SLC6A4

Summary

SLC6A4 (solute carrier family 6 member 4, HGNC:11050) is a protein-coding gene on chromosome 17q11.2, encoding Sodium-dependent serotonin transporter (P31645). Serotonin transporter that cotransports serotonin with one Na(+) ion in exchange for one K(+) ion and possibly one proton in an overall electroneutral transport cycle.

This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. The encoded protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is a target of psychomotor stimulants, such as amphetamines and cocaine, and is a member of the sodium:neurotransmitter symporter family. A repeat length polymorphism in the promoter of this gene has been shown to affect the rate of serotonin uptake. There have been conflicting results in the literature about the possible effect, if any, that this polymorphism may play in behavior and depression.

Source: NCBI Gene 6532 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Huntington disease (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 26
• Clinical variants (ClinVar): 925 total — 6 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 95
• Druggable target: yes — 422 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001045

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11050
Approved symbol	SLC6A4
Name	solute carrier family 6 member 4
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	5-HTT, SERT1
Ensembl gene	ENSG00000108576
Ensembl biotype	protein_coding
OMIM	182138
Entrez	6532

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000261707, ENST00000394821, ENST00000401766, ENST00000578609, ENST00000579221, ENST00000650711, ENST00000855095, ENST00000855096, ENST00000855097, ENST00000855098, ENST00000855099, ENST00000855100, ENST00000958994, ENST00000958995

RefSeq mRNA: 1 — MANE Select: NM_001045 NM_001045

CCDS: CCDS11256

Canonical transcript exons

ENST00000650711 — 15 exons

Exon	Start	End
ENSE00002728713	30222819	30222915
ENSE00003553925	30203172	30203339
ENSE00003850203	30235613	30235697
ENSE00003889021	30217166	30217304
ENSE00003890165	30209143	30209242
ENSE00003890473	30210515	30210646
ENSE00003891402	30215611	30215714
ENSE00003891628	30218797	30218931
ENSE00003892023	30216082	30216216
ENSE00003892410	30212740	30212867
ENSE00003893866	30211312	30211424
ENSE00003893977	30218118	30218337
ENSE00003894242	30221616	30222081
ENSE00003894359	30207732	30207832
ENSE00003895678	30194319	30198530

Expression profiles

Bgee: expression breadth ubiquitous, 162 present calls, max score 98.87.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5036 / max 70.1071, expressed in 158 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46672	31.8293	1820
165183	0.2370	59
46670	0.1340	68
46674	0.0715	16
46669	0.0611	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	98.87	gold quality
jejunal mucosa	UBERON:0000399	95.34	gold quality
ileal mucosa	UBERON:0000331	90.20	gold quality
lower lobe of lung	UBERON:0008949	89.91	silver quality
adult organism	UBERON:0007023	88.50	gold quality
placenta	UBERON:0001987	88.23	gold quality
upper lobe of left lung	UBERON:0008952	86.58	gold quality
upper lobe of lung	UBERON:0008948	86.43	gold quality
lung	UBERON:0002048	84.67	gold quality
duodenum	UBERON:0002114	82.72	gold quality
buccal mucosa cell	CL:0002336	80.59	silver quality
superior vestibular nucleus	UBERON:0007227	79.65	gold quality
oral cavity	UBERON:0000167	79.35	gold quality
small intestine	UBERON:0002108	76.34	gold quality
small intestine Peyer’s patch	UBERON:0003454	75.89	gold quality
islet of Langerhans	UBERON:0000006	75.02	gold quality
tongue squamous epithelium	UBERON:0006919	74.68	silver quality
mononuclear cell	CL:0000842	71.69	gold quality
monocyte	CL:0000576	71.68	gold quality
esophagus squamous epithelium	UBERON:0006920	71.32	gold quality
jejunum	UBERON:0002115	70.81	gold quality
leukocyte	CL:0000738	70.58	gold quality
epithelium of esophagus	UBERON:0001976	70.18	gold quality
hair follicle	UBERON:0002073	69.16	gold quality
right uterine tube	UBERON:0001302	68.59	gold quality
visceral pleura	UBERON:0002401	66.47	gold quality
esophagus mucosa	UBERON:0002469	66.10	gold quality
squamous epithelium	UBERON:0006914	66.08	silver quality
lower esophagus mucosa	UBERON:0035834	63.65	gold quality
mucosa of transverse colon	UBERON:0004991	62.50	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.66
E-MTAB-5061	yes	17.30
E-GEOD-81608	yes	9.78
E-ENAD-27	yes	5.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, CTCF, FEV, HNRNPK, TXK, YBX1, ZIC2

miRNA regulators (miRDB)

161 targeting SLC6A4, 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-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-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• A putative three-dimensional arrangement of the human serotonin transporter transmembrane helices: a tool to aid experimental studies. (PMID:11775000)
• The 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism. (PMID:11803447)
• Upstream polymorphisms modulate transcription of SLC6A4 and affect serotonin uptake activity. No association was found, however, with major psychosis symptomatology among 1820 inpatients. (PMID:11803453)
• Data do not support the implication of the serotonin transporter gene (5-HTT) in the psychiatric comorbidities of NF1. (PMID:11803526)
• Transmission disequilibrium mapping at the serotonin transporter gene region in autistic disorder (PMID:11920155)
• A polymorphism in the promoter region of the serotonin transporter gene has been linked to the gender-specific association of suicide attempts by females. (PMID:11927194)
• 5-HTT-VNTR allele 12 is a risk factor for schizophrenic disorders in Chinese populations. (PMID:11979062)
• study did not support the involvement of 5-HTTLPR, TPH, MAO-A, or DRD4 polymorphisms in mood disorders (PMID:11992558)
• SLC6A4 polymorphism is associated with a higher risk of myocardial infarction (PMID:12081984)
• No significant differences in allele/genotype distribution of the 5-HTTLPR were found between 191 controls and obsessive-compulsive disorder (PMID:12082589)
• evaluated the relationship between attention deficit hyperactivity disorder and polymorphism of the two regions of the 5-HTT gene [variable number of tandem repeats (VNTR) and 5-HTTLRR] in a sample of Turkish children (PMID:12097805)
• The silencer activity of the novel human serotonin transporter linked polymorphic regions. (PMID:12098489)
• Absence of association of the serotonin transporter gene polymorphism with the mentally healthy subset of fibromyalgia patients. (PMID:12111622)
• results suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele (PMID:12130784)
• Association of regulatory region polymorphism and abnormal eating behaviors (PMID:12140775)
• VNTR polymorphisms in male opiate addicts (PMID:12173460)
• In generalized anxiety disorder, the number of serotonin transporters is not modified, although the functional efficiency of the transporter might be altered. (PMID:12188031)
• 5-HT transporter gene promoter variants seemingly exert a small effect on 5-HT blood levels in autistic children, which largely does not account for hyperserotoninemia (PMID:12192626)
• Family-based association studies show a link between this gene and major psychiatric disorders. (PMID:12218657)
• the serotonin transporter varients are not a major determinant of the group mean platelet serotonin elevation seen in autism. (PMID:12232775)
• possible involvement of the serotonin transporter in susceptibility to ADHD. (PMID:12232786)
• Study shows no association of reportedly functional promoter polymorphism at SLC6A4 with alcohol dependence or with any of alcoholism subtypes based on sex, comorbid drug dependence, or age of alcoholism onset. (PMID:12351926)
• association between serotonin transporter gene polymorphism and family history of suicide and attempted suicide (PMID:12374478)
• The polymorphism does not appear to be involved in a genetic predisposition to the disease but may affect the frequency of attacks in patients with migraine. (PMID:12390616)
• The variable number of tandem repeats (VNTR) polymorphism significantly influences the age at onset but the serotonin transporter gene linked polymorphic region (5-HTTLPR) polymorphism did not. (PMID:12431765)
• study tested the hypothesis that the 5-HTT gene-linked polymorphic-region (5-HTTLPR) polymorphism is associated with SSRI antidepressant response by evaluating depressive symptoms for Chinese patients diagnosed with major depression (PMID:12476327)
• A relationship of L/S gene with the disease was detected in Russians and Tatars, the presence of heterozygotic genotype was associated with early onset of chronic alcoholizm and acute alcoholic psychosis in Tatars and with later alcoholization in Russians (PMID:12534269)
• present findings failed to replicate prior work suggesting that the short variant of the 5-HTTLPR allele is associated with higher Neuroticism and lower Agreeableness (PMID:12605095)
• Individuals homozygous for the serotonin transporter allele exhibit a weaker loudness dependence (LD) compared to heterozygous subjects; the LD may serve as an endophenotype in human serotonin research. (PMID:12629533)
• Review. The serotonin transporter gene has 2 types of functional polymorphisms which are good candidates for etiological involvement in various psychiatric conditions. Both affect the transcription ratio of 5-HTT gene & its protein expression. (PMID:12630565)
• No significant difference was demonstrated for genotype or allele frequency, when comparing methamphetamine dependent and control cases for 5-HTT serotonin transporter polymorphisms. (PMID:12658362)
• Serotonin transporter promoter polymorphism associated with aggression, attention deficit, and conduct disorder in adoptee population (PMID:12658617)
• HTT genotype frequencies significantly differed between schizophrenic patients who made violent suicide attempts and both, those who attempted suicide with a non-violent method and those who never attempted suicide (PMID:12707931)
• The frequency of the SLC6A4 long (L) allele of the serotonin transporter is significantly higher in African-Americans than has been reported for European-Americans (typically 56-60%). (PMID:12749731)
• No association between either the 5HT transporter or the variable number tandem repeat in ADHD was found. (PMID:12782968)
• Polymorphism of the serotonin transporter gene may contribute to the susceptibility to the symptomatology of schizophrenia but not to the development of the disorder itself, at least in the Korean population. (PMID:12824740)
• analyzed the possible cooperation effect between the PlA2 allele (GPIIIa) and LL genotype (SLC6A4) in the development of myocardial infarction (PMID:12855229)
• a functional polymorphism in the promoter region of the serotonin transporter gene was found to moderate the influence of stressful life events on depression (PMID:12869766)
• Meta-analysis of the 5-HTT promoter 44 bp insertion/deletion polymorphism in suicide behavior showed a significant association following sensitivity analysis. 5-HTT may play a role in the predisposition to suicide. (PMID:12874600)
• Serotonin transporters are preserved in the neocortex of anxious Alzheimer’s disease patients. (PMID:12876460)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc6a4a	ENSDARG00000061165
mus_musculus	Slc6a4	ENSMUSG00000020838
rattus_norvegicus	Slc6a4	ENSRNOG00000003476

Paralogs (19): SLC6A13 (ENSG00000010379), SLC6A7 (ENSG00000011083), SLC6A16 (ENSG00000063127), SLC6A15 (ENSG00000072041), SLC6A2 (ENSG00000103546), SLC6A12 (ENSG00000111181), SLC6A8 (ENSG00000130821), SLC6A6 (ENSG00000131389), SLC6A11 (ENSG00000132164), SLC6A3 (ENSG00000142319), SLC6A1 (ENSG00000157103), SLC6A20 (ENSG00000163817), SLC6A18 (ENSG00000164363), SLC6A5 (ENSG00000165970), SLC6A19 (ENSG00000174358), SLC6A9 (ENSG00000196517), SLC6A17 (ENSG00000197106), SLC6A14 (ENSG00000268104), (ENSG00000273554)

Protein

Protein identifiers

Sodium-dependent serotonin transporter — P31645 (reviewed: P31645)

Alternative names: 5HT transporter, Solute carrier family 6 member 4

All UniProt accessions (3): P31645, J3KPR9, J3QKP3

UniProt curated annotations — full annotation on UniProt →

Function. Serotonin transporter that cotransports serotonin with one Na(+) ion in exchange for one K(+) ion and possibly one proton in an overall electroneutral transport cycle. Transports serotonin across the plasma membrane from the extracellular compartment to the cytosol thus limiting serotonin intercellular signaling. Essential for serotonin homeostasis in the central nervous system. In the developing somatosensory cortex, acts in glutamatergic neurons to control serotonin uptake and its trophic functions accounting for proper spatial organization of cortical neurons and elaboration of sensory circuits. In the mature cortex, acts primarily in brainstem raphe neurons to mediate serotonin uptake from the synaptic cleft back into the pre-synaptic terminal thus terminating serotonin signaling at the synapse. Modulates mucosal serotonin levels in the gastrointestinal tract through uptake and clearance of serotonin in enterocytes. Required for enteric neurogenesis and gastrointestinal reflexes. Regulates blood serotonin levels by ensuring rapid high affinity uptake of serotonin from plasma to platelets, where it is further stored in dense granules via vesicular monoamine transporters and then released upon stimulation. Mechanistically, the transport cycle starts with an outward-open conformation having Na1(+) and Cl(-) sites occupied. The binding of a second extracellular Na2(+) ion and serotonin substrate leads to structural changes to outward-occluded to inward-occluded to inward-open, where the Na2(+) ion and serotonin are released into the cytosol. Binding of intracellular K(+) ion induces conformational transitions to inward-occluded to outward-open and completes the cycle by releasing K(+) possibly together with a proton bound to Asp-98 into the extracellular compartment. Na1(+) and Cl(-) ions remain bound throughout the transport cycle. Additionally, displays serotonin-induced channel-like conductance for monovalent cations, mainly Na(+) ions. The channel activity is uncoupled from the transport cycle and may contribute to the membrane resting potential or excitability.

Subunit / interactions. Monomer or homooligomer. Interacts with TGFB1I1. Interacts with SEC23A, SEC24C and PATJ. Interacts with NOS1; the interaction may diminish the cell surface localization of SERT in the brain and, correspondingly, reduce serotonin reuptake. Interacts with filamentous actin and STX1A. Interacts (via the N-terminus) with STX1A (via the H3 domain); this interaction regulates SLC4A6 channel conductance. Interacts (via C-terminus) with SCAMP2; the interaction is direct and retains transporter molecules intracellularly. Interacts with ITGAV:ITGB3. Interacts (via C-terminus) with ITGB3; this interaction regulates SLC6A4 trafficking.

Subcellular location. Cell membrane. Endomembrane system. Endosome membrane. Synapse. Cell junction. Focal adhesion. Cell projection. Neuron projection.

Tissue specificity. Expressed in platelets (at protein level).

Post-translational modifications. Phosphorylation at Thr-276 increases 5-HT uptake and is required for cGMP-mediated SERT regulation.

Polymorphism. A polymorphism in the promoter region (5-HTT gene-linked polymorphic region, 5-HTTLPR) is located approximately 1 kb upstream of the transcription initiation site and is composed of 16 repeat elements. The polymorphism consists of a 44-bp insertion or deletion involving repeat elements 6 to 8. The short allele is associated with lower transcriptional efficiency of the promoter compared with the long allele. Over half of the Caucasian population has a short allele. Individuals with one or two copies of the short allele exhibit more depressive symptoms, diagnosable depression and suicidality in relation to stressful life events than individuals homozygous for the long allele. The 5-HTTLPR polymorphism may influence susceptibility to anxiety [MIM:607834]. The polymorphism Val-425 seems to be linked to a susceptibility to obsessive-compulsive disorder (OCD) [MIM:164230]. Genetic variations in SLC6A4 determine the genetic susceptibility to alcoholism [MIM:103780]. Polymorphisms that alter SLC6A4 expression or function may increase the susceptibility to autism.

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. SLC6A4 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P31645-1	1	yes
P31645-2	2

RefSeq proteins (1): NP_001036* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000175	Na/ntran_symport	Family
IPR013086	Na/ntran_symport_serotonin_N	Domain
IPR037272	SNS_sf	Homologous_superfamily

Pfam: PF00209, PF03491

Catalyzed reactions (Rhea), 1 shown:

• serotonin(out) + K(+)(in) + Na(+)(out) + H(+)(in) = serotonin(in) + K(+)(out) + Na(+)(in) + H(+)(out) (RHEA:75839)

UniProt features (107 total): helix 32, binding site 16, topological domain 13, transmembrane region 12, strand 9, sequence variant 7, turn 5, modified residue 3, region of interest 2, glycosylation site 2, mutagenesis site 2, chain 1, compositionally biased region 1, disulfide bond 1, splice variant 1

Structure

Experimental structures (PDB)

30 structures.

PDB	Method	Resolution (Å)
9HCO	ELECTRON MICROSCOPY	2.78
7TXT	ELECTRON MICROSCOPY	3
5I6X	X-RAY DIFFRACTION	3.14
5I71	X-RAY DIFFRACTION	3.15
5I73	X-RAY DIFFRACTION	3.24
9IY7	ELECTRON MICROSCOPY	3.27
6VRH	ELECTRON MICROSCOPY	3.3
7LIA	ELECTRON MICROSCOPY	3.3
5I74	X-RAY DIFFRACTION	3.4
9PNS	ELECTRON MICROSCOPY	3.4
5I75	X-RAY DIFFRACTION	3.49
7LI6	ELECTRON MICROSCOPY	3.5
7MGW	ELECTRON MICROSCOPY	3.5
6AWO	X-RAY DIFFRACTION	3.53
6DZZ	ELECTRON MICROSCOPY	3.6
6AWN	X-RAY DIFFRACTION	3.62
7LWD	ELECTRON MICROSCOPY	3.65
6AWP	X-RAY DIFFRACTION	3.8
6VRL	ELECTRON MICROSCOPY	3.8
7LI8	ELECTRON MICROSCOPY	3.9
7LI9	ELECTRON MICROSCOPY	3.9
6AWQ	X-RAY DIFFRACTION	4.05
6DZY	ELECTRON MICROSCOPY	4.1
6VRK	ELECTRON MICROSCOPY	4.1
7LI7	ELECTRON MICROSCOPY	4.1
6DZV	ELECTRON MICROSCOPY	4.2
6DZW	ELECTRON MICROSCOPY	4.3
5I6Z	X-RAY DIFFRACTION	4.53
6W2B	X-RAY DIFFRACTION	4.7
6W2C	X-RAY DIFFRACTION	6.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31645-F1	85.38	0.75

Antibody-complex structures (SAbDab): 26 — 5I6X, 5I6Z, 5I71, 5I73, 5I74, 5I75, 6AWN, 6AWO, 6AWP, 6AWQ, 6DZV, 6DZZ, 6VRH, 6VRK, 6VRL, 6W2B, 6W2C, 7LI6, 7LI7, 7LI8, 7LI9, 7LIA, 7LWD, 7MGW, 7TXT (+1 more)

Functional residue map

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

Ligand- & substrate-binding residues (16): 94; 96; 97; 98; 98; 101; 336; 368; 434; 437; 438; 439 …

Post-translational modifications (3): 47, 142, 276

Disulfide bonds (1): 200–209

Glycosylation sites (2): 208, 217

Mutagenesis-validated functional residues (2):

Position	Phenotype
101	disrupts chloride ion dependence of serotonin transport. results in larger serotonin-induced currents independent of the
336	impairs serotonin transport. results in chloride ion-independent serotonin transport; when associated with a-101 or c-10

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-380615	Serotonin clearance from the synaptic cleft
R-HSA-442660	SLC-mediated transport of neurotransmitters
R-HSA-112311	Neurotransmitter clearance
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System

MSigDB gene sets: 774 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_CIRCADIAN_RHYTHM, GOBP_MEMORY, E2F_Q4, GOBP_SYNAPTIC_VESICLE_LOCALIZATION, GOBP_ESTABLISHMENT_OF_SPINDLE_ORIENTATION, GOBP_HINDBRAIN_DEVELOPMENT, MODULE_92, E2F_Q4_01, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_COGNITION, GRUETZMANN_PANCREATIC_CANCER_DN

GO Biological Process (33): response to hypoxia (GO:0001666), neurotransmitter transport (GO:0006836), amino acid transport (GO:0006865), response to nutrient (GO:0007584), memory (GO:0007613), circadian rhythm (GO:0007623), response to xenobiotic stimulus (GO:0009410), response to toxic substance (GO:0009636), positive regulation of gene expression (GO:0010628), positive regulation of serotonin secretion (GO:0014064), obsolete monoamine transport (GO:0015844), negative regulation of cerebellar granule cell precursor proliferation (GO:0021941), negative regulation of synaptic transmission, dopaminergic (GO:0032227), response to estradiol (GO:0032355), sodium ion transmembrane transport (GO:0035725), vasoconstriction (GO:0042310), negative regulation of neuron differentiation (GO:0045665), positive regulation of cell cycle (GO:0045787), negative regulation of organ growth (GO:0046621), behavioral response to cocaine (GO:0048148), enteric nervous system development (GO:0048484), brain morphogenesis (GO:0048854), serotonin uptake (GO:0051610), membrane depolarization (GO:0051899), male mating behavior (GO:0060179), platelet aggregation (GO:0070527), cellular response to retinoic acid (GO:0071300), cellular response to cGMP (GO:0071321), regulation of thalamus size (GO:0090067), conditioned place preference (GO:1990708), obsolete serotonin transport (GO:0006837), transmembrane transport (GO:0055085), neurotransmitter reuptake (GO:0098810)

GO Molecular Function (16): integrin binding (GO:0005178), monoatomic cation channel activity (GO:0005261), neurotransmitter transmembrane transporter activity (GO:0005326), serotonin:sodium:chloride symporter activity (GO:0005335), monoamine transmembrane transporter activity (GO:0008504), antiporter activity (GO:0015297), syntaxin-1 binding (GO:0017075), cocaine binding (GO:0019811), sodium ion binding (GO:0031402), identical protein binding (GO:0042802), nitric-oxide synthase binding (GO:0050998), actin filament binding (GO:0051015), serotonin binding (GO:0051378), protein binding (GO:0005515), transmembrane transporter activity (GO:0022857), metal ion binding (GO:0046872)

GO Cellular Component (15): plasma membrane (GO:0005886), focal adhesion (GO:0005925), endosome membrane (GO:0010008), endomembrane system (GO:0012505), presynaptic membrane (GO:0042734), neuron projection (GO:0043005), membrane raft (GO:0045121), synapse (GO:0045202), postsynaptic membrane (GO:0045211), serotonergic synapse (GO:0099154), endosome (GO:0005768), membrane (GO:0016020), cell projection (GO:0042995), anchoring junction (GO:0070161), presynapse (GO:0098793)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Neurotransmitter clearance	1
SLC-mediated transmembrane transport	1
Transmission across Chemical Synapses	1
Neuronal System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
response to chemical	3
cation binding	3
transport	2
protein-containing complex binding	2
heterocyclic compound binding	2
synaptic membrane	2
cell junction	2
synapse	2
response to stress	1
response to decreased oxygen levels	1
response to nutrient levels	1
learning or memory	1
rhythmic process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
serotonin secretion	1
regulation of serotonin secretion	1
positive regulation of monoatomic ion transport	1
positive regulation of secretion by cell	1
cerebellar granule cell precursor proliferation	1
regulation of cerebellar granule cell precursor proliferation	1
negative regulation of neural precursor cell proliferation	1
synaptic transmission, dopaminergic	1
regulation of synaptic transmission, dopaminergic	1
negative regulation of synaptic transmission	1
response to lipid	1
response to oxygen-containing compound	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
blood vessel diameter maintenance	1
neuron differentiation	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
cell cycle	1
positive regulation of cellular process	1
regulation of cell cycle	1
organ growth	1
regulation of organ growth	1

Protein interactions and networks

STRING

2252 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC6A4	DRD4	P21917	978
SLC6A4	HTR1A	P08908	968
SLC6A4	HTR2A	P28223	961
SLC6A4	TPH1	P17752	951
SLC6A4	MAOA	P21397	943
SLC6A4	COMT	P21964	943
SLC6A4	HTR1B	P28222	932
SLC6A4	TPH2	Q8IWU9	926
SLC6A4	BDNF	P23560	922
SLC6A4	HTR1D	P28221	920
SLC6A4	HTR2C	P28335	915
SLC6A4	DRD2	P14416	909
SLC6A4	SLC18A2	Q05940	881
SLC6A4	HTR2B	P41595	872
SLC6A4	MAOB	P27338	866

IntAct

10 interactions, top by confidence:

A	B	Type	Score
SLC6A4	Gpm6b	psi-mi:“MI:0915”(physical association)	0.460
Gpm6b	SLC6A4	psi-mi:“MI:0403”(colocalization)	0.460
	SLC6A4	psi-mi:“MI:0915”(physical association)	0.400
SLC6A4	GPM6B	psi-mi:“MI:0915”(physical association)	0.370
SLC6A4	PICK1	psi-mi:“MI:0915”(physical association)	0.370
RFXANK	BLTP3B	psi-mi:“MI:0914”(association)	0.350
SLC6A4	RER1	psi-mi:“MI:0914”(association)	0.350
KRAS		psi-mi:“MI:0914”(association)	0.350

BioGRID (66): HSPA1A (Reconstituted Complex), HSPA1A (FRET), HSPA1A (Affinity Capture-Western), HSPA8 (Affinity Capture-Western), HSP90AB1 (Affinity Capture-Western), STIP1 (Affinity Capture-Western), STUB1 (Affinity Capture-Western), PTGES3 (Affinity Capture-Western), SLC6A4 (Reconstituted Complex), SLC6A4 (Reconstituted Complex), SLC6A4 (Affinity Capture-Western), VAMP2 (Affinity Capture-Western), VAMP2 (FRET), SLC6A4 (Affinity Capture-MS), PPP3CA (Reconstituted Complex)

ESM2 similar proteins: A5PJX7, A7Y2W8, O18875, O35316, O35899, O55192, O88576, P23975, P23977, P23978, P27799, P28570, P28571, P28572, P28573, P30531, P31641, P31643, P31645, P31646, P31647, P31648, P31649, P31650, P31651, P31652, P31661, P48029, P48055, P48056, P48057, P48065, P48066, P51143, P51905, Q00589, Q01959, Q28039, Q2PG55, Q60857

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

26 interactions.

A	Effect	B	Mechanism
PRKG1	up-regulates	SLC6A4	phosphorylation
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	“down-regulates activity”	SLC6A4	“chemical inhibition”
paroxetine	“down-regulates activity”	SLC6A4	“chemical inhibition”
zotepine	“down-regulates activity”	SLC6A4	“chemical inhibition”
Norzotepine	“down-regulates activity”	SLC6A4	“chemical inhibition”
venlafaxine	“down-regulates activity”	SLC6A4	“chemical inhibition”
levomilnacipran	“down-regulates activity”	SLC6A4	“chemical inhibition”
protriptyline	“down-regulates activity”	SLC6A4	“chemical inhibition”
fluoxetine	“down-regulates activity”	SLC6A4	“chemical inhibition”
trimipramine	“down-regulates activity”	SLC6A4	“chemical inhibition”
Phenelzine	“down-regulates activity”	SLC6A4	“chemical inhibition”
clomipramine	“down-regulates activity”	SLC6A4	“chemical inhibition”
dothiepin	“down-regulates activity”	SLC6A4	“chemical inhibition”
doxepin	“down-regulates activity”	SLC6A4	“chemical inhibition”
2-[[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine	“down-regulates activity”	SLC6A4	“chemical inhibition”
lofepramine	“down-regulates activity”	SLC6A4	“chemical inhibition”
SLC6A4	“up-regulates quantity”	serotonin	relocalization
TBK1	“up-regulates activity”	SLC6A4	phosphorylation
SRC	“up-regulates quantity by stabilization”	SLC6A4	phosphorylation
(S)-duloxetine	“down-regulates activity”	SLC6A4	“chemical inhibition”
desipramine	“down-regulates activity”	SLC6A4	“chemical inhibition”
atomoxetine	“down-regulates activity”	SLC6A4	“chemical inhibition”
nefazodone	“down-regulates activity”	SLC6A4	“chemical inhibition”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	8
Uncertain significance	374
Likely benign	348
Benign	88

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1393012	NM_001388492.1(HTT):c.2710C>T (p.Gln904Ter)	Pathogenic
1464611	NM_001388492.1(HTT):c.2085del (p.Gly697fs)	Pathogenic
1494729	NM_001388492.1(HTT):c.5821_5833del (p.Ser1941fs)	Pathogenic
1808621	GRCh37/hg19 4p16.3-15.33(chr4:1-12785001)x1	Pathogenic
409	NC_000004.11:g.3076606GCA[40_?]	Pathogenic
417745	NM_001388492.1(HTT):c.8150T>A (p.Phe2717Tyr)	Pathogenic
1300132	NM_001045.6(SLC6A4):c.1745dup (p.Thr583fs)	Likely pathogenic
1357041	NM_001388492.1(HTT):c.8110-1G>A	Likely pathogenic
1375718	NM_001388492.1(HTT):c.1403-1G>C	Likely pathogenic
1687507	NM_001388492.1(HTT):c.54GCA[40] (p.Gln18_Gln38dup)	Likely pathogenic
3779748	NM_001388492.1(HTT):c.99_102del (p.Gln33fs)	Likely pathogenic
3779749	NM_001388492.1(HTT):c.99del (p.Gln33fs)	Likely pathogenic
3897713	NM_001388492.1:c.52CAG[55_59]	Likely pathogenic
4845680	NM_001388492.1(HTT):c.6921C>G (p.Leu2307=)	Likely pathogenic

SpliceAI

14356 predictions. Top by Δscore:

Variant	Effect	Δscore
17:30198358:G:C	donor_gain	1.0000
17:30209137:TCTTA:T	donor_loss	1.0000
17:30209138:CTTA:C	donor_loss	1.0000
17:30209139:TTA:T	donor_loss	1.0000
17:30209140:TACCA:T	donor_loss	1.0000
17:30209141:A:AC	donor_gain	1.0000
17:30209141:A:AT	donor_loss	1.0000
17:30209142:C:CC	donor_gain	1.0000
17:30209238:CCTCC:C	acceptor_gain	1.0000
17:30209239:CTCC:C	acceptor_gain	1.0000
17:30209239:CTCCC:C	acceptor_gain	1.0000
17:30209240:TCC:T	acceptor_gain	1.0000
17:30209240:TCCCT:T	acceptor_gain	1.0000
17:30209241:CC:C	acceptor_gain	1.0000
17:30209241:CCC:C	acceptor_gain	1.0000
17:30209242:CC:C	acceptor_gain	1.0000
17:30209243:C:CC	acceptor_gain	1.0000
17:30209243:CTGG:C	acceptor_loss	1.0000
17:30209244:T:C	acceptor_loss	1.0000
17:30210506:GATAC:G	donor_loss	1.0000
17:30210507:ATAC:A	donor_loss	1.0000
17:30210508:TACT:T	donor_loss	1.0000
17:30210509:AC:A	donor_loss	1.0000
17:30210511:TCAC:T	donor_loss	1.0000
17:30210513:A:AC	donor_gain	1.0000
17:30210513:ACAAA:A	donor_loss	1.0000
17:30210514:C:CA	donor_gain	1.0000
17:30210514:CA:C	donor_gain	1.0000
17:30210514:CAA:C	donor_gain	1.0000
17:30210514:CAAA:C	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000084243 (17:30221401 C>A), RS1000214259 (17:30213564 C>T), RS1000333027 (17:30207895 C>G), RS1000390981 (17:30200963 G>A,C), RS1000433300 (17:30221215 G>A), RS1000481779 (17:30209129 A>G), RS1000571188 (17:30232115 A>C), RS1000619997 (17:30193921 C>G), RS1000860365 (17:30220583 A>C,G), RS1000879684 (17:30226332 T>C), RS1000941423 (17:30213508 G>A), RS1001027397 (17:30226371 T>A), RS1001028247 (17:30232482 C>G), RS1001058571 (17:30226111 T>A), RS1001150670 (17:30221528 C>T)

Disease associations

OMIM: gene MIM:182138 | disease phenotypes: MIM:617435, MIM:164230, MIM:143100

GenCC curated gene-disease

Disease	Classification	Inheritance
Huntington disease	Definitive	Autosomal dominant
Lopes-Maciel-Rodan syndrome	Strong	Autosomal recessive
juvenile Huntington disease	Supportive	Autosomal dominant
obsessive-compulsive disorder	Limited	Autosomal dominant
autism spectrum disorder	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Huntington disease	Definitive	AD
autism spectrum disorder	Disputed	AD

Mondo (6): Lopes-Maciel-Rodan syndrome (MONDO:0054573), obsessive-compulsive disorder (MONDO:0008114), cerebral palsy (MONDO:0006497), Huntington disease (MONDO:0007739), autism spectrum disorder (MONDO:0005258), juvenile Huntington disease (MONDO:0016621)

Orphanet (2): Juvenile Huntington disease (Orphanet:248111), Huntington disease (Orphanet:399)

HPO phenotypes

95 total (30 of 95 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000496	Abnormality of eye movement
HP:0000545	Myopia
HP:0000708	Atypical behavior
HP:0000713	Agitation
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000722	Compulsive behaviors
HP:0000726	Dementia
HP:0000733	Motor stereotypy
HP:0000734	Disinhibition
HP:0000737	Irritability
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000746	Delusion
HP:0000751	Personality changes
HP:0000752	Hyperactivity
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001262	Excessive daytime somnolence
HP:0001263	Global developmental delay
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001332	Dystonia
HP:0001336	Myoclonus

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST003723_3	Serum sulfate level	3.000000e-07
GCST003996_29	Monobrow	1.000000e-22
GCST004862_46	Itch intensity from mosquito bite adjusted by bite size	8.000000e-06
GCST004923_3	Tuberculosis	3.000000e-08
GCST006946_29	Worry too long after an embarrassing experience	9.000000e-10
GCST007708_4	Worry/vulnerability (special factor of neuroticism)	1.000000e-09
GCST008059_167	Estimated glomerular filtration rate	1.000000e-10
GCST008163_275	Height	1.000000e-06
GCST008757_37	Alcohol consumption	2.000000e-09
GCST009379_154	Type 2 diabetes	1.000000e-09
GCST009524_311	Household income (MTAG)	2.000000e-09
GCST009524_49	Household income (MTAG)	1.000000e-09
GCST009890_3	Parental lifespan	6.000000e-09
GCST010703_115	Brain morphology (MOSTest)	1.000000e-28
GCST011100_6	Aging traits (healthspan, parental lifespan or longevity) (multivariate analysis)	3.000000e-08
GCST011122_50	Walking pace	1.000000e-09
GCST011365_124	Myocardial infarction	5.000000e-06
GCST90000050_29	Age at first birth	8.000000e-10
GCST90002395_560	Mean platelet volume	2.000000e-24
GCST90002395_561	Mean platelet volume	3.000000e-10
GCST90002395_562	Mean platelet volume	2.000000e-20
GCST90002398_442	Neutrophil count	5.000000e-13
GCST90002402_674	Platelet count	4.000000e-09
GCST90002407_422	White blood cell count	8.000000e-14
GCST90020028_1707	Hip circumference adjusted for BMI	5.000000e-08
GCST90020053_5	Frailty index	3.000000e-10

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0007864	sulfate measurement
EFO:0007906	synophrys measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0009589	worry measurement
EFO:0009695	household income
EFO:0007796	parental longevity
EFO:0004346	neuroimaging measurement
EFO:0009762	healthspan
EFO:0009101	age at first birth measurement
EFO:0004833	neutrophil count
EFO:0004309	platelet count
EFO:0008039	BMI-adjusted hip circumference
EFO:0009885	frailty measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
D006816	Huntington Disease	C10.228.140.079.545; C10.228.140.380.278; C10.228.662.262.249.750; C10.574.500.497; C16.320.400.430; F03.615.250.400; F03.615.400.390
D009771	Obsessive-Compulsive Disorder	F03.080.600

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2095201 (SELECTIVITY GROUP), CHEMBL2111346 (SELECTIVITY GROUP), CHEMBL228 (SINGLE PROTEIN), CHEMBL2363064 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

422 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 635,314 (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
CHEMBL1000	CETIRIZINE	4	26,030
CHEMBL1008	BEPRIDIL	4	11,776
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1085	ACETOPHENAZINE	4	5,134
CHEMBL1094636	NIRAPARIB	4	6,433
CHEMBL1095777	INDACATEROL	4	2,735
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL1106	EPINASTINE	4	8,530
CHEMBL1112	ARIPIPRAZOLE	4	24,205
CHEMBL1113	AMOXAPINE	4	20,128
CHEMBL1117	IDARUBICIN	4	136,065
CHEMBL1118	DESVENLAFAXINE	4	6,152
CHEMBL1162	NORETHINDRONE	4	91,150
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1172	DESLORATADINE	4	19,720
CHEMBL1175	DULOXETINE	4	28,527
CHEMBL118	CELECOXIB	4	112,844
CHEMBL1187833	UMECLIDINIUM	4	1,095
CHEMBL1189679	PALONOSETRON	4	9,399
CHEMBL1193	PHENIRAMINE	4	11,218
CHEMBL1198857	VILANTEROL	4
CHEMBL1200322	ESCITALOPRAM OXALATE	4
CHEMBL1200438	TIOCONAZOLE	4
CHEMBL1200492	NEFAZODONE HYDROCHLORIDE	4
CHEMBL1200623	ETHYLESTRENOL	4
CHEMBL1200666	CALCIPOTRIENE	4
CHEMBL1200776	CINACALCET HYDROCHLORIDE	4
CHEMBL1200781	CITALOPRAM HYDROBROMIDE	4
CHEMBL1200934	NORGESTIMATE	4
CHEMBL1201066	VENLAFAXINE HYDROCHLORIDE	4

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

PharmGKB clinical annotations

29 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1042173	Efficacy	3	ondansetron	Alcohol abuse
rs1042173	Dosage	3	morphine	Pain
rs2066713	Toxicity	3	ethanol	Alcohol abuse
rs25531	Toxicity	3	ethanol	Alcohol abuse
rs25531	Efficacy	4	citalopram
rs25531	Efficacy	4	fluoxetine	Major Depressive Disorder
rs4251417	Toxicity	3	ethanol	Alcohol abuse
rs57098334	Efficacy	3	paroxetine	Depression
rs57098334	Efficacy	3	fluoxetine	Depression;Major Depressive Disorder
rs57098334	Toxicity	3	antidepressants	Depression
rs57098334	Efficacy	4	sertraline	Major Depressive Disorder;Panic Disorder
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Toxicity	3	clomipramine
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Efficacy	3	paroxetine	Major Depressive Disorder;Mood Disorder;Panic Disorder
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Toxicity	3	fluoxetine	Major Depressive Disorder
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Toxicity	3	Selective serotonin reuptake inhibitors
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Efficacy	4	venlafaxine	Anxiety Disorders;Depression
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Efficacy	4	citalopram	Major Depressive Disorder
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Efficacy	4	escitalopram	Depression;Depressive Disorder
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Efficacy	4	sertraline	Major Depressive Disorder;Panic Disorder
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Toxicity	4	sertraline	Anxiety Disorders;Major Depressive Disorder
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Efficacy	4	fluoxetine	Major Depressive Disorder;Obsessive-Compulsive Disorder
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Efficacy	3	ondansetron	Alcohol abuse
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Toxicity	3	peginterferon alfa-2b;ribavirin	Chronic hepatitis C virus infection
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Efficacy	3	buprenorphine;methadone	Opioid-Related Disorders
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Efficacy	3	bupropion	Tobacco Use Disorder
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Toxicity	3	ethanol	Alcohol abuse
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Toxicity	3	risperidone	Drug Toxicity
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Toxicity	3	mirtazapine	Major Depressive Disorder
SLC6A4 HTTLPR long form (L allele), SLC6A4 HTTLPR short form (S allele)	Efficacy	3	fluvoxamine	Major Depressive Disorder

PharmGKB variants

9 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs25531	SLC6A4	3	2.75	3	fluoxetine;citalopram;ethanol
rs140700	SLC6A4		0.00	0
rs1042173	SLC6A4	3	2.50	2	ondansetron;morphine
rs2020933	SLC6A4		0.00	0
rs3813034	SLC6A4		0.00	0
rs57098334	SLC6A4	3	2.75	4	antidepressants;fluoxetine;paroxetine;sertraline
rs4251417	SLC6A4	3	3.25	1	ethanol
rs2066713	SLC6A4	3	3.25	1	ethanol
rs7224199	SLC6A4		0.00	0

PharmGKB dosing guidelines

1 guidelines.

Source	Drug	Guideline	Dosing?	Recommendation?
CPIC	citalopram;desvenlafaxine;duloxetine;escitalopram;fluoxetine;fluvoxamine;levomilnacipran;milnacipran;paroxetine;sertraline;venlafaxine;vilazodone;vortioxetine	Annotation of CPIC Guideline for citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone, vortioxetine and SLC6A4

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Monoamine transporter subfamily

Most potent curated ligand interactions (38 total), top 25:

Ligand	Action	Affinity	Parameter
paroxetine	Inhibition	10.1	pKd
[3H]paroxetine	Inhibition	9.7	pKd
clomipramine	Inhibition	9.55	pKd
vilazodone	Inhibition	9.3	pIC50
sertraline	Inhibition	9.1	pKi
dapoxetine	Inhibition	8.95	pIC50
vortioxetine	Inhibition	8.8	pKi
escitalopram	Inhibition	8.68	pKd
fluvoxamine	Inhibition	8.66	pKd
fluoxetine	Inhibition	8.5	pKi
citalopram	Inhibition	8.36	pKi
H05	Inhibition	8.32	pKi
duloxetine	Inhibition	8.3	pKi
[3H]citalopram	Inhibition	8.3	pKd
nortriptyline	Inhibition	8.16	pKi
dosulepin	Inhibition	8.07	pKi
atomoxetine	Inhibition	8.05	pKd
desvenlafaxine	Inhibition	7.82	pKi
amoxapine	Inhibition	7.74	pKi
protriptyline	Inhibition	7.71	pKd
imipramine	Inhibition	7.69	pKi
venlafaxine	Inhibition	7.57	pIC50
milnacipran	Inhibition	7.3	pIC50
ziprasidone	Inhibition	7.28	pKi
lofepramine	Inhibition	7.22	pKi

Binding affinities (BindingDB)

826 measured of 910 human assays (1028 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(Z)-2-[18F]fluoroethyl 3-(4-(2-iodovinyl)phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2-carboxylate	KI	0.08 nM
CHEMBL2314215	KI	0.08 nM
1-[3-(4-isopropenylphenyl)-(2S,3S)-8-azabicyclo[3.2.1]oct-2-yl]-1-propanone	IC50	0.16 nM
2beta-carbomethoxy-3beta-(3’-((Z)-2-iodoethenyl)phenyl)nortropane	KI	0.2 nM
2beta-carbomethoxy-3beta-(3’-((Z)-2-bromoethenyl)phenyl)nortropane	KI	0.2 nM
2beta-Carbo(2-fluoropropoxy)-3beta-(3’-((Z)-2-iodoethenyl)phenyl)-nortropane	KI	0.26 nM
6-[2-[4-[(4-bromo-3-hydroxyphenyl)methyl]piperidin-1-yl]ethyl]chromen-4-one	KI	0.27 nM	US-8778970: Benzyl piperidine compound
(S,S)-reboxetine	KI	0.3 nM
1-[3-(4-vinylphenyl)-(2S,3S)-8-azabicyclo[3.2.1]oct-2-yl]-1-propanone	IC50	0.32 nM
2beta-Carbo(2-fluoroethoxy)-3beta-(3’-((Z)-2-bromoethenyl)phenyl)-nortropane	KI	0.33 nM
2beta-Carbo(2-fluoropropoxy)-3beta-(3’-((Z)-2-bmoroethenyl)phenyl)-nortropane	KI	0.33 nM
methyl 3-(4-iodophenyl)-(2S,3S)-8-azabicyclo[3.2.1]octane-2-carboxylate	IC50	0.36 nM
2beta-Carbo(2-fluoroethoxy)-3beta-(3’-((Z)-2-iodoethenyl)phenyl)-nortropane	KI	0.43 nM
2-Chlor-11-(2-dimethylaminoaethoxy)-dibenzo(b,f)-thiepin	KI	0.5 nM
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine	KI	0.6 nM
3-(4-Iodo-phenyl)-6-methyl-6-aza-bicyclo[3.2.2]nonane-4-carboxylic acid methyl ester	KI	0.67 nM
1-(3,4-dichlorophenyl)-5-[6-(trifluoromethyl)pyridazin-3-yl]oxy-9-azatricyclo[7.2.2.02,7]trideca-2(7),3,5-triene	IC50	0.7 nM	US-9045468: 2,5-methano- and 2,5-ethano-tetrahydrobenzazepine derivatives and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
3-(4-chloro-phenyl)-5-methylene-7-aza-tricyclo[5.3.0.04,8]decane	KI	0.82 nM
4-[[(3R)-4-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutyl]amino]butanamide	KI	0.91 nM	US-9296681: Cycloalkylmethylamines
4-(aminomethyl)-1-[2,5-difluoro-3-(3-fluorophenoxy)phenyl]piperidin-4-ol (E15)	IC50	0.912 nM	US-9920053: N-(hetero)aryl-substituted heteroyclic derivatives useful for the treatment of diseases or conditions related to the central nervous system
6-[2-[4-[(4-bromo-3-hydroxyphenyl)methyl]piperidin-1-yl]ethyl]-3-hydroxy-2,3-dihydrochromen-4-one	KI	1.1 nM	US-8778970: Benzyl piperidine compound
methyl 3-{4-[2-iodo-(E)-1-ethenyl]phenyl}-(2S,3S)-8-azabicyclo[3.2.1]octane-2-carboxylate	KI	1.15 nM
(1R)-1-[1-(3,4-dichlorophenyl)cyclobutyl]-N-(4-ethoxybutyl)-3-methylbutan-1-amine	KI	1.16 nM	US-10035761: Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives
6-[2-[4-[(4-bromo-3-hydroxyphenyl)methyl]piperidin-1-yl]ethyl]-2,3-dihydrochromen-4-one	KI	1.3 nM	US-8778970: Benzyl piperidine compound
9-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-1,4,9-triazaspiro[5.5]undecane	IC50	1.32 nM	US-9908897: Spirocyclic derivatives
3-[4-(2,2-Dibromo-vinyl)-phenyl]-8-methyl-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid methyl ester	KI	1.35 nM
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine	KI	1.4 nM
4-[[1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutyl]amino]butanamide	KI	1.5 nM	US-9296681: Cycloalkylmethylamines
4-(aminomethyl)-1-[3-fluoro-5-(3-fluorophenoxy)phenyl]piperidin-4-ol (E14)	IC50	1.51 nM	US-9920053: N-(hetero)aryl-substituted heteroyclic derivatives useful for the treatment of diseases or conditions related to the central nervous system
4-(3,4-dichlorophenyl)-1,1-dimethyl-7-pyrazin-2-yl-3,4-dihydro-2H-isoquinoline	IC50	1.8 nM	US-9034899: Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine	KI	1.9 nM	US-10183913: Pyrazole compound
5-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-6-chloro-1,3-dihydro-indol-2-one	KI	1.9 nM
4,5,6,7,8,9,10,11,13,17a,18,19,20,21,22,22a-hexadecahydro-23-methyl-14,17-etheno-19,22-imino-1H-cyclohept[c][1,9]oxaazacyclononadecine-3,12-dione	KI	1.9 nM
3-[(cyclopropylamino)methyl]-1-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3-ol (E30)	IC50	1.91 nM	US-9920053: N-(hetero)aryl-substituted heteroyclic derivatives useful for the treatment of diseases or conditions related to the central nervous system
6-[2-[4-[[4-bromo-3-(2-methoxyethoxy)phenyl]methyl]piperidin-1-yl]ethyl]chromen-4-one;hydrochloride	KI	2 nM	US-8778970: Benzyl piperidine compound
(3aS,7aS)-3a-(3-ethoxy-4-methoxyphenyl)-1-methyl-2,3,4,5,7,7a-hexahydroindol-6-one	IC50	2 nM	US-11555029: PD-1/PD-L1 inhibitors
6-[2-[4-[[4-bromo-3-(2-hydroxyethoxy)phenyl]methyl]piperidin-1-yl]ethyl]chromen-4-one;hydrochloride	KI	2.1 nM	US-8778970: Benzyl piperidine compound
4-(3,4-dichlorophenyl)-1,1-dimethyl-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-3,4-dihydro-2H-isoquinoline	IC50	2.1 nM	US-9034899: Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
1-{1-(cyclopentylmethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine	KI	2.2 nM	US-10183913: Pyrazole compound
(-)-1-{1-(2-cyclopentylethyl)-5-[(2,5-difluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylethanamine	KI	2.3 nM	US-10183913: Pyrazole compound
1-[1-(3,4-dichlorophenyl)cyclobutyl]-N-(2-ethoxyethyl)-3-methylbutan-1-amine	KI	2.38 nM	US-10035761: Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives
(1R)-1-[1-(3,4-dichlorophenyl)cyclobutyl]-N-(4-methoxybutyl)-3-methylbutan-1-amine	KI	2.39 nM	US-10035761: Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives
6-[4-(3,4-dichlorophenyl)-1,1-dimethyl-3,4-dihydro-2H-isoquinolin-7-yl]pyridazin-3-amine	IC50	2.4 nM	US-9034899: Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
2-(3-fluorophenoxy)-6-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)pyridine-4-carbonitrile	IC50	2.45 nM	US-9908897: Spirocyclic derivatives
6-[2-[4-[[4-bromo-3-(2-methoxyethoxy)phenyl]methyl]piperidin-1-yl]ethyl]-3-hydroxychromen-4-one	KI	2.5 nM	US-8778970: Benzyl piperidine compound
(6R)-2-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]-2,8-diazaspiro[4.5]decan-6-ol	IC50	2.57 nM	US-9908897: Spirocyclic derivatives
1-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(3-fluoro-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine hydrochloride	KI	2.6 nM	US-10183913: Pyrazole compound
1-{1-(cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine	KI	2.9 nM	US-10183913: Pyrazole compound
4-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-1-(4-fluoro-phenyl)-butan-1-one;propionate(HCl)	KI	2.92 nM
(S)-mianserin	KI	3 nM

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Ki	0.01	nM	CHEMBL23034
11.00	Ki	0.01	nM	CHEMBL361259
10.89	Ki	0.013	nM	CHEMBL2314218
10.89	Ki	0.013	nM	CHEMBL23034
10.52	Ki	0.03	nM	CHEMBL2314217
10.52	Ki	0.03	nM	CHEMBL239079
10.40	Ki	0.04	nM	PAROXETINE
10.40	Ki	0.04	nM	CHEMBL428706
10.40	Ki	0.04	nM	CHEMBL14531
10.37	Ki	0.043	nM	PAROXETINE
10.33	Ki	0.047	nM	CLOMIPRAMINE
10.30	Ki	0.05	nM	CHEMBL174088
10.30	Ki	0.05	nM	CHEMBL239297
10.30	Ki	0.05	nM	CHEMBL428706
10.22	Ki	0.06	nM	CHEMBL356750
10.15	Ki	0.07	nM	CHEMBL206580
10.12	Ki	0.075	nM	SERTRALINE
10.11	Ki	0.077	nM	PAROXETINE
10.10	Ki	0.08	nM	CHEMBL2314215
10.10	Ki	0.08	nM	CHEMBL230000
10.10	Ki	0.08	nM	PAROXETINE
10.10	Ki	0.08	nM	[3H]PAROXETINE
10.10	Ki	0.08	nM	CHEMBL395998
10.10	Ki	0.07943	nM	CHEMBL597000
10.10	Ki	0.07943	nM	CHEMBL598215
10.10	Ki	0.08	nM	CHEMBL14305
10.10	Ki	0.08	nM	CHEMBL14257
10.10	IC50	0.08	nM	PAROXETINE
10.06	IC50	0.088	nM	CLOMIPRAMINE
10.05	Ki	0.09	nM	CHEMBL114275
10.05	Ki	0.09	nM	CHEMBL380383
10.05	Ki	0.09	nM	PAROXETINE
10.01	Ki	0.097	nM	CHEMBL2314219
10.01	Ki	0.097	nM	CHEMBL114275
10.00	Ki	0.1	nM	CHEMBL114275
10.00	Ki	0.1	nM	CHEMBL83617
10.00	Ki	0.1	nM	CHEMBL238868
10.00	Ki	0.1	nM	CHEMBL1818448
9.96	IC50	0.11	nM	CHEMBL83617
9.96	Ki	0.11	nM	PAROXETINE
9.96	Ki	0.11	nM	CHEMBL275212
9.92	Ki	0.12	nM	CHEMBL183470
9.90	Ki	0.1259	nM	CHEMBL605209
9.90	Ki	0.1259	nM	6-(3,4-DICHLOROPHENYL)-1-[1-(METHYLOXY)-3-BUTEN-1-YL]-3-AZABICYCLO[4.1.0]HEPTANE (DIASTEREOMERIC MIX)
9.90	Ki	0.1259	nM	1-(METHOXYMETHYL)-6-(NAPHTHALEN-2-YL)-3-AZABICYCLO[4.1.0]HEPTANE (ENANTIOMERIC MIX)
9.89	Kd	0.13	nM	PAROXETINE
9.89	IC50	0.13	nM	CHEMBL552167
9.85	IC50	0.141	nM	SERTRALINE
9.82	Ki	0.15	nM	CHEMBL239302
9.80	IC50	0.16	nM	CHEMBL173344

PubChem BioAssay actives

3253 with measured affinity, of 6100 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
methyl 3-[4-[(Z)-2-iodoethenyl]phenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate	204199: Inhibition of [125I]RTI-55 binding to human serotonin transporter expressed in human embryonic kidney cells	ki	<0.0001	uM
2-[2-[(dimethylamino)methyl]phenyl]sulfanyl-5-iodoaniline	239382: Binding affinity for serotonin transporter expressed in LCK PK1 cells	ki	<0.0001	uM
5-chloro-2-[2-[(dimethylamino)methyl]-4-(2-fluoroethoxy)phenyl]sulfanylaniline	304585: Displacement of [125I]5-iodo-2-[[2,2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol from SERT expressed in LLCPK1 cells	ki	<0.0001	uM
Paroxetine	254322: Binding inhibition towards human serotonin transporter	ki	<0.0001	uM
2-[2-[(dimethylamino)methyl]phenyl]sulfanyl-5-(123I)iodo(123I)aniline	725180: Binding affinity to SERT (unknown origin)	ki	<0.0001	uM
methyl 3-[4-[(Z)-2-bromoethenyl]phenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate	204199: Inhibition of [125I]RTI-55 binding to human serotonin transporter expressed in human embryonic kidney cells	ki	<0.0001	uM
3-[(1S,2S)-2-[(dimethylamino)methyl]cyclopentyl]-1H-indole-5-carbonitrile	426683: Displacement of [125I]RTI-55 from human SERT expressed in HEK293 cells	ic50	0.0001	uM
2-[2-[(dimethylamino)methyl]-4-(2-fluoroethoxy)phenyl]sulfanyl-5-fluoroaniline	304585: Displacement of [125I]5-iodo-2-[[2,2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol from SERT expressed in LLCPK1 cells	ki	0.0001	uM
5-bromo-2-[2-[(dimethylamino)methyl]-4-(2-fluoroethoxy)phenyl]sulfanylaniline	304585: Displacement of [125I]5-iodo-2-[[2,2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol from SERT expressed in LLCPK1 cells	ki	0.0001	uM
5-bromo-2-[2-[(dimethylamino)methyl]-4-(3-fluoropropoxy)phenyl]sulfanylaniline	304585: Displacement of [125I]5-iodo-2-[[2,2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol from SERT expressed in LLCPK1 cells	ki	0.0001	uM
(1R,6S)-1-(methoxymethyl)-6-naphthalen-2-yl-3-azabicyclo[4.1.0]heptane	491805: Displacement of [N-methyl-3H]citalopram from human recombinant SERT expressed in pig LLCPK cells after 2 hrs by liquid scintillation counting	ki	0.0001	uM
(1R,5R,6R)-6-(methoxymethyl)-1-naphthalen-2-yl-3-azabicyclo[3.1.0]hexane	462683: Displacement of [3H]citalopram from human recombinant SERT expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0001	uM
(1R,5R,6R)-1-(3,4-dichlorophenyl)-6-(propan-2-yloxymethyl)-3-azabicyclo[3.1.0]hexane	462683: Displacement of [3H]citalopram from human recombinant SERT expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0001	uM
methyl 3-[4-[(Z)-2-bromoethenyl]phenyl]-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate	204199: Inhibition of [125I]RTI-55 binding to human serotonin transporter expressed in human embryonic kidney cells	ki	0.0001	uM
methyl 3-[4-[(Z)-2-iodoethenyl]phenyl]-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate	204199: Inhibition of [125I]RTI-55 binding to human serotonin transporter expressed in human embryonic kidney cells	ki	0.0001	uM
methyl 3-[4-(2,2-dibromoethenyl)phenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate	204199: Inhibition of [125I]RTI-55 binding to human serotonin transporter expressed in human embryonic kidney cells	ki	0.0001	uM
methyl (2S,3S)-3-[4-[(Z)-2-iodoethenyl]phenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate	204202: In vitro competitive binding versus [3H]citalopram in murine kidney cells transfected with cDNA for human serotonin transporter (SERT)	ki	0.0001	uM
(E)-but-2-enedioic acid;N-(2-methylpropyl)-N-[[4-(trifluoromethyl)phenyl]methyl]piperidin-4-amine	264861: Displacement of [3H]citalopram from SERT	ki	0.0001	uM
3-(4-iodophenyl)-5-methylidene-7-azatricyclo[5.3.0.04,8]decane	270530: Displacement of [3H]citalopram from human SERT transfected in HEK293 cells	ki	0.0001	uM
2-fluoroethyl 3-[4-[(Z)-2-iodoethenyl]phenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate	297724: Binding affinity to human SERT expressed in HEK293 cells	ki	0.0001	uM
2-(18F)fluoroethyl 3-[4-[(Z)-2-iodoethenyl]phenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate	413283: Displacement of 3Hcitalopram.HBr from human SERT transfected in human HEK293 cells	ki	0.0001	uM
6-[2-[4-(2-phenylquinolin-5-yl)piperazin-1-yl]ethyl]-4H-1,4-benzoxazin-3-one	344712: Displacement of [3H]citalopram from human SerT expressed pig LLCPK cells	ki	0.0002	uM
2-[2-[(dimethylamino)methyl]phenoxy]-5-iodoaniline	456161: Displacement of [3H]citalopram from human cloned SERT expressed in HEK293 cells	ki	0.0002	uM
3-[(1S,2S)-2-[(dimethylamino)methyl]cyclopropyl]-1H-indole-5-carbonitrile	254348: In vitro binding inhibition towards human serotonin transporter	ki	0.0002	uM
N-[[(1S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3H-2-benzofuran-5-yl]methyl]-4-(4-prop-2-ynoxybenzoyl)benzamide	1422256: Displacement of [125I]-RTI-55 from human SERT expressed in HEK293 cell membranes after 1 hr by gamma counting method	ki	0.0002	uM
3-[4-(2-amino-4-bromophenyl)sulfanyl-3-[(dimethylamino)methyl]phenoxy]propan-1-ol	304585: Displacement of [125I]5-iodo-2-[[2,2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol from SERT expressed in LLCPK1 cells	ki	0.0002	uM
(1S,5S,6S)-1-(3,4-dichlorophenyl)-6-(ethoxymethyl)-3-azabicyclo[3.1.0]hexane	462683: Displacement of [3H]citalopram from human recombinant SERT expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0002	uM
(1S,5S,6S)-1-(3,4-dichlorophenyl)-6-(propan-2-yloxymethyl)-3-azabicyclo[3.1.0]hexane	462683: Displacement of [3H]citalopram from human recombinant SERT expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0002	uM
3-(3,4-dichlorophenyl)-N-methyl-2,3-dihydro-1H-inden-1-amine	613076: Displacement of [3H]citalopram from human recombinant SERT scintillation proximity assay	ki	0.0002	uM
(2S)-1-[(2S,4R)-4-(5-fluoro-1-benzothiophen-2-yl)-2-methylpiperidin-1-yl]-3-[(2-methyl-1H-indol-4-yl)oxy]propan-2-ol	263905: Displacement of [3H]paroxetine from 5HT reuptake site	ki	0.0002	uM
methyl (2S,3S)-3-[3-[(E)-2-iodoethenyl]phenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate	271975: Displacement of [3H]citalopram from human SERT	ki	0.0002	uM
methyl (2S,3S)-3-[3-[(E)-2-bromoethenyl]phenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate	271975: Displacement of [3H]citalopram from human SERT	ki	0.0002	uM
2-[2-[(dimethylamino)methyl]phenyl]sulfanyl-5-methylaniline	239682: In vitro inhibition of [3H]citalopram binding to human serotonin transporter expressed in human HEK293 cells	ki	0.0003	uM
3-[2-[4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl]pyrimidin-5-yl]benzamide	1965878: Inhibition of SERT receptor (unknown origin)	ic50	0.0003	uM
3-[4-[4-[5-(4-chlorophenyl)pyrimidin-2-yl]piperazin-1-yl]butyl]-1H-indole-5-carbonitrile	1965878: Inhibition of SERT receptor (unknown origin)	ic50	0.0003	uM
(6S,10bR)-6-(4-ethynylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline	1388098: Binding affinity to SERT (unknown origin)	ki	0.0003	uM
5-(3,4-dichlorophenyl)-9-oxa-2-azaspiro[5.5]undecane	1388122: Binding affinity to human SERT	ki	0.0003	uM
3-[4-(dimethylamino)cyclohexen-1-yl]-1H-indole-5-carbonitrile	295437: Displacement of [125I]RTI-55 from human SERT expressed in HEK293 cells	ic50	0.0003	uM
2-[2-[(dimethylamino)methyl]-4-(2-fluoroethoxy)phenyl]sulfanylaniline	304585: Displacement of [125I]5-iodo-2-[[2,2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol from SERT expressed in LLCPK1 cells	ki	0.0003	uM
[3-amino-4-[4-bromo-2-[(dimethylamino)methyl]phenyl]sulfanylphenyl]methanol	312374: Displacement of [3H]citalopram from human SERT expressed in HEK293 cells	ki	0.0003	uM
[3-amino-4-[2-[(dimethylamino)methyl]-4-iodophenyl]sulfanylphenyl]methanol	312374: Displacement of [3H]citalopram from human SERT expressed in HEK293 cells	ki	0.0003	uM
(1R,5R,6R)-1-(3,4-dichlorophenyl)-6-(propoxymethyl)-3-azabicyclo[3.1.0]hexane	462683: Displacement of [3H]citalopram from human recombinant SERT expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0003	uM
(1S,5S,6S)-6-(cyclopentyloxymethyl)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane	462683: Displacement of [3H]citalopram from human recombinant SERT expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0003	uM
(1R,5S)-6-(butan-2-yloxymethyl)-6-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane	462683: Displacement of [3H]citalopram from human recombinant SERT expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0003	uM
(1S,5R)-6-(3,4-dichlorophenyl)-6-(2-propan-2-yloxyethyl)-3-azabicyclo[3.1.0]hexane	462683: Displacement of [3H]citalopram from human recombinant SERT expressed in BacMam virus-transduced cells by scintillation proximity assay	ki	0.0003	uM
Clomipramine	1245952: Displacement of [3H]-imipramine from human serotonin transporter expressed in HEK293 cells after 30 mins by liquid scintillation counting analysis	ki	0.0003	uM
2-[2-[(dimethylamino)methyl]phenyl]sulfanyl-5-(trifluoromethyl)aniline	204200: In vitro binding affinity on cloned Serotonin transporter	ki	0.0003	uM
(2S)-1-(1H-indol-4-yloxy)-3-[(2S,4R)-4-(4-methoxy-1-benzothiophen-2-yl)-2-methylpiperidin-1-yl]propan-2-ol	263905: Displacement of [3H]paroxetine from 5HT reuptake site	ki	0.0003	uM
(2S)-1-[(2S,4R)-4-(6-fluoro-1-benzothiophen-2-yl)-2-methylpiperidin-1-yl]-3-(1H-indol-4-yloxy)propan-2-ol	263905: Displacement of [3H]paroxetine from 5HT reuptake site	ki	0.0003	uM
(2R)-1-[(2S,4R)-4-(1-benzothiophen-5-yl)-2-methylpiperidin-1-yl]-3-[(2-methyl-1H-indol-4-yl)oxy]propan-2-ol	3170: Binding affinity at 5-HT reuptake site labeled with [3H]paroxetine	ki	0.0003	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Serotonin	increases reaction, affects binding, decreases response to substance, increases uptake, affects abundance (+3 more)	8
Fluoxetine	affects expression, decreases activity, decreases localization, affects response to substance, affects binding (+4 more)	7
N-Methyl-3,4-methylenedioxyamphetamine	decreases activity, decreases expression, affects expression, affects binding, affects reaction (+3 more)	6
Cocaine	decreases activity, decreases reaction, increases activity, increases import, increases uptake (+2 more)	5
Citalopram	increases activity, affects secretion, affects response to substance, affects binding, decreases activity (+2 more)	5
bisphenol A	increases expression, affects cotreatment, decreases methylation, decreases expression	3
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	3
Methamphetamine	increases reaction, decreases expression, decreases reaction, increases activity	3
Nortriptyline	decreases response to substance, affects response to substance, increases response to substance	3
Sertraline	affects response to substance, affects binding, decreases reaction, increases expression, increases response to substance	3
para-methyl-4-methylaminorex	decreases reaction, increases reaction, increases uptake, affects binding, decreases activity	2
Vortioxetine	affects binding, decreases activity, decreases expression	2
Clomipramine	decreases reaction, affects binding, decreases activity, affects secretion	2
Valproic Acid	affects expression, decreases expression	2
Selective Serotonin Reuptake Inhibitors	affects response to substance, decreases response to substance, increases response to substance	2
Paroxetine	decreases activity, decreases expression, affects binding	2
4-methylaminorex	decreases reaction, increases uptake	1
aristolochic acid I	increases expression	1
1-phenyl-2-(1-pyrrolidinyl)-1-pentanone	increases import, decreases reaction	1
1-(4-methylphenyl)propane-2-amine	increases activity	1
GSK-J4	increases expression	1
2-(4-bromo-2,5-dimethoxyphenyl)-N-((2-methoxyphenyl)methyl)ethanamine	increases import, decreases reaction	1
5-(2-aminopropyl)benzofuran	decreases reaction, increases import	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	decreases expression	1
nisoxetine	affects binding, decreases activity	1
ethyl-p-hydroxybenzoate	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1

ChEMBL screening assays

1055 unique, capped per target: 1021 binding, 18 functional, 9 admet, 6 toxicity, 1 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL805625	Binding	Selectivity ratio between serotonin and dopamine transporters	Design, synthesis, and biological evaluation of novel non-piperazine analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines as dopamine transporter inhibitors. — J Med Chem
CHEMBL1060392	Functional	Antagonist activity at human 5HT transporter expressed in staurosporine treated human JAR cells	Synthesis, potency, and in vivo evaluation of 2-piperazin-1-ylquinoline analogues as dual serotonin reuptake inhibitors and serotonin 5-HT1A receptor antagonists. — J Med Chem
CHEMBL1738001	Unclassified	PUBCHEM_BIOASSAY: Late-stage radioligand binding dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): PDSP screen Ki. (Class of assay: screening) [Related pubchem assays (depositor defined):AID1792, AID1796, AID1823, AID253	PubChem BioAssay data set

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1UG	Abcam U-87MG SLC6A4 KO	Cancer cell line	Male
CVCL_D4UF	HuH7-SLC6A4-KO-c2	Cancer cell line	Male
CVCL_D4UG	HuH7-SLC6A4-KO-c3	Cancer cell line	Male
CVCL_E7V1	293-hSERT	Transformed cell line	Female
CVCL_F1X5	ValiScreen human SLC6A4	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00652457	PHASE4	COMPLETED	Study of Memantine to Treat Huntington’s Disease
NCT01834911	PHASE4	COMPLETED	Effect of Tetrabenazine on Stroop Interference in HD
NCT02509793	PHASE4	UNKNOWN	A Pilot Study Assessing Impulsivity in Patients With Huntington’s Disease on Xenazine (Tetrabenazine)
NCT07601516	PHASE4	COMPLETED	Real World Effectiveness and Safety of Deutetrabenazine in Adult Chinese Patients With Huntington’s Disease (HD) Chorea in China
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
NCT00000373	PHASE4	COMPLETED	Treatment of Obsessive-Compulsive Disorder
NCT00001658	PHASE4	COMPLETED	Amoxicillin for the Treatment of Pediatric Autoimmune Disorders Associated With Streptococcal Infections
NCT00116532	PHASE4	COMPLETED	Escitalopram for the Treatment of Obsessive Compulsive Disorder (OCD)
NCT00182520	PHASE4	COMPLETED	Efficacy of Adding Topiramate to Current Treatment in Refractory Obsessive Compulsive Disorder (OCD)
NCT00182533	PHASE4	TERMINATED	Sertraline in Generalized Social Phobia With Co-Occurring Anxiety and Mood Disorders
NCT00211744	PHASE4	COMPLETED	Topiramate Augmentation in the Treatment of Obsessive-Compulsive Disorder
NCT00352469	PHASE4	COMPLETED	Trial of Seroquel SR for Alcohol Dependence and Comorbid Anxiety
NCT00352768	PHASE4	TERMINATED	Fluvoxamine Maleate in the Treatment of Obsessive-Compulsive Disorder: A Post-marketing Clinical Study in Children and Adolescents
NCT00382291	PHASE4	COMPLETED	Effectiveness of Sertraline and Cognitive Behavioral Therapy in Treating Pediatric Obsessive-Compulsive Disorder
NCT00464698	PHASE4	COMPLETED	Duloxetine for the Treatment of Obsessive Compulsive Disorder (OCD)
NCT00466609	PHASE4	COMPLETED	Using Drug Augmentation to Treat Obsessive Compulsive Disorder Patients Who Did Not Respond to Previous Treatment
NCT00564564	PHASE4	COMPLETED	Quetiapine Augmentation Versus Clomipramine Augmentation of SSRI for Obsessive-compulsive Disorder Patients
NCT00640133	PHASE4	ACTIVE_NOT_RECRUITING	Effectiveness of Deep Brain Stimulation for Treating People With Treatment Resistant Obsessive-Compulsive Disorder
NCT00680602	PHASE4	COMPLETED	Group Cognitive Behavioral Therapy Versus Fluoxetine for Obsessive-Compulsive Disorder: a Practical Trial
NCT00708240	PHASE4	UNKNOWN	Treatment Youth With Obsessive-Compulsive Disorder