GLRA3

Summary

GLRA3 (glycine receptor alpha 3, HGNC:4328) is a protein-coding gene on chromosome 4q34.1, encoding Glycine receptor subunit alpha-3 (O75311). Glycine receptors are ligand-gated chloride channels.

This gene encodes a member of the ligand-gated ion channel protein family. The encoded protein is a member of the glycine receptor subfamily. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8001 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 60 total
• Druggable target: yes
• MANE Select transcript: NM_006529

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4328
Approved symbol	GLRA3
Name	glycine receptor alpha 3
Location	4q34.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000145451
Ensembl biotype	protein_coding
OMIM	600421
Entrez	8001

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000274093, ENST00000340217, ENST00000436738, ENST00000483010

RefSeq mRNA: 2 — MANE Select: NM_006529 NM_001042543, NM_006529

CCDS: CCDS3822, CCDS43283

Canonical transcript exons

ENST00000274093 — 10 exons

Exon	Start	End
ENSE00000996779	174788816	174788943
ENSE00001130811	174656743	174656787
ENSE00001130817	174659054	174659197
ENSE00001130825	174677078	174677292
ENSE00001130831	174682802	174682939
ENSE00001389991	174828741	174829247
ENSE00001895157	174636920	174644064
ENSE00002435453	174766963	174767030
ENSE00002437150	174715488	174715570
ENSE00003658286	174728475	174728698

Expression profiles

Bgee: expression breadth broad, 90 present calls, max score 76.93.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0091 / max 43.2579, expressed in 214 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
54952	0.9564	209
54951	0.0527	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.93	gold quality
pancreatic ductal cell	CL:0002079	71.34	silver quality
prefrontal cortex	UBERON:0000451	70.84	gold quality
islet of Langerhans	UBERON:0000006	70.82	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.59	gold quality
Brodmann (1909) area 9	UBERON:0013540	67.92	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	65.07	gold quality
cingulate cortex	UBERON:0003027	64.90	gold quality
anterior cingulate cortex	UBERON:0009835	64.68	gold quality
right frontal lobe	UBERON:0002810	64.04	gold quality
hypothalamus	UBERON:0001898	64.03	gold quality
frontal cortex	UBERON:0001870	63.06	gold quality
neocortex	UBERON:0001950	62.58	gold quality
cortical plate	UBERON:0005343	61.21	gold quality
endothelial cell	CL:0000115	59.04	gold quality
cerebral cortex	UBERON:0000956	58.86	gold quality
amygdala	UBERON:0001876	58.34	gold quality
lower lobe of lung	UBERON:0008949	57.26	silver quality
decidua	UBERON:0002450	56.55	gold quality
substantia nigra	UBERON:0002038	55.81	gold quality
forebrain	UBERON:0001890	55.80	gold quality
telencephalon	UBERON:0001893	55.73	gold quality
epithelial cell of pancreas	CL:0000083	55.37	silver quality
nucleus accumbens	UBERON:0001882	54.69	gold quality
cartilage tissue	UBERON:0002418	54.60	gold quality
ganglionic eminence	UBERON:0004023	54.44	gold quality
midbrain	UBERON:0001891	54.14	gold quality
hair follicle	UBERON:0002073	53.46	gold quality
brain	UBERON:0000955	53.35	gold quality
central nervous system	UBERON:0001017	53.08	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.50
E-MTAB-7249	no	28.37

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

108 targeting GLRA3, 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-4682	100.00	68.89	1258
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-6755-5P	99.95	65.59	464
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-579-3P	99.86	71.66	3628

Literature-anchored findings (GeneRIF, showing 10)

• the spliced insert within the large TM 3-4 loop of alpha3 Gly receptors serves to stabilize the overall spatial structure of the domain, and present a control unit that regulates gating of the receptor ion channel (PMID:19661067)
• Results indicate that the multifunctional basic motif of the TM3-4 loop is capable of mediating a karyopherin-dependent intracellular sorting of full-length GlyRs. (PMID:19959465)
• Protein kinase (PK)A-dependent phosphorylation of alpha3 GlyRs produces a conformational change that propagates to the glycine-binding site. (PMID:23834509)
• 3.0 A X-ray structure of the human glycine receptor-alpha3 homopentamer in complex with a high affinity, high-specificity antagonist, strychnine (PMID:26416729)
• data show that the current-voltage relationships of homomeric channels formed by the alpha2 or alpha3 subunits change upon receptor desensitization from a linear to an inwardly rectifying shape, in contrast to their heteromeric counterparts. (PMID:27382060)
• X-ray crystal structure of human homopentameric GlyRalpha3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2.6-A resolution. (PMID:27991902)
• Using quantitative photoactivated localisation microscopy the authors found that alpha-1 and alpha-3 containing glycine receptors display the same alpha3:beta2 stoichiometry and gephyrin binding. (PMID:28883437)
• This study explores the roles of Tyr and Trp residues in the extracellular domains of the glycine receptor alpha 3 and shows that four such residues that have not been previously studied (Y24, Y58, W170, and Y197) contribute significantly to the function of the protein. (PMID:29947514)
• In this study, the association between the common rs10011025 variant in the GLRA3 locus, and albuminuria, was confirmed in 1259 independent Finnish individuals with type 1 diabetes (p = 0.0013), and meta-analysis of all Finnish individuals yielded a genome-wide significant association. (PMID:30120300)
• Determines location of mouse glycine alpha 3. (PMID:7894176)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	glra3	ENSDARG00000011066
mus_musculus	Glra3	ENSMUSG00000038257
rattus_norvegicus	Glra3	ENSRNOG00000049792

Paralogs (45): GABRA3 (ENSG00000011677), GABRA1 (ENSG00000022355), CHRNA3 (ENSG00000080644), GABRP (ENSG00000094755), CHRNA4 (ENSG00000101204), GLRA2 (ENSG00000101958), GABRE (ENSG00000102287), CHRNE (ENSG00000108556), GABRA4 (ENSG00000109158), GLRB (ENSG00000109738), GABRR2 (ENSG00000111886), GABRG2 (ENSG00000113327), CHRNB4 (ENSG00000117971), CHRNA2 (ENSG00000120903), CHRNA10 (ENSG00000129749), CHRND (ENSG00000135902), CHRNA1 (ENSG00000138435), GABRA6 (ENSG00000145863), GABRB2 (ENSG00000145864), GLRA1 (ENSG00000145888), GABRR1 (ENSG00000146276), CHRNB3 (ENSG00000147432), CHRNA6 (ENSG00000147434), HTR3B (ENSG00000149305), GABRA2 (ENSG00000151834), CHRNB2 (ENSG00000160716), GABRG1 (ENSG00000163285), GABRB1 (ENSG00000163288), GABRB3 (ENSG00000166206), CHRFAM7A (ENSG00000166664), HTR3A (ENSG00000166736), CHRNA5 (ENSG00000169684), CHRNB1 (ENSG00000170175), CHRNA9 (ENSG00000174343), CHRNA7 (ENSG00000175344), HTR3C (ENSG00000178084), GABRG3 (ENSG00000182256), GABRR3 (ENSG00000183185), HTR3E (ENSG00000186038), HTR3D (ENSG00000186090)

Protein

Protein identifiers

Glycine receptor subunit alpha-3 — O75311 (reviewed: O75311)

All UniProt accessions (1): O75311

UniProt curated annotations — full annotation on UniProt →

Function. Glycine receptors are ligand-gated chloride channels. Channel opening is triggered by extracellular glycine. Channel characteristics depend on the subunit composition; heteropentameric channels display faster channel closure. Plays an important role in the down-regulation of neuronal excitability. Contributes to the generation of inhibitory postsynaptic currents. Contributes to increased pain perception in response to increased prostaglandin E2 levels. Plays a role in cellular responses to ethanol.

Subunit / interactions. Homopentamer (in vitro). Heteropentamer composed of GLRA3 and GLRB. Both homopentamers and heteropentamers form functional ion channels, but their characteristics are subtly different.

Subcellular location. Postsynaptic cell membrane. Perikaryon. Cell projection. Dendrite. Synapse. Cell membrane.

Tissue specificity. Widely distributed throughout the central nervous system.

Post-translational modifications. Phosphorylated by PKA; this causes down-regulation of channel activity.

Domain organisation. The N-terminal domain carries structural determinants essential for agonist and antagonist binding. The channel pore is formed by pentameric assembly of the second transmembrane domain from all five subunits. The cytoplasmic loop is an important determinant of channel inactivation kinetics.

Miscellaneous. The alpha subunit binds strychnine.

Similarity. Belongs to the ligand-gated ion channel (TC 1.A.9) family. Glycine receptor (TC 1.A.9.3) subfamily. GLRA3 sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O75311-1	Alpha-3L	yes
O75311-2	Alpha-3K

RefSeq proteins (2): NP_001036008, NP_006520* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006028	GABAA/Glycine_rcpt	Family
IPR006029	Neurotrans-gated_channel_TM	Domain
IPR006201	Neur_channel	Family
IPR006202	Neur_chan_lig-bd	Domain
IPR008127	Glycine_rcpt_A	Family
IPR008130	Glycine_rcpt_A3	Family
IPR018000	Neurotransmitter_ion_chnl_CS	Conserved_site
IPR036719	Neuro-gated_channel_TM_sf	Homologous_superfamily
IPR036734	Neur_chan_lig-bd_sf	Homologous_superfamily
IPR038050	Neuro_actylchol_rec	Homologous_superfamily

Pfam: PF02931, PF02932

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (56 total): strand 18, helix 11, topological domain 5, binding site 4, turn 4, transmembrane region 4, modified residue 2, disulfide bond 2, signal peptide 1, chain 1, site 1, glycosylation site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
9BWC	ELECTRON MICROSCOPY	2.19
9BWB	ELECTRON MICROSCOPY	2.21
9BWJ	ELECTRON MICROSCOPY	2.21
9BVH	ELECTRON MICROSCOPY	2.58
9BWG	ELECTRON MICROSCOPY	2.59
5TIN	X-RAY DIFFRACTION	2.61
9BU3	ELECTRON MICROSCOPY	2.8
9BVJ	ELECTRON MICROSCOPY	2.8
5VDH	X-RAY DIFFRACTION	2.85
9BU2	ELECTRON MICROSCOPY	2.87
9BZP	ELECTRON MICROSCOPY	2.88
5CFB	X-RAY DIFFRACTION	3.04
9BWE	ELECTRON MICROSCOPY	3.07
5VDI	X-RAY DIFFRACTION	3.1
5TIO	X-RAY DIFFRACTION	3.25
9BP7	ELECTRON MICROSCOPY	3.6
9BP0	ELECTRON MICROSCOPY	3.67
9BOY	ELECTRON MICROSCOPY	3.81
9BOZ	ELECTRON MICROSCOPY	3.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75311-F1	84.69	0.62

Functional residue map

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

Catalytic / active sites (1): 294 (important for obstruction of the ion pore in the closed conformation)

Ligand- & substrate-binding residues (4): 225; 227; 235–240; 248

Post-translational modifications (2): 370, 379

Disulfide bonds (2): 171–185, 231–242

Glycosylation sites (1): 71

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission

MSigDB gene sets: 188 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, MORF_ITGA2, E2F_Q4_01, MODULE_328, GOZGIT_ESR1_TARGETS_DN, chr4q34, GOBP_INORGANIC_ANION_TRANSPORT, MORF_RAD51L3, GOBP_CELL_CELL_SIGNALING, E2F1DP1_01, E2F1DP2_01, GOBP_CHLORIDE_TRANSPORT, GOBP_REGULATION_OF_POSTSYNAPTIC_MEMBRANE_POTENTIAL, MORF_CTSB, BLALOCK_ALZHEIMERS_DISEASE_UP

GO Biological Process (7): protein homooligomerization (GO:0051260), presynaptic modulation of chemical synaptic transmission (GO:0099171), chloride transmembrane transport (GO:1902476), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), monoatomic ion transmembrane transport (GO:0034220), excitatory postsynaptic potential (GO:0060079)

GO Molecular Function (11): transmembrane signaling receptor activity (GO:0004888), excitatory extracellular ligand-gated monoatomic ion channel activity (GO:0005231), glycine binding (GO:0016594), extracellularly glycine-gated chloride channel activity (GO:0016934), glycine-gated chloride ion channel activity (GO:0022852), metal ion binding (GO:0046872), monoatomic ion channel activity (GO:0005216), extracellular ligand-gated monoatomic ion channel activity (GO:0005230), chloride channel activity (GO:0005254), protein binding (GO:0005515), transmitter-gated monoatomic ion channel activity (GO:0022824)

GO Cellular Component (11): plasma membrane (GO:0005886), glycine-gated chloride channel complex (GO:0016935), dendrite (GO:0030425), presynaptic membrane (GO:0042734), perikaryon (GO:0043204), postsynaptic membrane (GO:0045211), glycinergic synapse (GO:0098690), membrane (GO:0016020), chloride channel complex (GO:0034707), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transmission across Chemical Synapses	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
presynapse	2
extracellular ligand-gated monoatomic ion channel activity	2
cation binding	2
chloride channel activity	2
ligand-gated monoatomic anion channel activity	2
synaptic membrane	2
protein complex oligomerization	1
modulation of chemical synaptic transmission	1
chloride transport	1
monoatomic anion transmembrane transport	1
transport	1
monoatomic anion transport	1
inorganic anion transport	1
monoatomic ion transport	1
transmembrane transport	1
regulation of postsynaptic membrane potential	1
chemical synaptic transmission, postsynaptic	1
signaling receptor activity	1
excitatory postsynaptic potential	1
amino acid binding	1
carboxylic acid binding	1
inhibitory extracellular ligand-gated monoatomic ion channel activity	1
extracellularly glycine-gated ion channel activity	1
transmitter-gated monoatomic ion channel activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
ligand-gated monoatomic ion channel activity	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
binding	1
transmitter-gated channel activity	1
membrane	1
cell periphery	1
chloride channel complex	1
plasma membrane protein complex	1
neuron projection	1
dendritic tree	1
neuronal cell body	1
postsynapse	1

Protein interactions and networks

STRING

844 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLRA3	GARS1	P41250	721
GLRA3	GPHN	Q9NQX3	551
GLRA3	HIGD2B	Q4VC39	467
GLRA3	SLC6A5	Q9Y345	445
GLRA3	GRIK1	P39086	440
GLRA3	CEP44	Q9C0F1	434
GLRA3	GRIA4	P48058	420
GLRA3	DRICH1	Q6PGQ1	416
GLRA3	SLC6A9	P48067	407
GLRA3	THRB	P10828	405
GLRA3	GRIN3A	Q8TCU5	403
GLRA3	TRAK2	O60296	399
GLRA3	NALF1	B1AL88	398
GLRA3	C16orf89	Q6UX73	398
GLRA3	HLA-A	P01891	371
GLRA3	KCNC2	Q96PR1	371

IntAct

6 interactions, top by confidence:

A	B	Type	Score
GLRA3	KCTD2	psi-mi:“MI:0915”(physical association)	0.560
GLRA3	KCTD2	psi-mi:“MI:0914”(association)	0.560
GLRA3	GLRA3	psi-mi:“MI:0407”(direct interaction)	0.440
GLRA3	AIFM1	psi-mi:“MI:0915”(physical association)	0.400
GLRA3	GCNT3	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): KCTD2 (Affinity Capture-MS), AIFM1 (Proximity Label-MS), GLRB (Affinity Capture-MS), KCTD17 (Affinity Capture-MS), TBL2 (Affinity Capture-MS), KCTD2 (Affinity Capture-MS), GCNT3 (Affinity Capture-MS), GABRB3 (Affinity Capture-MS), FGG (Affinity Capture-MS), CBX6 (Affinity Capture-MS)

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

Diamond homologs: A0A1S4H2E2, A8MPY1, D1LYT2, G5EBR3, O14764, O75311, O93430, P0C2W5, P15431, P18505, P18506, P19019, P20781, P22771, P22933, P23416, P24045, P25123, P28472, P47870, P48167, P48168, P63079, P63080, P63137, P63138, Q08832, Q61603, Q75NA5, Q7TNC8, Q94900, Q9BLY8, Q9GJS9, Q9V9Y4, F1R8P4, O00591, O09028, O18276, P07727, P08219

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
glycine	“up-regulates activity”	GLRA3	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	52
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2517 predictions. Top by Δscore:

Variant	Effect	Δscore
4:174644062:ATCCT:A	acceptor_loss	1.0000
4:174644063:TCC:T	acceptor_loss	1.0000
4:174644064:CCTG:C	acceptor_loss	1.0000
4:174659050:TTA:T	donor_loss	1.0000
4:174659051:TACCT:T	donor_loss	1.0000
4:174659052:A:AC	donor_gain	1.0000
4:174659052:AC:A	donor_gain	1.0000
4:174659052:ACCTT:A	donor_loss	1.0000
4:174659053:C:CG	donor_gain	1.0000
4:174659053:CC:C	donor_gain	1.0000
4:174659053:CCTT:C	donor_gain	1.0000
4:174659053:CCTTA:C	donor_gain	1.0000
4:174677076:A:AC	donor_gain	1.0000
4:174677077:C:CC	donor_gain	1.0000
4:174677924:A:AC	donor_gain	1.0000
4:174677925:T:C	donor_gain	1.0000
4:174677944:A:AC	donor_gain	1.0000
4:174677945:C:CC	donor_gain	1.0000
4:174682935:CCCAA:C	acceptor_gain	1.0000
4:174682936:CCAAC:C	acceptor_gain	1.0000
4:174715486:A:AC	donor_gain	1.0000
4:174715487:C:CC	donor_gain	1.0000
4:174715487:CAG:C	donor_gain	1.0000
4:174728470:CTCA:C	donor_loss	1.0000
4:174728471:TCACC:T	donor_loss	1.0000
4:174728472:CACC:C	donor_loss	1.0000
4:174728473:A:C	donor_loss	1.0000
4:174728474:C:CT	donor_loss	1.0000
4:174728515:G:C	donor_gain	1.0000
4:174767028:GGC:G	acceptor_gain	1.0000

AlphaMissense

3073 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:174643839:A:G	W448R	1.000
4:174643839:A:T	W448R	1.000
4:174643861:A:C	F440L	1.000
4:174643861:A:T	F440L	1.000
4:174643863:A:G	F440L	1.000
4:174643871:G:C	P437R	1.000
4:174643871:G:T	P437Q	1.000
4:174643873:G:C	F436L	1.000
4:174643873:G:T	F436L	1.000
4:174643875:A:G	F436L	1.000
4:174643895:T:A	D429V	1.000
4:174643895:T:C	D429G	1.000
4:174643895:T:G	D429A	1.000
4:174643896:C:A	D429Y	1.000
4:174643896:C:G	D429H	1.000
4:174643907:G:T	A425D	1.000
4:174659111:A:C	N338K	1.000
4:174659111:A:T	N338K	1.000
4:174659118:G:T	A336D	1.000
4:174659119:C:G	A336P	1.000
4:174659121:G:T	A335E	1.000
4:174659125:A:G	Y334H	1.000
4:174659126:C:A	E333D	1.000
4:174659126:C:G	E333D	1.000
4:174659130:A:G	L332P	1.000
4:174659133:A:G	L331P	1.000
4:174659133:A:T	L331H	1.000
4:174659136:G:T	A330E	1.000
4:174659141:A:C	F328L	1.000
4:174659141:A:T	F328L	1.000

dbSNP variants (sampled 300 via entrez): RS1000003644 (4:174706043 C>A), RS1000020521 (4:174824861 T>A,C), RS10000456 (4:174728790 T>C,G), RS1000061229 (4:174751955 A>C), RS1000066782 (4:174637471 C>T), RS1000073360 (4:174747115 G>A), RS10000870 (4:174779109 C>G,T), RS1000087728 (4:174818938 A>G), RS1000088693 (4:174779143 C>T), RS1000091712 (4:174751694 T>C), RS10000921 (4:174794288 T>C), RS10000984 (4:174723413 T>C,G), RS1000100165 (4:174670360 T>C), RS10001193 (4:174729820 A>T), RS1000129546 (4:174642116 T>C)

Disease associations

OMIM: gene MIM:600421 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002382_1	Urinary albumin excretion rate in type 1 diabetes	8.000000e-07
GCST002900_2	Obesity in adult survivors of childhood cancer exposed to cranial radiation	1.000000e-06
GCST004302_14	Primary biliary cholangitis	2.000000e-06
GCST005352_16	Paclitaxel disposition in epithelial ovarian cancer	6.000000e-06
GCST008851_4	Depressive symptom (fatigue) (ordinal trait)	1.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005667	urinary albumin excretion rate
EFO:0007006	depressive symptom measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1075092 (SINGLE PROTEIN), CHEMBL4106144 (PROTEIN COMPLEX)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — Glycine receptors

Most potent curated ligand interactions (11 total), top 11:

Ligand	Action	Affinity	Parameter
HU-210	Antagonist	7.3	pIC50
WIN55212-2	Antagonist	7.0	pIC50
onternabez	Antagonist	7.0	pIC50
picrotoxinin	Channel blocker	6.4	pIC50
ginkgolide B	Channel blocker	5.7	pIC50
Δ9-tetrahydrocannabinol	Potentiation	5.3	pEC50
(12E,20Z,18S)-8-hydroxyvariabilin	Antagonist	5.2	pIC50
picrotin	Channel blocker	5.2	pIC50
Cu2+	Inhibition	5.0	pIC50
nifedipine	Antagonist	4.5	pIC50
Zn2+	Inhibition	3.8	pIC50

ChEMBL bioactivities

40 potent at pChembl≥5 of 50 total, top 37 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.96	Kd	11	nM	CHEMBL4070615
7.87	EC50	13.49	nM	CHEMBL4227298
7.30	EC50	50	nM	CHEMBL4070615
7.18	EC50	66	nM	CHEMBL4070615
7.16	Kd	70	nM	CHEMBL4083687
6.72	Kd	190	nM	CHEMBL4074873
6.52	Kd	300	nM	CHEMBL4284872
6.48	EC50	330	nM	CHEMBL4074873
6.43	EC50	370	nM	CHEMBL4083687
6.35	EC50	450	nM	CHEMBL4074873
6.34	EC50	454	nM	CHEMBL4074873
6.30	EC50	500	nM	CHEMBL4282578
6.18	EC50	660.7	nM	CHEMBL4227048
6.16	EC50	700	nM	CHEMBL4284872
6.05	EC50	900	nM	CHEMBL4290867
6.05	EC50	900	nM	CHEMBL4295252
5.92	EC50	1210	nM	CHEMBL4285964
5.68	EC50	2100	nM	CHEMBL4278706
5.66	EC50	2200	nM	CHEMBL4283686
5.66	EC50	2200	nM	CHEMBL4276816
5.64	EC50	2300	nM	CHEMBL4290271
5.64	EC50	2300	nM	CHEMBL4277386
5.60	EC50	2500	nM	CHEMBL4281910
5.57	EC50	2700	nM	CHEMBL4292781
5.51	EC50	3100	nM	CHEMBL4282176
5.48	EC50	3300	nM	CHEMBL4292523
5.43	EC50	3700	nM	CHEMBL4276816
5.41	EC50	3900	nM	CHEMBL1314103
5.40	EC50	3981	nM	CHEMBL4228024
5.38	EC50	4200	nM	CHEMBL4290682
5.28	EC50	5200	nM	CHEMBL4283686
5.27	EC50	5400	nM	CHEMBL4291111
5.21	EC50	6100	nM	CHEMBL4290451
5.16	IC50	7000	nM	CHEMBL464651
5.15	EC50	7120	nM	CHEMBL4279153
5.07	EC50	8500	nM	CHEMBL4226572
5.06	EC50	8700	nM	CHEMBL4280238

PubChem BioAssay actives

40 with measured affinity, of 326 total; 28 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(3S,3aS,9bS)-2-(1,3-benzodioxol-5-ylsulfonyl)-3,5-dimethyl-1,3,3a,9b-tetrahydropyrrolo[3,4-c][1,6]naphthyridin-4-one	1426392: Binding affinity to human glycine alpha3 receptor expressed in HEK293T cells by SPR assay	kd	0.0110	uM
3,5-ditert-butyl-2,6-dihydroxybenzoic acid	1388379: Positive allosteric modulation of human GlyRalpha3beta expressed in CHO cells assessed as potentiation of EC20 glycine-induced ion flux by HT assay	ec50	0.0135	uM
(3aS,9bS)-2-(1,3-benzodioxol-5-ylsulfonyl)-5-methyl-1,3,3a,9b-tetrahydropyrrolo[3,4-c]quinolin-4-one	1401009: Binding affinity to human GlyRalpha3cryst by SPR method	kd	0.0700	uM
(3aS,9bS)-2-(1-benzofuran-5-ylsulfonyl)-5-methyl-1,3,3a,9b-tetrahydropyrrolo[3,4-c][1,6]naphthyridin-4-one	1426392: Binding affinity to human glycine alpha3 receptor expressed in HEK293T cells by SPR assay	kd	0.1900	uM
6-[3-(5-chloro-2-methoxyphenoxy)azetidin-1-yl]sulfonyl-3H-1,3-benzoxazol-2-one	1401009: Binding affinity to human GlyRalpha3cryst by SPR method	kd	0.3000	uM
1-(1,3-benzodioxol-5-ylsulfonyl)-3-(5-chloro-2-methoxyphenoxy)azetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	0.5000	uM
4-[[(2R)-8-fluoro-3-oxo-4-[[2-(trifluoromethyl)phenyl]methyl]-1,4-benzothiazin-2-yl]methyl]benzoic acid	1388379: Positive allosteric modulation of human GlyRalpha3beta expressed in CHO cells assessed as potentiation of EC20 glycine-induced ion flux by HT assay	ec50	0.6607	uM
5-[3-(5-chloro-2-methoxyphenoxy)azetidin-1-yl]sulfonyl-1,3-benzothiazole	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	0.9000	uM
5-[3-(5-chloro-2-methoxyphenoxy)azetidin-1-yl]sulfonyl-1H-indazole	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	0.9000	uM
1-(1,3-benzodioxol-5-ylsulfonyl)-3-(5-fluoro-2-methoxyphenoxy)azetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	1.2100	uM
(2S,3S)-1-(1,3-benzodioxol-5-ylsulfonyl)-3-(5-chloro-2-methoxyphenoxy)-2-methylazetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.1000	uM
1,1,1-trifluoro-2-[4-[[2-piperidin-1-yl-4-(trifluoromethyl)-4,5-dihydro-1,3-thiazol-5-yl]sulfonyl]phenyl]propan-2-ol	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.2000	uM
2-[4-[[2-ethylimino-4-(trifluoromethyl)-1,3-thiazolidin-5-yl]sulfonyl]phenyl]-1,1,1-trifluoropropan-2-ol	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.2000	uM
6-[3-(5-chloro-2-methoxyphenoxy)azetidin-1-yl]sulfonyl-1H-indazole	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.3000	uM
1-(1,3-benzodioxol-5-ylsulfonyl)-3-(2-methoxyphenoxy)azetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.3000	uM
5-[3-(5-chloro-2-methoxyphenoxy)azetidin-1-yl]sulfonyl-1-methylbenzimidazole	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.5000	uM
(2R,3R)-1-(1,3-benzodioxol-5-ylsulfonyl)-3-(5-chloro-2-methoxyphenoxy)-2-methylazetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	2.7000	uM
1-(1,3-benzodioxol-5-ylsulfonyl)-3-(2-methoxy-5-methylphenoxy)azetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	3.1000	uM
5-[3-(5-chloro-2-methoxyphenoxy)azetidin-1-yl]sulfonyl-1-methylindazole	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	3.3000	uM
4-fluoro-N-(2-quinolin-8-yloxyethyl)benzenesulfonamide	1388051: Positive allosteric modulation of recombinant human glycine receptor alpha3 expressed in CHOK1 cells at -60 mV holding potential by whole cell patch-clamp method	ec50	3.9000	uM
N-(2-quinolin-8-yloxyethyl)benzenesulfonamide	1388379: Positive allosteric modulation of human GlyRalpha3beta expressed in CHO cells assessed as potentiation of EC20 glycine-induced ion flux by HT assay	ec50	3.9811	uM
(3S)-1-(1,3-benzodioxol-5-ylsulfonyl)-3-(2-fluorophenyl)pyrrolidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	4.2000	uM
1-(1,3-benzodioxol-5-ylsulfonyl)-N-(2-methoxyphenyl)azetidin-3-amine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	5.4000	uM
1-(1,3-benzodioxol-5-ylsulfonyl)-3-(2-fluoro-6-methoxyphenoxy)azetidine	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	6.1000	uM
(5Z)-5-[(E,2S)-13-(furan-3-yl)-10-hydroxy-2,6,10-trimethyltridec-6-enylidene]-4-hydroxy-3-methylfuran-2-one	474949: Antagonist activity at human recombinant alpha 3 GlyR expressed in HEK293 cells assessed as inhibition of glycine current influx by whole cell patch clamp assay	ic50	7.0000	uM
(3R)-1-(1,3-benzodioxol-5-ylsulfonyl)-3-(3-chlorophenyl)pyrrolidin-3-ol	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	7.1200	uM
2-[4-[(E)-5-[(3S,3aR,4S,5R,7aR)-4’-hydroxy-3,4’,7-trimethyl-3’,5’-dioxospiro[1,2,3,3a,5,7a-hexahydroindene-4,2’-oxolane]-5-yl]-4-methylpent-4-enyl]-5-oxo-2H-pyrrol-1-yl]acetic acid	1388382: Positive allosteric modulation of human GlyRalpha3 expressed in HEK293 cells assessed as potentiation of glycine-induced current flux by electrophysiology method	ec50	8.5000	uM
1-[1-(1,3-benzodioxol-5-ylsulfonyl)azetidin-3-yl]benzimidazole	1400990: Positive allosteric modulation of human GlyRalpha3beta expressed in HEK293T cells assessed as increase in glycine-induced chloride ion flux measured for 4 mins by FLIPR assay	ec50	8.7000	uM

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases methylation	2
methyleugenol	decreases expression	1
bisphenol A	increases methylation	1
sodium arsenite	increases expression	1
fipronil	decreases activity	1
bisphenol S	decreases methylation	1
Hexachlorocyclohexane	decreases activity	1
Benzo(a)pyrene	decreases expression	1
Estradiol	increases expression, affects cotreatment, decreases expression	1
Lead	affects methylation	1
Mercury	increases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1
Dinoprostone	decreases reaction, increases activity, affects cotreatment	1
Excitatory Amino Acid Agents	affects cotreatment, decreases reaction, increases activity	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

32 unique, capped per target: 28 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1107106	Functional	Agonist activity at human recombinant alpha 3 GlyR expressed in HEK293 cells assessed as potentiation of glycine current by whole cell patch clamp assay	Ircinialactams: subunit-selective glycine receptor modulators from Australian sponges of the family Irciniidae. — Bioorg Med Chem
CHEMBL2401361	Binding	Modulation of recombinant GlyR-alpha3 (unknown origin) expressed in HEK293 cells assessed as inhibition of glycine-induced current by automated planar patch-clamp automated electrophysiology assay	Australian marine sponge alkaloids as a new class of glycine-gated chloride channel receptor modulator. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 1 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0XU	B’SYS CHO GlyRalpha3	Spontaneously immortalized cell line	Female
CVCL_YA51	IDG-HEK293T-GLRA3-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

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