SLC6A5

Summary

SLC6A5 (solute carrier family 6 member 5, HGNC:11051) is a protein-coding gene on chromosome 11p15.1, encoding Sodium- and chloride-dependent glycine transporter 2 (Q9Y345). Sodium- and chloride-dependent glycine transporter.

This gene encodes a sodium- and chloride-dependent glycine neurotransmitter transporter. This integral membrane glycoprotein is responsible for the clearance of extracellular glycine during glycine-mediated neurotransmission. This protein is found in glycinergic axons and maintains a high presynaptic pool of neurotransmitter at glycinergic synapses. Mutations in this gene cause hyperekplexia; a heterogenous neurological disorder characterized by exaggerated startle responses and neonatal apnea. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 9152 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperekplexia 3 (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 893 total — 43 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes
• MANE Select transcript: NM_004211

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11051
Approved symbol	SLC6A5
Name	solute carrier family 6 member 5
Location	11p15.1
Locus type	gene with protein product
Status	Approved
Aliases	GLYT2, GlyT-2
Ensembl gene	ENSG00000165970
Ensembl biotype	protein_coding
OMIM	604159
Entrez	9152

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 1 nonsense_mediated_decay, 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000298923, ENST00000525748, ENST00000528440

RefSeq mRNA: 2 — MANE Select: NM_004211 NM_001318369, NM_004211

CCDS: CCDS7854

Canonical transcript exons

ENST00000525748 — 16 exons

Exon	Start	End
ENSE00001098537	20604286	20604424
ENSE00001206097	20601129	20601665
ENSE00001389337	20599608	20599675
ENSE00002178467	20654713	20659285
ENSE00003498055	20627980	20628083
ENSE00003531339	20652289	20652456
ENSE00003533991	20636307	20636419
ENSE00003578035	20614679	20614820
ENSE00003615854	20637172	20637303
ENSE00003618751	20630691	20630815
ENSE00003629736	20626708	20626842
ENSE00003640761	20617752	20617884
ENSE00003651067	20646834	20646934
ENSE00003674279	20607007	20607138
ENSE00003690537	20607479	20607652
ENSE00003690902	20638459	20638558

Expression profiles

Bgee: expression breadth broad, 36 present calls, max score 83.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.9265 / max 88.2809, expressed in 1410 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103634	6.9265	1410
113429	0.0348	14
113431	0.0063	4
113430	0.0045	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	83.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.29	gold quality
oocyte	CL:0000023	72.61	gold quality
superior vestibular nucleus	UBERON:0007227	68.04	silver quality
medulla oblongata	UBERON:0001896	66.14	silver quality
adrenal tissue	UBERON:0018303	65.41	gold quality
buccal mucosa cell	CL:0002336	63.36	silver quality
pancreatic ductal cell	CL:0002079	61.51	silver quality
deltoid	UBERON:0001476	59.72	gold quality
pons	UBERON:0000988	57.70	gold quality
sperm	CL:0000019	57.11	gold quality
superficial temporal artery	UBERON:0001614	57.11	gold quality
ileal mucosa	UBERON:0000331	56.34	silver quality
pylorus	UBERON:0001166	55.48	gold quality
cerebellar vermis	UBERON:0004720	55.44	gold quality
trachea	UBERON:0003126	55.43	gold quality
cardia of stomach	UBERON:0001162	55.08	gold quality
epithelial cell of pancreas	CL:0000083	54.83	gold quality
layer of synovial tissue	UBERON:0007616	54.79	gold quality
urethra	UBERON:0000057	54.59	gold quality
saphenous vein	UBERON:0007318	54.54	gold quality
pericardium	UBERON:0002407	54.46	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
medial globus pallidus	UBERON:0002477	54.25	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
gingival epithelium	UBERON:0001949	54.18	gold quality
thymus	UBERON:0002370	54.18	gold quality
trigeminal ganglion	UBERON:0001675	54.14	gold quality
nipple	UBERON:0002030	54.13	gold quality
synovial joint	UBERON:0002217	54.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting SLC6A5, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-6794-3P	98.76	66.99	894
HSA-MIR-323A-5P	98.59	65.13	651
HSA-MIR-4266	98.53	67.29	1035
HSA-MIR-6511A-5P	98.13	67.47	1770

Literature-anchored findings (GeneRIF, showing 14)

• Variants not associated with bipolar disorder or schizophrenia. (PMID:16691125)
• SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites. (PMID:16751771)
• results are consistent with GLYT2 being a disease gene in human hyperekplexia (PMID:16884688)
• SLC6A5 gene is associated with schizophrenia. (PMID:18638388)
• Inspiratory-modulated neurons with pacemaker properties are present in the preBotzinger complex of newborn transgenic mice and express the glycine tranporter (GlyT)2 protein. (PMID:20219997)
• A transgenic cell line is studied in which green fluorescent protein (GFP) is expressed under the control of the promoter for the glycine transporter GlyT2 during zebrafish development. (PMID:21397641)
• This study firmly establishes the combination of missense, nonsense, frameshift, and splice site mutations in the GlyT2 gene as the second major cause of startle disease. (PMID:22700964)
• A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2. (PMID:22753417)
• Constitutive endocytosis and turnover of the neuronal glycine transporter GlyT2 is dependent on ubiquitination of a C-terminal lysine cluster. (PMID:23484054)
• Report that in the presence of a GlyT2 mechanism-based toxicity, reversible inhibitors might allow a tolerable balance between efficacy and toxicity. (PMID:23962079)
• analysis of the human SLC6A5 gene mutation associated with hyperekplexia (PMID:25480793)
• An overview of hyperekplexia-associated mutations in the neuronal glycine transporter 2 (GlyT2) with special focus on dominant mutations that effect the quaternary structure of GlyT2 (review). (PMID:29859229)
• Photoswitchable ORG25543 Congener Enables Optical Control of Glycine Transporter 2. (PMID:32191428)
• The allosteric inhibition of glycine transporter 2 by bioactive lipid analgesics is controlled by penetration into a deep lipid cavity. (PMID:33450225)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc6a5	ENSDARG00000067964
mus_musculus	Slc6a5	ENSMUSG00000039728
rattus_norvegicus	Slc6a5	ENSRNOG00000031662
caenorhabditis_elegans		WBGENE00004905

Paralogs (19): SLC6A13 (ENSG00000010379), SLC6A7 (ENSG00000011083), SLC6A16 (ENSG00000063127), SLC6A15 (ENSG00000072041), SLC6A2 (ENSG00000103546), SLC6A4 (ENSG00000108576), SLC6A12 (ENSG00000111181), SLC6A8 (ENSG00000130821), SLC6A6 (ENSG00000131389), SLC6A11 (ENSG00000132164), SLC6A3 (ENSG00000142319), SLC6A1 (ENSG00000157103), SLC6A20 (ENSG00000163817), SLC6A18 (ENSG00000164363), SLC6A19 (ENSG00000174358), SLC6A9 (ENSG00000196517), SLC6A17 (ENSG00000197106), SLC6A14 (ENSG00000268104), (ENSG00000273554)

Protein

Protein identifiers

Sodium- and chloride-dependent glycine transporter 2 — Q9Y345 (reviewed: Q9Y345)

Alternative names: Solute carrier family 6 member 5

All UniProt accessions (2): Q9Y345, J3KNC4

UniProt curated annotations — full annotation on UniProt →

Function. Sodium- and chloride-dependent glycine transporter. Terminates the action of glycine by its high affinity sodium-dependent reuptake into presynaptic terminals. May be responsible for the termination of neurotransmission at strychnine-sensitive glycinergic synapses. Lacks sodium- and chloride-dependent glycine transporter activity. Lacks sodium- and chloride-dependent glycine transporter activity.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in medulla, and to a lesser extent in spinal cord and cerebellum.

Post-translational modifications. N-glycosylated.

Disease relevance. Hyperekplexia 3 (HKPX3) [MIM:614618] A neurologic disorder characterized by neonatal hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. Notably, in some cases, symptoms resolved in the first year of life. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A5 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y345-1	1	yes
Q9Y345-2	2
Q9Y345-3	3

RefSeq proteins (2): NP_001305298, NP_004202* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000175	Na/ntran_symport	Family
IPR037272	SNS_sf	Homologous_superfamily

Pfam: PF00209

Catalyzed reactions (Rhea), 1 shown:

• glycine(out) + chloride(out) + 3 Na(+)(out) = glycine(in) + chloride(in) + 3 Na(+)(in) (RHEA:70695)

UniProt features (66 total): sequence variant 21, transmembrane region 12, binding site 8, mutagenesis site 5, sequence conflict 5, glycosylation site 4, topological domain 3, modified residue 3, splice variant 2, chain 1, region of interest 1, disulfide bond 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9HUE	ELECTRON MICROSCOPY	2.49
9HUF	ELECTRON MICROSCOPY	2.79
9HUG	ELECTRON MICROSCOPY	2.97
9R1H	ELECTRON MICROSCOPY	3.02

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y345-F1	74.63	0.43

Functional residue map

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

Ligand- & substrate-binding residues (8): 206; 208; 209; 213; 477; 509; 574; 577

Post-translational modifications (3): 56, 57, 84

Disulfide bonds (1): 311–320

Glycosylation sites (4): 343, 353, 358, 364

Mutagenesis-validated functional residues (5):

Position	Phenotype
449	loss of glycine transport.
705	decreased surface expression. decreased glycine transport.
705	decreased glycine transport.
705	no effect on glycine transport.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-442660	SLC-mediated transport of neurotransmitters
R-HSA-5619089	Defective SLC6A5 causes hyperekplexia 3 (HKPX3)
R-HSA-1643685	Disease
R-HSA-382551	Transport of small molecules
R-HSA-425366
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5619102	SLC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters

MSigDB gene sets: 522 (showing top): GOBP_RESPONSE_TO_IONIZING_RADIATION, BENPORATH_ES_WITH_H3K27ME3, JAEGER_METASTASIS_DN, NKX25_02, GOCC_SECRETORY_GRANULE, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_GROWTH, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_NEUROTRANSMITTER_TRANSPORT, KYNG_DNA_DAMAGE_DN

GO Biological Process (5): neurotransmitter transport (GO:0006836), chemical synaptic transmission (GO:0007268), sodium ion transmembrane transport (GO:0035725), synaptic transmission, glycinergic (GO:0060012), glycine import across plasma membrane (GO:1903804)

GO Molecular Function (4): glycine:sodium symporter activity (GO:0015375), metal ion binding (GO:0046872), symporter activity (GO:0015293), transmembrane transporter activity (GO:0022857)

GO Cellular Component (5): endosome (GO:0005768), plasma membrane (GO:0005886), membrane (GO:0016020), dense core granule (GO:0031045), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
SLC-mediated transmembrane transport	1
SLC transporter disorders	1
Transport of small molecules	1
Disorders of transmembrane transporters	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	1
anterograde trans-synaptic signaling	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
chemical synaptic transmission	1
glycine transport	1
amino acid import across plasma membrane	1
carboxylic acid transmembrane transport	1
neutral L-amino acid:sodium symporter activity	1
organic acid:sodium symporter activity	1
glycine transmembrane transporter activity	1
cation binding	1
secondary active transmembrane transporter activity	1
transporter activity	1
transmembrane transport	1
endomembrane system	1
cytoplasmic vesicle	1
membrane	1
cell periphery	1
cellular anatomical structure	1
secretory granule	1
cell junction	1

Protein interactions and networks

STRING

1252 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC6A5	GLRA1	P23415	950
SLC6A5	GLRB	P48167	918
SLC6A5	SLC1A5	Q15758	880
SLC6A5	GPHN	Q9NQX3	849
SLC6A5	ARHGEF9	O43307	847
SLC6A5	DPYSL5	Q9BPU6	836
SLC6A5	SDCBP	O00560	830
SLC6A5	SLC32A1	Q9H598	739
SLC6A5	SLC17A6	Q9P2U8	723
SLC6A5	GARS1	P41250	714
SLC6A5	GAD1	Q99259	713
SLC6A5	GAD2	Q05329	631
SLC6A5	SDCBP2	Q9H190	587
SLC6A5	SLC17A7	Q9P2U7	584
SLC6A5	DBX1	A6NMT0	543

IntAct

6 interactions, top by confidence:

A	B	Type	Score
SLC6A5	GPR89A	psi-mi:“MI:0914”(association)	0.350
PFKM	ARHGAP44	psi-mi:“MI:0914”(association)	0.350
SLC6A5	SCAMP3	psi-mi:“MI:0914”(association)	0.350
SLC6A5	BAG2	psi-mi:“MI:0914”(association)	0.350
SLC6A6	ELP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (56): GNB2 (Affinity Capture-MS), GPR89A (Affinity Capture-MS), TBC1D24 (Affinity Capture-MS), ARL6IP5 (Affinity Capture-MS), GNG5 (Affinity Capture-MS), ATP5F1 (Affinity Capture-MS), GOLGA5 (Affinity Capture-MS), ATP5B (Affinity Capture-MS), FAM134C (Affinity Capture-MS), NAT14 (Affinity Capture-MS), FAM134C (Affinity Capture-MS), NAT14 (Affinity Capture-MS), STX1A (Affinity Capture-Western), SLC6A5 (Affinity Capture-MS), CERS6 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K1Q8, A0AV02, A2A6C4, A5D7L5, A6QNW6, B1MTL0, B2RXE2, C1BKZ7, O18917, P04920, P0DX17, P13808, P16283, P23347, P23348, P35523, P35524, P48746, P48751, P58295, Q0P5V9, Q14940, Q15043, Q15477, Q3MJ16, Q504Y0, Q50L42, Q5FWH7, Q5RB85, Q5RD44, Q64347, Q6A4L1, Q6SJP2, Q761V0, Q8BXR1, Q8CJI3, Q8K0H7, Q8R420, Q8VI23, Q91WD2

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	26
Uncertain significance	352
Likely benign	358
Benign	78

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1207401	NM_004211.5(SLC6A5):c.679+1G>T	Pathogenic
1323615	NM_004211.5(SLC6A5):c.1315C>T (p.Arg439Ter)	Pathogenic
1353821	NM_004211.5(SLC6A5):c.2124C>A (p.Tyr708Ter)	Pathogenic
1373505	NM_004211.5(SLC6A5):c.1266_1267dup (p.Tyr423fs)	Pathogenic
1394178	NM_004211.5(SLC6A5):c.997_998del (p.Ile333fs)	Pathogenic
1437471	NM_004211.5(SLC6A5):c.1621C>T (p.Gln541Ter)	Pathogenic
1453382	NC_000011.9:g.(?20621219)(20668500_?)del	Pathogenic
1454424	NM_004211.5(SLC6A5):c.1759del (p.Ile586_Val587insTer)	Pathogenic
1455981	NM_004211.5(SLC6A5):c.1680_1681dup (p.Pro561fs)	Pathogenic
1457616	NC_000011.9:g.(?20668360)(20668500_?)del	Pathogenic
1458893	NM_004211.5(SLC6A5):c.90C>A (p.Cys30Ter)	Pathogenic
1971213	NM_004211.5(SLC6A5):c.811+1G>T	Pathogenic
2015912	NM_004211.5(SLC6A5):c.342del (p.Gly115fs)	Pathogenic
2018966	NM_004211.5(SLC6A5):c.769C>T (p.Gln257Ter)	Pathogenic
2079085	NM_004211.5(SLC6A5):c.1969+1G>A	Pathogenic
2087072	NM_004211.5(SLC6A5):c.1374G>A (p.Trp458Ter)	Pathogenic
2149851	NM_004211.5(SLC6A5):c.1286C>T (p.Pro429Leu)	Pathogenic
2425045	NC_000011.9:g.(?20612464)(20622873_?)del	Pathogenic
2858966	NM_004211.5(SLC6A5):c.31A>T (p.Lys11Ter)	Pathogenic
2991866	NM_004211.5(SLC6A5):c.1680_1681del (p.Pro561fs)	Pathogenic
31540	NM_004211.5(SLC6A5):c.1530T>G (p.Ser510Arg)	Pathogenic
3244667	NC_000011.9:g.(?20621219)(20625990_?)del	Pathogenic
3244668	NC_000011.9:g.(?20625977)(20687645_?)del	Pathogenic
3244670	NC_000011.9:g.(?20617213)(20623070_?)del	Pathogenic
3664122	NM_004211.5(SLC6A5):c.1893del (p.Val632fs)	Pathogenic
38370	NM_004211.5(SLC6A5):c.1444T>C (p.Trp482Arg)	Pathogenic
38371	NM_004211.5(SLC6A5):c.323del (p.Pro108fs)	Pathogenic
4081932	NM_004211.5(SLC6A5):c.1917T>A (p.Tyr639Ter)	Pathogenic
4703079	NM_004211.5(SLC6A5):c.621C>G (p.Tyr207Ter)	Pathogenic
4711307	NM_004211.5(SLC6A5):c.538_539del (p.Gln180fs)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

5210 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:20604317:G:C	R191P	1.000
11:20604325:T:A	W194R	1.000
11:20604325:T:C	W194R	1.000
11:20604326:G:C	W194S	1.000
11:20604327:G:C	W194C	1.000
11:20604327:G:T	W194C	1.000
11:20604343:T:C	F200L	1.000
11:20604345:C:A	F200L	1.000
11:20604345:C:G	F200L	1.000
11:20604350:T:C	L202P	1.000
11:20604361:G:A	G206R	1.000
11:20604361:G:C	G206R	1.000
11:20604361:G:T	G206W	1.000
11:20604362:G:A	G206E	1.000
11:20604362:G:T	G206V	1.000
11:20604373:G:A	G210R	1.000
11:20604373:G:C	G210R	1.000
11:20604373:G:T	G210W	1.000
11:20604374:G:A	G210E	1.000
11:20604379:G:C	G212R	1.000
11:20604379:G:T	G212C	1.000
11:20604380:G:A	G212D	1.000
11:20604380:G:T	G212V	1.000
11:20604384:T:A	N213K	1.000
11:20604384:T:G	N213K	1.000
11:20604388:T:A	W215R	1.000
11:20604388:T:C	W215R	1.000
11:20604392:G:C	R216T	1.000
11:20604392:G:T	R216M	1.000
11:20604394:T:C	F217L	1.000

dbSNP variants (sampled 300 via entrez): RS1000072103 (11:20653071 T>C), RS1000076031 (11:20651822 G>A,C,T), RS1000088483 (11:20658621 A>C,G), RS1000114446 (11:20610456 C>G,T), RS1000285983 (11:20613533 A>G), RS1000389614 (11:20640857 C>T), RS1000440868 (11:20609715 C>G,T), RS1000526318 (11:20621346 A>G), RS1000529280 (11:20642349 G>A), RS1000552848 (11:20657579 A>C), RS1000586729 (11:20616818 G>A,C), RS1000677798 (11:20605274 C>A), RS1000695200 (11:20653351 G>A), RS1000705273 (11:20647655 A>G), RS1000709203 (11:20635016 G>A)

Disease associations

OMIM: gene MIM:604159 | disease phenotypes: MIM:614618

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperekplexia 3	Definitive	Autosomal recessive
hereditary hyperekplexia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hyperekplexia 3	Definitive	AR

Mondo (2): hyperekplexia 3 (MONDO:0013827), hereditary hyperekplexia (MONDO:0021022)

Orphanet (1): Hereditary hyperekplexia (Orphanet:3197)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001279	Syncope
HP:0001288	Gait disturbance
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001373	Joint dislocation
HP:0001387	Joint stiffness
HP:0001537	Umbilical hernia
HP:0002020	Gastroesophageal reflux
HP:0002036	Hiatus hernia
HP:0002063	Rigidity
HP:0002069	Bilateral tonic-clonic seizure
HP:0002104	Apnea
HP:0002267	Exaggerated startle response
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002827	Hip dislocation
HP:0003552	Muscle stiffness
HP:0003623	Neonatal onset
HP:0005943	Respiratory arrest
HP:0011412	Ventouse delivery
HP:0012420	Meconium stained amniotic fluid

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3060 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Glycine transporter subfamily

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
GT-0198	Inhibition	8.8	pIC50
Org 25543	Inhibition	7.8	pIC50
ALX 1393	Inhibition	7.0	pIC50
opiranserin	Inhibition	6.07	pIC50
bitopertin	Inhibition	4.52	pEC50

ChEMBL bioactivities

180 potent at pChembl≥5 of 249 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.42	IC50	3.8	nM	CHEMBL88588
7.82	IC50	15.3	nM	CHEMBL3325502
7.80	IC50	16	nM	CHEMBL88588
7.80	IC50	16	nM	CHEMBL5723564
7.62	IC50	24	nM	CHEMBL153717
7.59	IC50	25.5	nM	CHEMBL4587165
7.58	IC50	26	nM	CHEMBL475562
7.54	IC50	29.2	nM	CHEMBL4515597
7.52	IC50	30	nM	CHEMBL153731
7.50	IC50	31.6	nM	CHEMBL4572247
7.50	IC50	31.5	nM	CHEMBL239601
7.48	IC50	33	nM	CHEMBL358473
7.37	IC50	43	nM	CHEMBL155273
7.32	IC50	47.9	nM	CHEMBL4562565
7.32	IC50	48.3	nM	CHEMBL4535356
7.29	IC50	51.9	nM	CHEMBL3325511
7.26	IC50	54.6	nM	CHEMBL4227139
7.25	IC50	56	nM	CHEMBL153630
7.24	IC50	58	nM	CHEMBL150560
7.21	IC50	62.1	nM	CHEMBL3325505
7.19	IC50	64.8	nM	CHEMBL4527071
7.18	IC50	65.8	nM	CHEMBL3325509
7.17	IC50	67	nM	CHEMBL150377
7.16	IC50	69.2	nM	CHEMBL4542099
7.15	IC50	71.4	nM	CHEMBL3325503
7.11	IC50	77	nM	CHEMBL431997
7.11	IC50	77	nM	CHEMBL348200
7.10	IC50	79.6	nM	CHEMBL3325501
7.09	IC50	81	nM	CHEMBL153075
7.08	IC50	84	nM	CHEMBL92310
7.07	IC50	86	nM	CHEMBL153139
7.05	IC50	89	nM	CHEMBL357936
7.04	IC50	91.3	nM	CHEMBL4549008
7.00	IC50	99.1	nM	CHEMBL3325508
7.00	IC50	100	nM	CHEMBL475562
7.00	IC50	99	nM	CHEMBL153410
6.98	IC50	105	nM	CHEMBL3325507
6.97	IC50	107	nM	CHEMBL3325506
6.95	IC50	112	nM	CHEMBL3325495
6.94	IC50	115	nM	CHEMBL3325499
6.92	IC50	120	nM	CHEMBL348211
6.89	IC50	130	nM	CHEMBL4540633
6.89	IC50	130	nM	CHEMBL149571
6.89	IC50	130	nM	CHEMBL150901
6.89	IC50	130	nM	CHEMBL150796
6.85	IC50	140	nM	CHEMBL150954
6.85	IC50	140	nM	CHEMBL153148
6.84	IC50	143	nM	CHEMBL4228560
6.82	IC50	151	nM	CHEMBL4592570
6.82	IC50	152	nM	CHEMBL4562110

PubChem BioAssay actives

178 with measured affinity, of 692 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
N-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-phenylmethoxybenzamide	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.0038	uM
N-[1-[3-(dimethylamino)propyl]piperidin-4-yl]-4-[[4-(trifluoromethyl)phenoxy]methyl]benzamide	1162231: Inhibition of human GlyT2 transfected in HEK293 cells assessed as [3H]glycine uptake after 2 hrs	ic50	0.0153	uM
2-[(7-hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)methyl]-N-[(E)-4-phenylbut-3-enyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.0240	uM
(2S)-6-amino-2-[[(Z)-octadec-9-enoyl]amino]hexanoic acid;hydrochloride	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.0255	uM
(2S)-2-amino-3-[(3-fluorophenyl)-(2-phenylmethoxyphenyl)methoxy]propanoic acid	1634027: Inhibition of human GlyT2 expressed in porcine aorta epithelial cells assessed as reduction in [3H]-Glycine uptake at pH 7.5 by scintillation spectroscopy	ic50	0.0260	uM
(2S)-4-methylsulfanyl-2-[[(Z)-octadec-9-enoyl]amino]butanoic acid	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.0292	uM
2-[(7-hydroxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)methyl]-N-[(E)-4-phenylbut-3-enyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.0300	uM
[1-[4-[6-[[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methoxy]-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl]cyclopentyl]methanol	306199: Inhibition of [3H]glycine uptake at human GlyT2 expressed in HEK293 cells	ic50	0.0315	uM
(2S)-5-amino-2-[[(Z)-octadec-9-enoyl]amino]pentanoic acid;hydrochloride	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.0316	uM
2-[(5-hydroxy-1,3-dihydroisoindol-2-yl)methyl]-N-[(E)-4-phenylbut-3-enyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.0330	uM
2-[[(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]methyl]-N-[(E)-4-phenylbut-3-enyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.0430	uM
(2S)-5-(diaminomethylideneamino)-2-[[(Z)-octadec-9-enoyl]amino]pentanoic acid;dihydrochloride	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.0479	uM
(2R)-6-amino-2-[[(Z)-octadec-9-enoyl]amino]hexanoic acid;hydrochloride	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.0483	uM
N-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-4-[[4-(trifluoromethyl)phenoxy]methyl]benzamide	1162231: Inhibition of human GlyT2 transfected in HEK293 cells assessed as [3H]glycine uptake after 2 hrs	ic50	0.0519	uM
(2S)-3-(1H-indol-3-yl)-2-[[(Z)-octadec-9-enoyl]amino]propanoic acid	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.0546	uM
2-[[2-(4-hydroxyphenyl)ethylamino]methyl]-N-[(E)-4-phenylbut-3-enyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.0560	uM
2-[(7-hydroxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)methyl]-N-[(E)-4-phenylbut-3-enyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.0580	uM
N-(1-benzylpiperidin-4-yl)-4-[[4-(trifluoromethyl)phenoxy]methyl]benzamide	1162231: Inhibition of human GlyT2 transfected in HEK293 cells assessed as [3H]glycine uptake after 2 hrs	ic50	0.0621	uM
(2R)-3-hydroxy-2-[[(Z)-octadec-9-enoyl]amino]propanoic acid	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.0648	uM
N-[1-(2-hydroxyethyl)piperidin-4-yl]-4-[[4-(trifluoromethyl)phenoxy]methyl]benzamide	1162231: Inhibition of human GlyT2 transfected in HEK293 cells assessed as [3H]glycine uptake after 2 hrs	ic50	0.0658	uM
2-[(7-hydroxy-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl)methyl]-N-[(E)-4-phenylbut-3-enyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.0670	uM
(2R)-5-(diaminomethylideneamino)-2-[[(Z)-octadec-9-enoyl]amino]pentanoic acid;dihydrochloride	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.0692	uM
N-[1-[2-(dimethylamino)ethyl]piperidin-4-yl]-4-[[4-(trifluoromethyl)phenoxy]methyl]benzamide	1162231: Inhibition of human GlyT2 transfected in HEK293 cells assessed as [3H]glycine uptake after 2 hrs	ic50	0.0714	uM
4-butoxy-N-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxybenzamide	73804: Inhibition of human Glycine Transporter type-2	ic50	0.0770	uM
N-[4-(4-chlorophenyl)butyl]-2-[[2-(4-hydroxyphenyl)ethylamino]methyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.0770	uM
N-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-4-[[4-(trifluoromethyl)phenoxy]methyl]benzamide	1162231: Inhibition of human GlyT2 transfected in HEK293 cells assessed as [3H]glycine uptake after 2 hrs	ic50	0.0796	uM
2-[[(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]methyl]-N-(4-phenylbutyl)benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.0810	uM
N-[[1-(dimethylamino)cyclohexyl]methyl]-3,5-dimethoxy-4-phenylmethoxybenzamide	73804: Inhibition of human Glycine Transporter type-2	ic50	0.0840	uM
2-[[2-(4-hydroxyphenyl)ethylamino]methyl]-N-[4-(4-methylphenyl)butyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.0860	uM
2-[(7-hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)methyl]-N-(4-phenylbutyl)benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.0890	uM
methyl (2S)-6-amino-2-[[(Z)-octadec-9-enoyl]amino]hexanoate;hydrochloride	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.0913	uM
N-[4-(3-chlorophenyl)butyl]-2-[[2-(4-hydroxyphenyl)ethylamino]methyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.0990	uM
N-[1-(2-fluoroethyl)piperidin-4-yl]-4-[[4-(trifluoromethyl)phenoxy]methyl]benzamide	1162231: Inhibition of human GlyT2 transfected in HEK293 cells assessed as [3H]glycine uptake after 2 hrs	ic50	0.0991	uM
N-(1-methylpiperidin-4-yl)-4-[[4-(trifluoromethyl)phenoxy]methyl]benzamide	1162231: Inhibition of human GlyT2 transfected in HEK293 cells assessed as [3H]glycine uptake after 2 hrs	ic50	0.1050	uM
N-(1-ethylpiperidin-4-yl)-4-[[4-(trifluoromethyl)phenoxy]methyl]benzamide	1162231: Inhibition of human GlyT2 transfected in HEK293 cells assessed as [3H]glycine uptake after 2 hrs	ic50	0.1070	uM
N-[1-(1-methylpiperidin-4-yl)pyrrolidin-3-yl]-4-[[4-(trifluoromethyl)phenoxy]methyl]benzamide	1162231: Inhibition of human GlyT2 transfected in HEK293 cells assessed as [3H]glycine uptake after 2 hrs	ic50	0.1120	uM
N-[(3S)-1-(1-methylpiperidin-4-yl)pyrrolidin-3-yl]-4-[[4-(trifluoromethyl)phenoxy]methyl]benzamide	1162231: Inhibition of human GlyT2 transfected in HEK293 cells assessed as [3H]glycine uptake after 2 hrs	ic50	0.1150	uM
N-[4-(3,4-dichlorophenyl)butyl]-2-[[2-(4-hydroxyphenyl)ethylamino]methyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.1200	uM
(2S)-3-(1H-imidazol-5-yl)-2-[[(Z)-octadec-9-enoyl]amino]propanoic acid;hydrochloride	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.1300	uM
2-[[(2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)amino]methyl]-N-[(E)-4-phenylbut-3-enyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.1300	uM
2-[[2-(4-hydroxyphenyl)ethylamino]methyl]-N-[4-(4-methoxyphenyl)butyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.1300	uM
2-[(6-hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)methyl]-N-[(E)-4-phenylbut-3-enyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.1300	uM
2-[[2-(4-hydroxyphenyl)ethylamino]methyl]-N-[4-[4-(trifluoromethyl)phenyl]butyl]benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.1400	uM
2-[[2-(4-hydroxyphenyl)ethylamino]methyl]-N-(4-phenylbut-3-ynyl)benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.1400	uM
(2S)-4-methyl-2-[[(Z)-octadec-9-enoyl]amino]pentanoic acid	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.1430	uM
(2S)-2-[[(Z)-octadec-9-enoyl]amino]-4-phenylbutanoic acid	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.1510	uM
(2S)-4-amino-2-[[(Z)-octadec-9-enoyl]amino]butanoic acid;hydrochloride	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.1520	uM
2-[[2-(4-hydroxyphenyl)ethylamino]methyl]-N-(4-phenylbutyl)benzamide	73805: Inhibitory activity against human glycine transporter type 2 (hGlyT2) expressed in Chinese hamster ovary (CHO) cell line	ic50	0.1700	uM
N-[1-(3-hydroxypropyl)piperidin-4-yl]-4-[[4-(trifluoromethyl)phenoxy]methyl]benzamide	1162231: Inhibition of human GlyT2 transfected in HEK293 cells assessed as [3H]glycine uptake after 2 hrs	ic50	0.1810	uM
(2S)-3-amino-2-[[(Z)-octadec-9-enoyl]amino]propanoic acid;hydrochloride	1638480: Inhibition of recombinant human GlyT2a expressed in Xenopus laevis oocytes assessed as reduction in channel current by two-electrode voltage clamp electrophysiology	ic50	0.1820	uM

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
testosterone undecanoate	increases expression	1
arsenite	increases methylation	1
tebuconazole	decreases expression	1
abrine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Copper	affects cotreatment, decreases expression	1
Sodium Selenite	decreases expression	1

ChEMBL screening assays

54 unique, capped per target: 50 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1007113	Binding	Inhibition of [3H]glycine uptake at human glycine transporter 2 expressed in CHO cells by scintillation counter	Discovery of benzoylpiperazines as a novel class of potent and selective GlyT1 inhibitors. — Bioorg Med Chem Lett
CHEMBL5209611	Functional	Substrate uptake by the Glycine Transporter-2 (GlyT2, SLC6A5) as assessed by the fluorescent FLIPR membrane potential dye in HEK-293 JumpIN-SLC6A5 cells (PubChem AID: 1794825)	Membrane potential based assay for SLC6A5 using HEK-293 SLC6A5 OE cells

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01476514	Not specified	TERMINATED	Effects of Mutations of the Glycine Gene Associated With Hyperekplexia on Central Pain Processing
NCT05168969	Not specified	COMPLETED	Hyperekplexia in Patients With CTNNB1 Mutation
NCT05652101	Not specified	RECRUITING	Hyperekplexia : Adaptative Skills and Neurodevelopmental Trajectory
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening