SLC6A1

Summary

SLC6A1 (solute carrier family 6 member 1, HGNC:11042) is a protein-coding gene on chromosome 3p25.3, encoding Sodium- and chloride-dependent GABA transporter 1 (P30531). Mediates transport of gamma-aminobutyric acid (GABA) together with sodium and chloride and is responsible for the reuptake of GABA from the synapse. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a gamma-aminobutyric acid (GABA) transporter that localizes to the plasma membrane. The encoded protein removes GABA from the synaptic cleft, restoring it to presynaptic terminals.

Source: NCBI Gene 6529 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epilepsy with myoclonic atonic seizures (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 1,029 total — 94 pathogenic, 86 likely-pathogenic
• Phenotypes (HPO): 51
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_003042

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11042
Approved symbol	SLC6A1
Name	solute carrier family 6 member 1
Location	3p25.3
Locus type	gene with protein product
Status	Approved
Aliases	GAT1, GABATR, GABATHG, GAT-1, hGAT-1
Ensembl gene	ENSG00000157103
Ensembl biotype	protein_coding
OMIM	137165
Entrez	6529

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 31 protein_coding, 8 retained_intron, 3 nonsense_mediated_decay

ENST00000287766, ENST00000425938, ENST00000460480, ENST00000462473, ENST00000495636, ENST00000642201, ENST00000642515, ENST00000642639, ENST00000642735, ENST00000642766, ENST00000642767, ENST00000642820, ENST00000642831, ENST00000643326, ENST00000643396, ENST00000643498, ENST00000644175, ENST00000644314, ENST00000644803, ENST00000645029, ENST00000645054, ENST00000645281, ENST00000645575, ENST00000645592, ENST00000645598, ENST00000645776, ENST00000645974, ENST00000645985, ENST00000646022, ENST00000646035, ENST00000646060, ENST00000646072, ENST00000646088, ENST00000646487, ENST00000646570, ENST00000646702, ENST00000646836, ENST00000646886, ENST00000646924, ENST00000647194, ENST00000647384, ENST00000698198

RefSeq mRNA: 5 — MANE Select: NM_003042 NM_001348250, NM_001348251, NM_001348252, NM_001348253, NM_003042

CCDS: CCDS2603, CCDS87043, CCDS87044

Canonical transcript exons

ENST00000287766 — 16 exons

Exon	Start	End
ENSE00001030330	11028735	11028847
ENSE00001030332	11029221	11029352
ENSE00001030333	11025773	11025876
ENSE00001030334	11022336	11022468
ENSE00001030339	11025449	11025583
ENSE00001030341	11017843	11017974
ENSE00001030345	11033639	11033739
ENSE00001030353	11031177	11031279
ENSE00001030361	11026235	11026359
ENSE00001216676	11015672	11015733
ENSE00001216693	11036862	11039247
ENSE00001216700	11017059	11017449
ENSE00003473555	11034531	11034698
ENSE00003535875	11020213	11020322
ENSE00003688119	11018598	11018698
ENSE00003822717	10992748	10992929

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 98.94.

FANTOM5 (CAGE): breadth broad, TPM avg 8.9269 / max 1019.1066, expressed in 226 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35312	7.9517	210
35314	0.8371	75
35311	0.1284	71
35317	0.0098	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	98.94	gold quality
lateral globus pallidus	UBERON:0002476	98.72	gold quality
cerebellar vermis	UBERON:0004720	98.65	gold quality
subthalamic nucleus	UBERON:0001906	98.56	gold quality
postcentral gyrus	UBERON:0002581	98.40	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.37	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.24	gold quality
superior vestibular nucleus	UBERON:0007227	98.14	gold quality
parietal lobe	UBERON:0001872	98.13	gold quality
prefrontal cortex	UBERON:0000451	97.88	gold quality
orbitofrontal cortex	UBERON:0004167	97.74	gold quality
caudate nucleus	UBERON:0001873	97.71	gold quality
amygdala	UBERON:0001876	97.68	gold quality
medulla oblongata	UBERON:0001896	97.68	gold quality
superior frontal gyrus	UBERON:0002661	97.64	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.52	gold quality
substantia nigra pars compacta	UBERON:0001965	97.51	gold quality
frontal cortex	UBERON:0001870	97.50	gold quality
frontal lobe	UBERON:0016525	97.50	gold quality
putamen	UBERON:0001874	97.46	gold quality
inferior vagus X ganglion	UBERON:0005363	97.45	gold quality
occipital lobe	UBERON:0002021	97.43	gold quality
ventral tegmental area	UBERON:0002691	97.43	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.38	gold quality
primary visual cortex	UBERON:0002436	97.30	gold quality
cingulate cortex	UBERON:0003027	97.30	gold quality
anterior cingulate cortex	UBERON:0009835	97.30	gold quality
nucleus accumbens	UBERON:0001882	97.28	gold quality
temporal lobe	UBERON:0001871	97.16	gold quality
right frontal lobe	UBERON:0002810	97.16	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	71.58
E-HCAD-25	yes	38.89
E-GEOD-84465	yes	24.46
E-GEOD-93593	yes	22.25
E-ANND-3	yes	6.33

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SMAD4, THRA, YY1

miRNA regulators (miRDB)

132 targeting SLC6A1, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-34C-5P	99.97	70.45	1577

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• role of transmembrane domain I in transition between cation leak and transport modes (PMID:12446715)
• part of extracellular loop IV of GAT1 is conformationally sensitive, and its modification selectively abolishes the interaction of the transporter with GABA (PMID:12925537)
• the extracellular part of TMD I is conformationally sensitive, lines the permeation pathway, and forms a more extended structure than expected from a membrane-embedded alpha-helix. (PMID:14744863)
• GAT1 over-expressing transgenic mice display cognitive deterioration in associative learning and new object recognition retention, compared with wild-type littermates. (PMID:15106822)
• GAT1 oligomerization is driven by an interplay of polar and hydrophobic interactions in transmembrane helix II (PMID:15496410)
• transmembrane domains 1 and 3 come in close proximity within the transporter monomer (PMID:15905165)
• there are substantial differences in the distribution and density of GAT-1-ir axon terminals between areas and layers of the human neocortex (PMID:17099065)
• concentrative endoplasmic reticulum-export is contingent on a direct interaction of GAT1 with Sec24D. (PMID:17210573)
• Weight reduction with sibutramine is associated with altered gastric functions and increased peptide YY and is significantly associated with SLC6A4 genotype. (PMID:17544870)
• Owing to the low level of LD and presence of recombination hotspots, SLC6A1 may be an example of a problematic gene for association and haplotype tagging-based genetic studies (PMID:17941974)
• It might therefore represent the principle, sufficient for sorting out less-effective or non-GAT ligands such as beta-Pro, (S)-nipecotic acid, (R)-baclofen, Glu, and Leu. (PMID:17967412)
• The temperature and voltage dependence of GAT1 were used to estimate the physiological turnover rate to be 79-93 s(-1) (37 degrees C, -50 to -90 mV). (PMID:17994179)
• Interaction with calnexin led to accumulation of GAT1 in concentric bodies corresponding to previously described multilamellar ER-derived structures. (PMID:18367207)
• These data indicate a high load of genetic variance within SLC6A1 on pathological anxiety (PMID:18607529)
• the insertion polymorphism leads to increased SLC6A1 promoter activity because, in part, of creation of an enhancer element when present as multiple copies (PMID:19077666)
• the transmembrane domain 8 of the {gamma}-aminobutyric acid transporter GAT-1 lines a cytoplasmic accessibility pathway into its binding pocket (PMID:19201752)
• The results suggest tight coupling of GAT1-mediated charge flux and GABA flux. (PMID:19622377)
• A 46 bp cis-regulator in the promoter sequence is responsible for stimulation of bone morphogenetic protein-2 (BMP2) on gat1 expression in cerebral cortex. (PMID:20237276)
• This chapter reviews data suggesting that neurogliaform cells produce electrophysiological effects onto other neurons in the cortical cell network via GABA(B)R-mediated volume transmission that is highly regulated by GAT1 activity. (PMID:20655483)
• A glutamine residue conserved in the neurotransmitter:sodium:symporters is essential for the interaction of chloride with the GABA transporter GAT-1. (PMID:21098479)
• GABA Transporter Mutagenesis Database (GATMD), a web-accessible, relational database of manually annotated biochemical, functional and pharmacological data reported on GAT1. (PMID:21131297)
• TM10 of GAT-1 lines an accessibility pathway from the extracellular space into the binding pocket and plays a role in the opening and closing of the extracellular transporter gate. (PMID:22235131)
• analysis of binding and translocation processes in the GABA transporter (PMID:22737235)
• a functional interaction of the external and internal gates of GAT-1 is essential for transport (PMID:23288838)
• The aromatic and charge pairs of the thin extracellular gate of the GABA transporter GAT-1 are differently impacted by mutation. (PMID:25143384)
• 3p25.3 microdeletion of GABA transporters SLC6A1 and SLC6A11 results in intellectual disability, epilepsy and stereotypic behavior. (PMID:25256099)
• Cysteine mutagenesis of GAT-1 pointed to conformationally sensitive proximity of extracellular loops 2 and 4 in this protein. (PMID:25339171)
• Evidence for a Revised Ion/Substrate Coupling Stoichiometry of GABA Transporters. (PMID:25824654)
• targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six SLC6A1 mutations in seven individuals, all of whom have epilepsy with myoclonic-atonic seizures (MAE). (PMID:25865495)
• Genome-wide significant associations were highly biological plausible, including associations within GABA transporter 1, SLC6A1 (solute carrier family 6, member 1), and exonic hits in LOC100129340 (mitofusin-1-like (PMID:26081443)
• Protein expression as assessed by Western blot showed that GABA-transporter 1 was equally expressed in mild and severe hippocampal sclerosis (PMID:26212582)
• Results show that SLC6A1 minor genotypes/alleles were protective against risk for alcoholism in 3 ethnically diverse cohorts. (PMID:26727527)
• the “extra” residue in transmembrane domain 10 of the GABA transporter GAT-1 provides extra bulk, probably in the form of a pi-helix, which is required for stringent gating and tight coupling of ion and substrate fluxes in the GABA transporter family. (PMID:28213519)
• results suggest that selected SLC6A1 gene variants may have a significant effect on the ADHD risk. (PMID:28442423)
• Most patients carrying pathogenic SLC6A1 variants have an myoclonic atonic epilepsy phenotype with language delay and mild/moderate intellectual disability before epilepsy onset. However, intellectual disability alone or associated with focal epilepsy can also be observed. (PMID:29315614)
• Study results revealed that lower SLC6A1 expression indicated longer survival time and higher survival rate. MiR-200c-3p could directly target at SLC6A1 and reduce its expression. MiR-200c-3p inhibited the proliferation, migration and invasion in 786-O cells by down-regulating SLC6A1 expression. (PMID:29394133)
• This study demonstrated that SLC6A1 is an important contributor to childhood epilepsy and that reduced GAT-1 function is a common consequence of epilepsy-causing SLC6A1 variants. (PMID:30132828)
• We highlight strong evidence that mutations in SLC6A1…confer a high risk for schizophrenia (PMID:31932766)
• Overexpression of SLC6A1 associates with drug resistance and poor prognosis in prostate cancer. (PMID:32252682)
• GAT-1 (rs2697153) and GAT-3 (rs2272400) polymorphisms are associated with febrile seizures and temporal lobe epilepsy. (PMID:32301730)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc6a1b	ENSDARG00000039647
danio_rerio	slc6a1a	ENSDARG00000045944
mus_musculus	Slc6a1	ENSMUSG00000030310
rattus_norvegicus	Slc6a1	ENSRNOG00000006527

Paralogs (19): SLC6A13 (ENSG00000010379), SLC6A7 (ENSG00000011083), SLC6A16 (ENSG00000063127), SLC6A15 (ENSG00000072041), SLC6A2 (ENSG00000103546), SLC6A4 (ENSG00000108576), SLC6A12 (ENSG00000111181), SLC6A8 (ENSG00000130821), SLC6A6 (ENSG00000131389), SLC6A11 (ENSG00000132164), SLC6A3 (ENSG00000142319), SLC6A20 (ENSG00000163817), SLC6A18 (ENSG00000164363), SLC6A5 (ENSG00000165970), SLC6A19 (ENSG00000174358), SLC6A9 (ENSG00000196517), SLC6A17 (ENSG00000197106), SLC6A14 (ENSG00000268104), (ENSG00000273554)

Protein

Protein identifiers

Sodium- and chloride-dependent GABA transporter 1 — P30531 (reviewed: P30531)

Alternative names: Solute carrier family 6 member 1

All UniProt accessions (13): P30531, A0A2R8Y3X2, A0A2R8Y495, A0A2R8Y4I3, A0A2R8Y867, A0A2R8YCM3, A0A2R8YDD5, A0A2R8YEF0, A0A2R8YF74, A0A2R8YFI0, A0A8V8TMZ9, B7Z3C5, C9J5P8

UniProt curated annotations — full annotation on UniProt →

Function. Mediates transport of gamma-aminobutyric acid (GABA) together with sodium and chloride and is responsible for the reuptake of GABA from the synapse. The translocation of GABA, however, may also occur in the reverse direction leading to the release of GABA. The direction and magnitude of GABA transport is a consequence of the prevailing thermodynamic conditions, determined by membrane potential and the intracellular and extracellular concentrations of Na(+), Cl(-) and GABA. Can also mediate sodium- and chloride-dependent transport of hypotaurine but to a much lower extent as compared to GABA.

Subunit / interactions. Interacts (via PDZ domain-binding motif) with PALS1; interaction increases SLC6A1-mediated GABA uptake.

Subcellular location. Cell membrane. Presynapse.

Disease relevance. Myoclonic-atonic epilepsy (MAE) [MIM:616421] A form of epilepsy characterized by myoclonic-atonic and absence seizures, appearing in early childhood. Patients have delayed development before the onset of seizures and show varying degrees of intellectual disability following seizure onset. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. This protein is the target of psychomotor stimulants such as amphetamines or cocaine.

Similarity. Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A1 subfamily.

RefSeq proteins (5): NP_001335179, NP_001335180, NP_001335181, NP_001335182, NP_003033* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000175	Na/ntran_symport	Family
IPR002980	Na/ntran_symport_GABA_GAT1	Family
IPR037272	SNS_sf	Homologous_superfamily

Pfam: PF00209

Catalyzed reactions (Rhea), 2 shown:

• 4-aminobutanoate(out) + chloride(out) + 2 Na(+)(out) = 4-aminobutanoate(in) + chloride(in) + 2 Na(+)(in) (RHEA:70687)
• hypotaurine(out) + chloride(out) + 2 Na(+)(out) = hypotaurine(in) + chloride(in) + 2 Na(+)(in) (RHEA:71243)

UniProt features (100 total): helix 34, topological domain 13, transmembrane region 12, sequence variant 12, binding site 9, turn 5, glycosylation site 3, sequence conflict 3, modified residue 2, strand 2, chain 1, region of interest 1, short sequence motif 1, compositionally biased region 1, disulfide bond 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7Y7V	ELECTRON MICROSCOPY	2.2
7Y7W	ELECTRON MICROSCOPY	2.4
7Y7Y	ELECTRON MICROSCOPY	2.4
7Y7Z	ELECTRON MICROSCOPY	3.2
7SK2	ELECTRON MICROSCOPY	3.82

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30531-F1	88.57	0.78

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 (9): 59; 61; 62; 66; 295; 327; 392; 395; 396

Post-translational modifications (2): 18, 591

Disulfide bonds (1): 164–173

Glycosylation sites (3): 176, 181, 184

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-442660	SLC-mediated transport of neurotransmitters
R-HSA-888593	Reuptake of GABA
R-HSA-112310	Neurotransmitter release cycle
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-382551	Transport of small molecules
R-HSA-425366
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-888590	GABA synthesis, release, reuptake and degradation

MSigDB gene sets: 325 (showing top): GOBP_MEMORY, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_CIRCULATORY_SYSTEM_PROCESS, MODULE_162, GOBP_NEUROTRANSMITTER_UPTAKE, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_ASSOCIATIVE_LEARNING, MODULE_64, GOCC_CELL_SURFACE, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, AAAYRNCTG_UNKNOWN

GO Biological Process (17): amino acid transport (GO:0006865), chemical synaptic transmission (GO:0007268), memory (GO:0007613), associative learning (GO:0008306), sodium ion transmembrane transport (GO:0035725), synapse organization (GO:0050808), gamma-aminobutyric acid reuptake (GO:0051936), gamma-aminobutyric acid import (GO:0051939), inorganic anion import across plasma membrane (GO:0098658), sodium ion import across plasma membrane (GO:0098719), transport across blood-brain barrier (GO:0150104), chloride transmembrane transport (GO:1902476), amino acid transmembrane transport (GO:0003333), neurotransmitter transport (GO:0006836), gamma-aminobutyric acid transport (GO:0015812), transmembrane transport (GO:0055085), neurotransmitter reuptake (GO:0098810)

GO Molecular Function (8): gamma-aminobutyric acid:sodium:chloride symporter activity (GO:0005332), gamma-aminobutyric acid transmembrane transporter activity (GO:0015185), sodium:chloride symporter activity (GO:0015378), metal ion binding (GO:0046872), amino acid:sodium symporter activity (GO:0005283), protein binding (GO:0005515), symporter activity (GO:0015293), transmembrane transporter activity (GO:0022857)

GO Cellular Component (9): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), axon (GO:0030424), neuronal cell body (GO:0043025), presynapse (GO:0098793), GABA-ergic synapse (GO:0098982), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
SLC-mediated transmembrane transport	1
GABA synthesis, release, reuptake and degradation	1
Transmission across Chemical Synapses	1
Neuronal System	1
Transport of small molecules	1
Neurotransmitter release cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transport	3
gamma-aminobutyric acid transport	3
amino acid transport	2
transmembrane transport	2
synapse	2
anterograde trans-synaptic signaling	1
learning or memory	1
learning	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
cell junction organization	1
amino acid neurotransmitter reuptake	1
acidic amino acid transport	1
inorganic anion transport	1
inorganic ion import across plasma membrane	1
sodium ion transmembrane transport	1
inorganic cation import across plasma membrane	1
vascular transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
carboxylic acid transport	1
nitrogen compound transport	1
cellular process	1
neurotransmitter uptake	1
establishment of localization in cell	1
presynapse	1
amino acid:sodium symporter activity	1
organic acid:sodium symporter activity	1
gamma-aminobutyric acid transmembrane transporter activity	1
secondary active monocarboxylate transmembrane transporter activity	1
sodium:chloride symporter activity	1
amino acid transmembrane transporter activity	1
carboxylic acid transmembrane transporter activity	1
monoatomic anion:sodium symporter activity	1
chloride:monoatomic cation symporter activity	1
cation binding	1
amino acid:monoatomic cation symporter activity	1
solute:sodium symporter activity	1
binding	1

Protein interactions and networks

STRING

2754 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC6A1	GABRD	O14764	901
SLC6A1	CASTOR3P	Q8NAP1	893
SLC6A1	GABRA5	P31644	857
SLC6A1	PPOX	P50336	826
SLC6A1	GAD2	Q05329	826
SLC6A1	GAD1	Q99259	797
SLC6A1	PVALB	P20472	779
SLC6A1	SLC32A1	Q9H598	742
SLC6A1	SEC24D	O94855	731
SLC6A1	STX1A	Q16623	722
SLC6A1	GABRA6	Q16445	673
SLC6A1	SLC17A7	Q9P2U7	642
SLC6A1	STXBP1	P61764	634
SLC6A1	GABRG2	P18507	634
SLC6A1	SLC1A2	P43004	626

IntAct

15 interactions, top by confidence:

A	B	Type	Score
HSF2BP	SLC6A1	psi-mi:“MI:0915”(physical association)	0.560
SLC6A1	DNAJC5	psi-mi:“MI:2364”(proximity)	0.470
SLC6A1	DNAJC5	psi-mi:“MI:0915”(physical association)	0.470
SLC6A1	DRD2	psi-mi:“MI:0915”(physical association)	0.370
SLC6A1	HTR6	psi-mi:“MI:0915”(physical association)	0.370
SLC6A1	ERN1	psi-mi:“MI:0914”(association)	0.350
SLC6A1	CLGN	psi-mi:“MI:0914”(association)	0.350
SLC5A2	CA2	psi-mi:“MI:0914”(association)	0.350
HTT	TPP1	psi-mi:“MI:0914”(association)	0.350
SLC6A1	TM4SF4	psi-mi:“MI:2364”(proximity)	0.270
SLC6A1	HSF2BP	psi-mi:“MI:0915”(physical association)	0.000
HUNK	SLC6A1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (72): DNAJC5 (FRET), SLC6A1 (Affinity Capture-Luminescence), HSF2BP (Two-hybrid), TM4SF4 (Affinity Capture-Luminescence), SLC6A1 (Reconstituted Complex), SLC6A1 (Two-hybrid), SLC6A1 (Two-hybrid), SLC6A1 (Positive Genetic), ARFGAP1 (Reconstituted Complex), STX1A (Affinity Capture-Western), SLC6A1 (Affinity Capture-RNA), NT5C3A (Affinity Capture-MS), ATP11C (Affinity Capture-MS), TRIM29 (Affinity Capture-MS), VTN (Affinity Capture-MS)

ESM2 similar proteins: A0A2K1ZPK4, B3MRS1, B4L7U0, B4NDL8, B9GNS0, B9NAE4, D3ZIS0, O49423, O64759, O77741, P23978, P30531, P31636, P31637, P31648, P38778, P38925, P48057, P49283, P51905, P53793, P53794, P65544, P65545, Q10177, Q10Q65, Q12078, Q21433, Q21434, Q2QN30, Q5R6J1, Q67UC7, Q695T7, Q6YSA9, Q6ZG85, Q84YJ9, Q869V1, Q8UEM1, Q91ZP4, Q92BT1

Diamond homologs: A5PJX7, A7Y2W8, A7Y2X0, B3MRS1, B3NV41, B4GVM9, B4JMC1, B4L7U0, B4MEG2, B4NDL8, B4PZQ4, B4R4T6, G5EBN9, O18875, O35316, O35899, O45813, O55192, O76689, O88575, O88576, P23975, P23977, P23978, P27799, P27922, P28570, P28571, P28572, P28573, P30531, P31641, P31643, P31645, P31646, P31647, P31648, P31649, P31650, P31651

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
85375-15-1	down-regulates	SLC6A1	“chemical inhibition”
tiagabine	“down-regulates activity”	SLC6A1	“chemical inhibition”
“1-(4,4-diphenylbut-3-enyl)-3-piperidinecarboxylic acid”	“down-regulates activity”	SLC6A1	“chemical inhibition”
“1-[2-[(diphenylmethylene)amino]oxyethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid”	“down-regulates activity”	SLC6A1	“chemical inhibition”
“1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid”	“down-regulates activity”	SLC6A1	“chemical inhibition”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1029 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	94
Likely pathogenic	86
Uncertain significance	326
Likely benign	344
Benign	77

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069245	NM_003042.4(SLC6A1):c.1004dup (p.Phe336fs)	Pathogenic
1070240	NM_003042.4(SLC6A1):c.1311dup (p.Asn438Ter)	Pathogenic
1073686	NM_003042.4(SLC6A1):c.643_661dup (p.Ala221fs)	Pathogenic
1074164	NM_003042.4(SLC6A1):c.566del (p.Val189fs)	Pathogenic
1172626	NM_003042.4(SLC6A1):c.690G>A (p.Trp230Ter)	Pathogenic
1323611	NM_003042.4(SLC6A1):c.1323+1G>A	Pathogenic
1335930	NM_003042.4(SLC6A1):c.1324-2del	Pathogenic
1358776	NM_003042.4(SLC6A1):c.199G>A (p.Val67Ile)	Pathogenic
1373916	NM_003042.4(SLC6A1):c.1513C>A (p.Pro505Thr)	Pathogenic
1383583	NM_003042.4(SLC6A1):c.1223T>G (p.Leu408Arg)	Pathogenic
1401658	NM_003042.4(SLC6A1):c.403_423del (p.Trp135_Ile141del)	Pathogenic
1406082	NM_003042.4(SLC6A1):c.1495T>C (p.Cys499Arg)	Pathogenic
1436731	NM_003042.4(SLC6A1):c.449del (p.Tyr150fs)	Pathogenic
1461681	NM_003042.4(SLC6A1):c.370G>A (p.Gly124Ser)	Pathogenic
1515924	NM_003042.4(SLC6A1):c.850-1G>A	Pathogenic
1707546	NM_003042.4(SLC6A1):c.888C>G (p.Tyr296Ter)	Pathogenic
1793201	NM_003042.4(SLC6A1):c.1104C>G (p.Tyr368Ter)	Pathogenic
1804984	NM_003042.4(SLC6A1):c.1607del (p.Val536fs)	Pathogenic
192368	NM_003042.4(SLC6A1):c.131G>A (p.Arg44Gln)	Pathogenic
192370	NM_003042.4(SLC6A1):c.1000G>C (p.Ala334Pro)	Pathogenic
192371	NM_003042.4(SLC6A1):c.1369_1370del (p.Gly457fs)	Pathogenic
1992307	NM_003042.4(SLC6A1):c.341_344delinsCC (p.Gly114fs)	Pathogenic
2008871	NM_003042.4(SLC6A1):c.581+1G>C	Pathogenic
2017932	NM_003042.4(SLC6A1):c.1199C>T (p.Thr400Ile)	Pathogenic
2021102	NM_003042.4(SLC6A1):c.714+2T>G	Pathogenic
2035698	NM_003042.4(SLC6A1):c.302A>C (p.Glu101Ala)	Pathogenic
2094177	NM_003042.4(SLC6A1):c.502del (p.Trp168fs)	Pathogenic
2096688	NM_003042.4(SLC6A1):c.689G>A (p.Trp230Ter)	Pathogenic
2104654	NM_003042.4(SLC6A1):c.914C>T (p.Ala305Val)	Pathogenic
2151968	NM_003042.4(SLC6A1):c.434C>T (p.Ser145Phe)	Pathogenic

SpliceAI

2303 predictions. Top by Δscore:

Variant	Effect	Δscore
3:10992925:CGCAG:C	donor_loss	1.0000
3:10992926:GCAGG:G	donor_loss	1.0000
3:10992927:CAGGT:C	donor_loss	1.0000
3:10992928:AGGTA:A	donor_loss	1.0000
3:10992929:GGTA:G	donor_loss	1.0000
3:10992930:G:T	donor_loss	1.0000
3:10992931:T:A	donor_loss	1.0000
3:11017352:G:GT	donor_gain	1.0000
3:11017415:G:GT	donor_gain	1.0000
3:11017446:GGGG:G	donor_gain	1.0000
3:11017447:GGGG:G	donor_gain	1.0000
3:11017973:GG:G	donor_gain	1.0000
3:11017974:GG:G	donor_gain	1.0000
3:11018592:TCCCA:T	acceptor_loss	1.0000
3:11018593:CCCA:C	acceptor_loss	1.0000
3:11018594:CCA:C	acceptor_loss	1.0000
3:11018595:CAGGC:C	acceptor_loss	1.0000
3:11018596:A:C	acceptor_loss	1.0000
3:11018597:GGC:G	acceptor_gain	1.0000
3:11018597:GGCGT:G	acceptor_gain	1.0000
3:11020310:TG:T	donor_gain	1.0000
3:11020311:GG:G	donor_gain	1.0000
3:11020318:TGGGA:T	donor_gain	1.0000
3:11020319:GGGA:G	donor_gain	1.0000
3:11020319:GGGAG:G	donor_gain	1.0000
3:11020320:G:GT	donor_gain	1.0000
3:11020320:GGA:G	donor_gain	1.0000
3:11020321:GA:G	donor_gain	1.0000
3:11020321:GAG:G	donor_gain	1.0000
3:11020323:G:T	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000093291 (3:11018134 G>A), RS1000188001 (3:11015951 T>A), RS1000326309 (3:11005737 C>T), RS1000378560 (3:11006086 C>T), RS1000450859 (3:10999658 G>A), RS1000537376 (3:10994572 G>A), RS1000559679 (3:11012574 A>G), RS1000659762 (3:11007154 G>A), RS1000673202 (3:10995011 G>A), RS1000820877 (3:11001114 A>C), RS1000839011 (3:11011534 C>T), RS1000840072 (3:11038342 C>T), RS1000908239 (3:11012222 C>T), RS1000997823 (3:11033002 A>G), RS1001074572 (3:11006222 C>T)

Disease associations

OMIM: gene MIM:137165 | disease phenotypes: MIM:616421, MIM:615369, MIM:117100

GenCC curated gene-disease

Disease	Classification	Inheritance
epilepsy with myoclonic atonic seizures	Definitive	Autosomal dominant
myoclonic-astatic epilepsy	Supportive	Unknown

Mondo (7): epilepsy with myoclonic atonic seizures (MONDO:0014633), intellectual disability (MONDO:0001071), autism spectrum disorder (MONDO:0005258), neurodevelopmental disorder (MONDO:0700092), developmental and epileptic encephalopathy 94 (MONDO:0014150), self-limited epilepsy with centrotemporal spikes (MONDO:0007295), (MONDO:0016025)

Orphanet (5): Epilepsy with myoclonic-atonic seizures (Orphanet:1942), Lennox-Gastaut syndrome (Orphanet:2382), Self-limited epilepsy with centrotemporal spikes (Orphanet:1945), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000154	Wide mouth
HP:0000179	Thick lower lip vermilion
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000289	Broad philtrum
HP:0000343	Long philtrum
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000568	Microphthalmia
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001159	Syndactyly
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001326	EEG with irregular generalized spike and wave complexes
HP:0001337	Tremor
HP:0001999	Abnormal facial shape
HP:0002121	Generalized non-motor (absence) seizure
HP:0002123	Generalized myoclonic seizure
HP:0002188	Delayed CNS myelination
HP:0002292	Frontal balding
HP:0002317	Unsteady gait
HP:0002332	Lack of peer relationships
HP:0002392	EEG with polyspike wave complexes
HP:0002650	Scoliosis
HP:0003621	Juvenile onset

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000245_10	Conduct disorder (maternal expressed emotions interaction)	6.000000e-06
GCST001450_8	Response to Vitamin E supplementation	6.000000e-06
GCST002981_1	Longitudinal alcohol consumption	1.000000e-07
GCST003772_4	Loneliness (linear analysis)	8.000000e-06
GCST009531_9	Body fat percentage	7.000000e-08
GCST010002_415	Refractive error	2.000000e-13
GCST010057_3	Lung function	1.000000e-09
GCST010057_5	Lung function	1.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0008342	parental emotion expression measurmement
EFO:0007645	longitudinal alcohol consumption measurement
EFO:0007865	loneliness measurement
EFO:0007800	body fat percentage
EFO:0004312	vital capacity
EFO:0004314	forced expiratory volume

MeSH disease descriptors (2)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1903 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 174,335 (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
CHEMBL1027	TIAGABINE	4	12,112
CHEMBL1695	TIAGABINE HYDROCHLORIDE	4	2,035
CHEMBL96	GAMMA-AMINOBUTYRIC ACID	1	160,188

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — GABA transporter subfamily

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
NNC-711	Inhibition	7.4	pIC50
tiagabine	Inhibition	7.2	pIC50
SKF89976A	Inhibition	6.9	pIC50
CI-966	Inhibition	6.6	pIC50
(R/S) EF-1500	Inhibition	5.7	pIC50
LU32-176B	Inhibition	5.4	pIC50
(R)-EF-1520	Inhibition	5.4	pIC50
(S)-EF-1520	Inhibition	3.9	pIC50

ChEMBL bioactivities

103 potent at pChembl≥5 of 128 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.00	IC50	10.1	nM	NIPECOTIC ACID
7.83	Ki	14.79	nM	CHEMBL1641613
7.77	Ki	16.98	nM	TIAGABINE
7.74	Ki	18.2	nM	CHEMBL1642396
7.72	Ki	19.05	nM	CHEMBL1642400
7.69	Ki	20.42	nM	CHEMBL1642378
7.66	Ki	21.88	nM	CHEMBL1642397
7.54	Ki	28.84	nM	CHEMBL1642376
7.53	Ki	29.51	nM	CHEMBL1642379
7.47	Ki	33.88	nM	CHEMBL1642384
7.42	Ki	38.02	nM	CHEMBL1642395
7.41	Ki	38.9	nM	CHEMBL1642401
7.39	Kd	40.5	nM	TIAGABINE
7.39	Ki	40.74	nM	CHEMBL1642375
7.38	Ki	41.69	nM	CHEMBL1642394
7.33	Ki	46.77	nM	CHEMBL1642388
7.32	Ki	47.86	nM	TIAGABINE
7.31	IC50	49	nM	TIAGABINE HYDROCHLORIDE
7.28	Ki	52.48	nM	CHEMBL1642398
7.27	Ki	53.7	nM	CHEMBL1642399
7.25	Kd	56	nM	CHEMBL4525620
7.25	Ki	56.23	nM	CHEMBL1642381
7.24	Kd	57.7	nM	CHEMBL4537310
7.23	Ki	58.88	nM	CHEMBL1642382
7.21	Ki	61.66	nM	CHEMBL1642391
7.18	Ki	66.07	nM	CHEMBL3398501
7.16	Ki	69.18	nM	CHEMBL1642374
7.16	IC50	70	nM	TIAGABINE
7.15	Ki	70.79	nM	CHEMBL1642393
7.14	Ki	72.44	nM	CHEMBL77626
7.14	Ki	72.44	nM	CHEMBL1642386
7.11	Ki	77.62	nM	CHEMBL1642385
7.05	Ki	89.13	nM	CHEMBL1642387
7.03	Ki	93.33	nM	CHEMBL1642367
7.03	Ki	93.33	nM	CHEMBL1642377
6.99	Ki	102.3	nM	CHEMBL1642368
6.95	Kd	111.9	nM	CHEMBL4525620
6.89	IC50	130	nM	CHEMBL38686
6.89	IC50	130	nM	CHEMBL77626
6.86	Ki	138	nM	CHEMBL1642402
6.83	Kd	146.8	nM	TIAGABINE
6.81	Kd	154.2	nM	CHEMBL4537310
6.81	IC50	154.9	nM	TIAGABINE
6.80	Ki	158.5	nM	CHEMBL1642389
6.78	Ki	166	nM	CHEMBL1642364
6.70	IC50	200	nM	CHEMBL103623
6.70	IC50	200	nM	CHEMBL38686
6.70	Ki	199.5	nM	CHEMBL1642365
6.67	Ki	213.8	nM	CHEMBL3398499
6.58	IC50	260	nM	CHEMBL77287

PubChem BioAssay actives

102 with measured affinity, of 304 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
piperidine-3-carboxylic acid	255262: Percent inhibition against GABA transporter at a compound concentration of 1 uM	ic50	0.0101	uM
(3R)-1-[(E)-4-(2-fluorophenyl)-4-(2-methylphenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0148	uM
Tiagabine	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0170	uM
(3R)-1-[(Z)-4-(2-chlorophenyl)-4-(2-fluorophenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0182	uM
(3R)-1-[(E)-4-(4-fluoro-2-methylphenyl)-4-(2-fluorophenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0191	uM
(3R)-1-[(Z)-4-(2-methylphenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0204	uM
(3R)-1-[(Z)-4-(2-bromophenyl)-4-(2-fluorophenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0219	uM
(3R)-1-[(Z)-4-(2-bromophenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0288	uM
(3R)-1-[(Z)-4-(2-ethylphenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0295	uM
(3R)-1-[(Z)-4-(4-fluoro-2-methylphenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0339	uM
(3R)-1-[(E)-4-(2-ethylphenyl)-4-(2-fluorophenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0380	uM
(3R)-1-[(E)-4-(4-fluoro-2-methylphenyl)-4-[2-(trifluoromethyl)phenyl]but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0389	uM
(3R)-1-[(Z)-4-(2-chlorophenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0407	uM
(3R)-1-[4,4-bis(2-methylphenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0417	uM
(3R)-1-[4,4-bis(2-fluorophenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0468	uM
Tiagabine Hydrochloride	764978: Inhibition of human GAT1 transfected in CHO cells assessed as [3H]GABA uptake after 20 mins by liquid scintillation counting analysis	ic50	0.0490	uM
(3R)-1-[(E)-4-(2-fluorophenyl)-4-[2-(trifluoromethoxy)phenyl]but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0525	uM
(3R)-1-[(E)-4-(2-fluorophenyl)-4-(2-methoxyphenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0537	uM
(3R,5S)-5-[[(2E)-2-[(5-naphthalen-1-ylfuran-2-yl)methylidene]hydrazinyl]methyl]piperidine-3-carboxylic acid	1573619: Non-competitive inhibition of human GAT1 expressed in COS cells assessed as reduction in [2H6]GABA uptake by measuring [2H6]GABA Kd(app) at 1 uM preincubated for 25 mins followed by [2H6]GABA addition and measured after 4 mins by liquid scintillation counting method (Rvb = 28.3 +/- 1.5 nM)	kd	0.0560	uM
(3R)-1-[(Z)-4-(2-methoxyphenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0562	uM
(3R,5S)-5-[[(2E)-2-[[5-[3,5-bis(trifluoromethyl)phenyl]furan-2-yl]methylidene]hydrazinyl]methyl]piperidine-3-carboxylic acid	1573619: Non-competitive inhibition of human GAT1 expressed in COS cells assessed as reduction in [2H6]GABA uptake by measuring [2H6]GABA Kd(app) at 1 uM preincubated for 25 mins followed by [2H6]GABA addition and measured after 4 mins by liquid scintillation counting method (Rvb = 28.3 +/- 1.5 nM)	kd	0.0577	uM
(3R)-1-[(Z)-4-phenyl-4-[2-(trifluoromethoxy)phenyl]but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0589	uM
(3R)-1-[(E)-4-(2-chlorophenyl)-4-(2-methylphenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0617	uM
(2S)-2-[(2R)-1-[4,4-bis(3-methylthiophen-2-yl)but-3-enyl]pyrrolidin-2-yl]-2-hydroxyacetic acid	1192147: Binding affinity to human GAT1 expressed in HEK293 cells using NO71156 as unlabelled marker by LC-ESI-MS-MS based competitive MS binding assay	ki	0.0661	uM
(3R)-1-[(Z)-4-(2-fluorophenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0692	uM
(3R)-1-[(E)-4-(2-methoxyphenyl)-4-(2-methylphenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0708	uM
(3R)-1-[(Z)-4-(2-fluorophenyl)-4-(2-methylphenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0724	uM
(3R)-1-(4,4-diphenylbut-3-enyl)piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0724	uM
(3R)-1-[(Z)-4-(2,6-dimethylphenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0776	uM
(3R)-1-[(Z)-4-(2-ethylphenyl)-4-(2-fluorophenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0891	uM
(3R)-1-[(Z)-4-phenyl-4-[2-(trifluoromethyl)phenyl]but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0933	uM
(3R)-1-[(E)-4-(2-methylphenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.0933	uM
(3R)-1-[(E)-4-(2-ethylphenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.1023	uM
1-(4,4-diphenylbut-3-enyl)piperidine-3-carboxylic acid	1602654: Inhibition of human GAT1 expressed in COS cells assessed as decrease in [3H]GABA uptake after 10 mins by scintillation counting analysis	ic50	0.1300	uM
1-[4,4-bis(5-methylthiophen-2-yl)but-3-enyl]-3-fluoropiperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.1380	uM
(3R)-1-[(E)-4-(2-chlorophenyl)-4-(2-fluorophenyl)but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.1585	uM
(3R)-1-[(E)-4-(2-chlorophenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.1660	uM
(3R)-1-[(E)-4-(2-bromophenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.1995	uM
1-(4,4-diphenylbut-3-enyl)-3,6-dihydro-2H-pyridine-5-carboxylic acid	487219: Binding affinity to GAT1	ic50	0.2000	uM
(2S)-2-[(2R)-1-(4,4-diphenylbut-3-enyl)pyrrolidin-2-yl]-2-hydroxyacetic acid	1192147: Binding affinity to human GAT1 expressed in HEK293 cells using NO71156 as unlabelled marker by LC-ESI-MS-MS based competitive MS binding assay	ki	0.2138	uM
1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid	205303: Inhibitory activity against human GABA transporter-1 (hGAT1)	ic50	0.2600	uM
(3R)-1-[2-(2-phenothiazin-10-ylethoxy)ethyl]piperidine-3-carboxylic acid	759052: Inhibition of GABA uptake at GAT-1 (unknown origin)	ic50	0.3090	uM
(3R)-1-[(Z)-4-(2,6-difluorophenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.3311	uM
(3R)-1-[4,4-bis[3-(phenoxymethyl)thiophen-2-yl]but-3-enyl]piperidine-3-carboxylic acid;hydrochloride	258716: Inhibition of GAT1 transport activity	ic50	0.3400	uM
(3R)-1-[(Z)-4-(2-fluorophenyl)-4-[2-(trifluoromethyl)phenyl]but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.3548	uM
(3R)-1-[(E)-4-(2-fluorophenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.3715	uM
(3R)-1-[(E)-4-(2-methoxyphenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.3715	uM
(3R)-1-[(E)-4-(2-methylphenyl)-4-[2-(trifluoromethyl)phenyl]but-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.3802	uM
(3R)-1-[(E)-4-(4-fluoro-2-methylphenyl)-4-phenylbut-3-enyl]piperidine-3-carboxylic acid	550890: Displacement of [3H]Tiagabine from human recombinant GAT1 expressed in HEK293 cells by equilibrium binding assay	ki	0.3802	uM
(3R)-1-[2-(2-benzo[b][1]benzazepin-11-ylethoxy)ethyl]piperidine-3-carboxylic acid	759052: Inhibition of GABA uptake at GAT-1 (unknown origin)	ic50	0.6456	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
gamma-Aminobutyric Acid	decreases reaction, increases uptake, increases export	2
Aflatoxin B1	affects expression, decreases expression, decreases methylation	2
ethyl-p-hydroxybenzoate	decreases expression	1
2-amino-9H-pyrido(2,3-b)indole	decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	increases methylation	1
ferrous chloride	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Troglitazone	decreases expression	1
Bosentan	affects expression	1
Tiagabine	decreases activity	1
Copper	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Lead	affects expression	1
Methapyrilene	increases methylation	1
N-Nitrosopyrrolidine	decreases expression	1
Niflumic Acid	decreases reaction, increases uptake	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	increases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

56 unique, capped per target: 55 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1166723	Binding	Binding affinity to GAT1	Azetidine derivatives as novel gamma-aminobutyric acid uptake inhibitors: synthesis, biological evaluation, and structure-activity relationship. — Eur J Med Chem
CHEMBL681450	Functional	Compound was tested for its ability to inhibit uptake of [3H]- GABA by cloned human GAT-1 transporter	On the bioactive conformation of the gaba uptake inhibitor SK&F 89976-A — Bioorg Med Chem Lett

Cellosaurus cell lines

5 cell lines: 3 finite cell line, 1 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A2TV	GM27899	Finite cell line	Male
CVCL_B0IL	GM28102	Finite cell line	Male
CVCL_D0I7	MHRCCGi001-A	Induced pluripotent stem cell	Male
CVCL_YE58	GM27387	Transformed cell line	Male
CVCL_YE59	GM27388	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)