyric-acid A receptor alpha-5-beta-3-gamma-2 subtype expressed in L (tk-) cells	ki	0.0003	uM
9-[(1-ethylimidazol-2-yl)methoxy]-6-phenyl-4,5,7,8-tetrazatetracyclo[9.2.2.02,10.03,7]pentadeca-2(10),3,5,8-tetraene	239566: Inhibition of [3H]Ro-151788 binding to recombinant human gamma-aminobutyric-acid A receptor alpha-5-beta-3-gamma-2 subtype expressed in L (tk-) cells	ki	0.0003	uM
3-phenyl-6-(pyridin-2-ylmethoxy)-[1,2,4]triazolo[3,4-a]phthalazine	1551051: Binding affinity to recombinant human GABA-A alpha5beta3gamma2 receptor expressed in L(tk) cells	ki	0.0003	uM
5-chloro-2,4,8,9,11-pentazatetracyclo[11.4.0.02,6.08,12]heptadeca-1(17),3,5,9,11,13,15-heptaene	468635: Displacement of [3H]Flumazenil from cloned human GABA alpha-5-beta-3-gamma-2 receptor expressed in HEK293 cells	ki	0.0003	uM
5-chloro-15-fluoro-2,4,8,9,11-pentazatetracyclo[11.4.0.02,6.08,12]heptadeca-1(13),3,5,9,11,14,16-heptaene	468641: Displacement of [3H]Flumazenil from human GABA alpha-5-beta-3-gamma-2 receptor expressed in insect SF9 cells	ki	0.0003	uM
3-(2,6-difluorophenyl)-5-[4-fluoro-3-(3-fluoro-2-pyridinyl)phenyl]pyridazine	262646: Displacement of [3H]Ro-151788 from recombinant human GABA-Aalpha5 receptor plus beta3gamma2	ki	0.0003	uM
ethyl 15-bromo-2,4,8,9,11-pentazatetracyclo[11.4.0.02,6.08,12]heptadeca-1(13),3,5,9,11,14,16-heptaene-5-carboxylate	448426: Binding affinity to GABAA alpha-5-beta-3-gamma-2 receptor	ki	0.0003	uM
7-bromo-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one	1889909: Displacement of [3H]flunitrazepam from human recombinant alpha5beta2gamma2 GABAA receptor expressed in HEK cell membrane by competitive radioligand binding assay	ki	0.0003	uM
ethyl 4-oxo-5-(pyridin-3-ylmethyl)imidazo[1,5-a]quinoxaline-3-carboxylate	1937104: Displacement of flumazenil from alpha5 GABAA receptor (unknown origin)	ki	0.0003	uM
2-phenyl-3aH-pyrazolo[4,3-c]quinolin-3-one	73523: Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-5-beta-3-gamma-2	ki	0.0003	uM
ethyl 8-azido-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate	72626: In vitro binding affinity for human GABA-A receptor alpha-5-beta-3-gamma-2 subunits expressed in L(tk-) cell membranes	ki	0.0003	uM
2-[3-[4-fluoro-3-(5-fluoro-2-pyridinyl)phenyl]imidazo[1,2-a]pyrimidin-7-yl]propan-2-ol	262147: Displacement of [3H]Ro 15-1788 from recombinant human GABA-Aalpha5 receptor plus beta-3-gamma-2 expressed in L(tk-) cells	ki	0.0004	uM
8-bromo-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine	1889909: Displacement of [3H]flunitrazepam from human recombinant alpha5beta2gamma2 GABAA receptor expressed in HEK cell membrane by competitive radioligand binding assay	ki	0.0004	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, affects cotreatment, increases expression	7
bisphenol A	decreases expression, increases methylation	2
sodium arsenite	affects methylation, affects cotreatment, increases abundance, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
p-Chloromercuribenzoic Acid	decreases expression, affects cotreatment	2
trichostatin A	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
imidazenil	affects activity	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, increases methylation	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1
Acetaminophen	decreases expression	1
Air Pollutants	increases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Carbamazepine	affects expression	1
Estradiol	affects expression	1
Folic Acid	decreases expression	1
Formaldehyde	increases expression	1
gamma-Aminobutyric Acid	affects binding, affects reaction, increases activity	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Methotrexate	decreases expression	1
Progesterone	decreases expression	1
Silicon Dioxide	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1

ChEMBL screening assays

413 unique, capped per target: 352 binding, 57 functional, 3 toxicity, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3363914	Binding	Displacement of [3H]Muscimol from rat GABAA receptor at 10 uM after 90 mins by microbeta counting analysis	Griseorhodins D-F, neuroactive intermediates and end products of post-PKS tailoring modification in Griseorhodin biosynthesis. — *J Nat Prod*
CHEMBL4810229	ADMET	Inhibition of GABA A receptor (unknown origin) at 0.1 to 1 uM	Discovery of Pemigatinib: A Potent and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor. — *J Med Chem*
CHEMBL5335653	Toxicity	Antagonist activity at GABA-A (unknown origin)	Discovery of a Novel Bifunctional Steroid Analog, YXG-158, as an Androgen Receptor Degrader and CYP17A1 Inhibitor for the Treatment of Enzalutamide-Resistant Prostate Cancer. — *J Med Chem*

Cellosaurus cell lines

4 cell lines: 2 transformed cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1JN	PrecisION hGABAA alpha5/beta3/gamma2-HEK	Transformed cell line	Female
CVCL_SP43	HAP1 GABRA5 (-) 1	Cancer cell line	Male
CVCL_SP44	HAP1 GABRA5 (-) 2	Cancer cell line	Male
CVCL_YA47	IDG-HEK293T-GABRA5-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00000374	Phase 4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	Phase 4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	Phase 4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	Phase 4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	Phase 4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	Phase 4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	Phase 4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	Phase 4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	Phase 4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	Phase 4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	Phase 4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	Phase 4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	Phase 4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	Phase 4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	Phase 4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	Phase 4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	Phase 4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	Phase 4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	Phase 4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	Phase 4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	Phase 4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	Phase 4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	Phase 4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	Phase 4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	Phase 4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	Phase 4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	Phase 4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	Phase 4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	Phase 4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	Phase 4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	Phase 4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	Phase 4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	Phase 4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	Phase 4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	Phase 4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	Phase 4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	Phase 4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	Phase 4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	Phase 4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	Phase 4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety
NCT00177580	Phase 4	COMPLETED	Improving Symptoms of Schizophrenia and Schizoaffective Disorder by Supplementing Medications With Pravastatin
NCT00182442	Phase 4	COMPLETED	Cognition, Functioning and Quality of Life
NCT00182494	Phase 4	UNKNOWN	Diabetes Prevention Program in Schizophrenia [DPPS]
NCT00183625	Phase 4	COMPLETED	Supported Employment and Skills Training in Conjunction With Pharmacotherapy in Schizophrenia Patients
NCT00186771	Phase 4	UNKNOWN	Magnetic Stimulation as a Treatment for Auditory Hallucinations in Schizophrenia
NCT00190749	Phase 4	COMPLETED	Safety Study of Olanzapine and a Comparator in Patients With Schizophrenia and Schizoaffective Disorder
NCT00191555	Phase 4	COMPLETED	Efficacy Study of Switching Stabilized Schizophrenic Patients From Conventional to Atypical Antipsychotic Treatment
NCT00194025	Phase 4	COMPLETED	Valproate in Late Life Schizophrenia
NCT00199940	Phase 4	COMPLETED	Safety And Efficacy Study Of Ziprasidone In Pediatric Psychotic Illness
NCT00202306	Phase 4	COMPLETED	Indicated Prevention of Psychotic Disorders With Low-dose Lithium
NCT00203788	Phase 4	COMPLETED	Improving Work Outcome in People With Recent-onset Schizophrenia
NCT00204061	Phase 4	COMPLETED	Early Pharmacological and Psychological Intervention for Late Prodromal States of Psychosis
NCT00205660	Phase 4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00206102	Phase 4	COMPLETED	A Study of the Cataractogenic Potential of Seroquel and Risperdal in the Treatment of Participants With Schizophrenia or Schizoaffective Disorder
NCT00208143	Phase 4	COMPLETED	Seroquel Therapy for Substance Use Disorders Comorbid With Schizophrenia
NCT00208169	Phase 4	COMPLETED	Abilify Therapy for Reducing Comorbid Substance Abuse
NCT00214578	Phase 4	COMPLETED	Seroquel on Glucose Metabolism
NCT00215579	Phase 4	COMPLETED	Determining the Effects of Risperdal Consta in Patients With Psychotic Disorders and Incomplete Adherence
NCT00216528	Phase 4	COMPLETED	A Study to Evaluate Symptomatic Remission in Schizophrenia With Long Acting Risperidone Microspheres
NCT00216632	Phase 4	COMPLETED	A Study of Treatment Success in Changing From Olanzapine to Long-acting Injectable Risperidone (RISPERDAL® CONSTA™)

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for GABRA5 across ~30M SureChEMBL compounds — explore on Sugi Predict.