GLRA2

Summary

GLRA2 (glycine receptor alpha 2, HGNC:4327) is a protein-coding gene on chromosome Xp22.2, encoding Glycine receptor subunit alpha-2 (P23416). Subunit of heteromeric glycine-gated chloride channels.

The glycine receptor consists of two subunits, alpha and beta, and acts as a pentamer. The protein encoded by this gene is an alpha subunit and can bind strychnine. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2742 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder, X-linked, syndromic, Pilorge type (Strong, GenCC)
• Clinical variants (ClinVar): 87 total — 5 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002063

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4327
Approved symbol	GLRA2
Name	glycine receptor alpha 2
Location	Xp22.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000101958
Ensembl biotype	protein_coding
OMIM	305990
Entrez	2742

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000218075, ENST00000355020, ENST00000415367, ENST00000443437

RefSeq mRNA: 4 — MANE Select: NM_002063 NM_001118885, NM_001118886, NM_001171942, NM_002063

CCDS: CCDS14160, CCDS48085

Canonical transcript exons

ENST00000218075 — 9 exons

Exon	Start	End
ENSE00001408123	14574333	14574400
ENSE00001880627	14730207	14731812
ENSE00001883609	14529536	14530125
ENSE00003473936	14532239	14532372
ENSE00003996138	14690710	14690859
ENSE00003996139	14607131	14607268
ENSE00003996140	14581183	14581406
ENSE00003996141	14604315	14604397
ENSE00003996142	14608991	14609205

Expression profiles

Bgee: expression breadth broad, 75 present calls, max score 95.80.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.5443 / max 240.7252, expressed in 157 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195596	1.4532	155
195597	0.0733	33
195595	0.0178	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	95.80	gold quality
type B pancreatic cell	CL:0000169	84.87	gold quality
olfactory bulb	UBERON:0002264	84.54	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.22	gold quality
ganglionic eminence	UBERON:0004023	81.60	gold quality
endometrium epithelium	UBERON:0004811	79.73	gold quality
frontal pole	UBERON:0002795	79.09	gold quality
paraflocculus	UBERON:0005351	78.76	gold quality
cerebellar hemisphere	UBERON:0002245	78.37	gold quality
cerebellar cortex	UBERON:0002129	78.35	gold quality
middle frontal gyrus	UBERON:0002702	78.07	gold quality
right hemisphere of cerebellum	UBERON:0014890	77.02	gold quality
cerebellum	UBERON:0002037	76.23	gold quality
hypothalamus	UBERON:0001898	73.74	gold quality
prefrontal cortex	UBERON:0000451	73.70	gold quality
diaphragm	UBERON:0001103	73.10	gold quality
hair follicle	UBERON:0002073	71.24	gold quality
ventricular zone	UBERON:0003053	70.80	gold quality
Brodmann (1909) area 10	UBERON:0013541	70.77	gold quality
rectum	UBERON:0001052	70.71	gold quality
cingulate cortex	UBERON:0003027	69.89	gold quality
anterior cingulate cortex	UBERON:0009835	69.68	gold quality
embryo	UBERON:0000922	68.78	gold quality
amygdala	UBERON:0001876	68.73	gold quality
cerebellar vermis	UBERON:0004720	67.28	gold quality
nucleus accumbens	UBERON:0001882	67.11	gold quality
cervix squamous epithelium	UBERON:0006922	66.85	gold quality
neocortex	UBERON:0001950	66.75	gold quality
Brodmann (1909) area 9	UBERON:0013540	66.02	gold quality
frontal cortex	UBERON:0001870	65.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.75
E-MTAB-7303	no	320.55

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

110 targeting GLRA2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-5010-3P	99.83	70.60	2357

Literature-anchored findings (GeneRIF, showing 6)

• Effects of 12 times normal atmospheric pressure of helium-oxygen gas (pressure) on ethanol-induced potentiation of GlyR function in Xenopus oocytes expressing human alpha1, alpha2 or the mutant alpha1(A52S) GlyRs were measured by voltage clamp technics (PMID:15147510)
• The molecular basis for the differential sensitivity of GlyR alpha(1) and GlyR alpha(2) to Zn(2+) potentiation is reported. (PMID:16144831)
• Enhancement of azurophil granule-phagosome fusion via glycine receptor alpha 2 subunit (GlyRalpha2)/transient receptor potential melastatin (TRPM)2/p38 MAP kinase signaling is a novel target for enhancement of neutrophil bactericidal activity. (PMID:20237295)
• investigated neural progenitor cells in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, immunocytochemistry, and quantitative real-time PCR (PMID:22606311)
• 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)
• GLRA2 gene mutations cause high myopia in humans and mice. (PMID:35396272)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	glra2	ENSDARG00000075012
mus_musculus	Glra2	ENSMUSG00000018589
rattus_norvegicus	Glra2	ENSRNOG00000003313

Paralogs (45): GABRA3 (ENSG00000011677), GABRA1 (ENSG00000022355), CHRNA3 (ENSG00000080644), GABRP (ENSG00000094755), CHRNA4 (ENSG00000101204), GABRE (ENSG00000102287), CHRNE (ENSG00000108556), GABRA4 (ENSG00000109158), GLRB (ENSG00000109738), GABRR2 (ENSG00000111886), GABRG2 (ENSG00000113327), CHRNB4 (ENSG00000117971), CHRNA2 (ENSG00000120903), CHRNA10 (ENSG00000129749), CHRND (ENSG00000135902), CHRNA1 (ENSG00000138435), GLRA3 (ENSG00000145451), GABRA6 (ENSG00000145863), GABRB2 (ENSG00000145864), GLRA1 (ENSG00000145888), GABRR1 (ENSG00000146276), CHRNB3 (ENSG00000147432), CHRNA6 (ENSG00000147434), HTR3B (ENSG00000149305), GABRA2 (ENSG00000151834), CHRNB2 (ENSG00000160716), GABRG1 (ENSG00000163285), GABRB1 (ENSG00000163288), GABRB3 (ENSG00000166206), CHRFAM7A (ENSG00000166664), HTR3A (ENSG00000166736), CHRNA5 (ENSG00000169684), CHRNB1 (ENSG00000170175), CHRNA9 (ENSG00000174343), CHRNA7 (ENSG00000175344), HTR3C (ENSG00000178084), GABRG3 (ENSG00000182256), GABRR3 (ENSG00000183185), HTR3E (ENSG00000186038), HTR3D (ENSG00000186090)

Protein

Protein identifiers

Glycine receptor subunit alpha-2 — P23416 (reviewed: P23416)

All UniProt accessions (2): P23416, A0A9S7JRE2

UniProt curated annotations — full annotation on UniProt →

Function. Subunit of heteromeric glycine-gated chloride channels. Plays a role in synaptic plasticity. Contributes to the generation of inhibitory postsynaptic currents, and is involved in the down-regulation of neuronal excitability. Plays a role in cellular responses to ethanol.

Subunit / interactions. Interacts with GLRB. Heteropentamer composed of GLRA2 and GLRB. Functional GLRB-GLRA2 heteropentamers contain four GLRA2 subunits and one GLRB subunit, although alternative subunit composition cannot be excluded. Homopentamer (in vitro). Both homopentamers and heteropentamers form functional ion channels, but their characteristics are subtly different.

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

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Pilorge type (MRXSP) [MIM:301076] A disorder characterized by global developmental delay with variably impaired intellectual development, speech delay, and behavioral abnormalities. Variable features include motor incoordination, seizures, and ocular abnormalities. Disease onset is in infancy, and severity is higly variable. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Channel opening is triggered by extracellular glycine. Channel opening is also triggered by taurine and beta-alanine. Inhibited by strychnine. Inhibited by picrotoxin. Channel activity is potentiated by 10-100 uM Zn(2+). Channel activity is marginally increased by 50 mM ethanol; it is strongly increased by a combination of 0.5 uM Zn(2+) and 50 mM ethanol. Channel activity is inhibited by 100-1000 uM Zn(2+).

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. GLRA2 sub-subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P23416-1	Alpha-2*	yes
P23416-2	Alpha-2B
P23416-3	3

RefSeq proteins (4): NP_001112357, NP_001112358, NP_001165413, NP_002054* (*=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
IPR008129	Glycine_rcpt_A2	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 (41 total): sequence variant 11, binding site 10, topological domain 5, transmembrane region 4, glycosylation site 2, disulfide bond 2, splice variant 2, signal peptide 1, chain 1, site 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
9Y7P	ELECTRON MICROSCOPY	2.5
9Y8Z	ELECTRON MICROSCOPY	2.5
9Y7Z	ELECTRON MICROSCOPY	2.78
9Y7W	ELECTRON MICROSCOPY	3.19
9Y96	ELECTRON MICROSCOPY	3.36
9Y95	ELECTRON MICROSCOPY	3.45
9Y7X	ELECTRON MICROSCOPY	3.55
9Y80	ELECTRON MICROSCOPY	3.55
5BKF	ELECTRON MICROSCOPY	3.6
7KUY	ELECTRON MICROSCOPY	3.6
9Y94	ELECTRON MICROSCOPY	3.6
5BKG	ELECTRON MICROSCOPY	3.8
7L31	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23416-F1	84.04	0.63

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): 295 (important for obstruction of the ion pore in the closed conformation)

Ligand- & substrate-binding residues (10): 99 (in one chain); 99; 99; 163 (in one chain); 163; 226; 228; 238 (in other chain); 238; 249

Disulfide bonds (2): 172–186, 232–243

Glycosylation sites (2): 72, 103

Mutagenesis-validated functional residues (1):

Position	Phenotype
350	no effect on the kinetics of inhibitory post-synaptic currents.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 224 (showing top): GOBP_RESPONSE_TO_ETHANOL, MODULE_328, GOBP_RESPONSE_TO_ZINC_ION, GGTGTGT_MIR329, MODULE_274, TGCGCANK_UNKNOWN, GOBP_RESPONSE_TO_ACID_CHEMICAL, MODULE_64, GOBP_INORGANIC_ANION_TRANSPORT, HASLINGER_B_CLL_WITH_11Q23_DELETION, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELL_CELL_SIGNALING, GOBP_RESPONSE_TO_METAL_ION, GOBP_CHLORIDE_TRANSPORT

GO Biological Process (11): neuropeptide signaling pathway (GO:0007218), monoatomic ion transmembrane transport (GO:0034220), modulation of chemical synaptic transmission (GO:0050804), cellular response to amino acid stimulus (GO:0071230), cellular response to zinc ion (GO:0071294), cellular response to ethanol (GO:0071361), chloride transmembrane transport (GO:1902476), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), regulation of postsynaptic membrane potential (GO:0060078), 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), transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential (GO:1904315), monoatomic ion channel activity (GO:0005216), extracellular ligand-gated monoatomic ion channel activity (GO:0005230), chloride channel activity (GO:0005254), transmitter-gated monoatomic ion channel activity (GO:0022824)

GO Cellular Component (9): plasma membrane (GO:0005886), chloride channel complex (GO:0034707), cell projection (GO:0042995), glycinergic synapse (GO:0098690), GABA-ergic synapse (GO:0098982), postsynaptic specialization membrane (GO:0099634), membrane (GO:0016020), synapse (GO:0045202), postsynaptic membrane (GO:0045211)

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
regulation of postsynaptic membrane potential	2
extracellular ligand-gated monoatomic ion channel activity	2
cation binding	2
chloride channel activity	2
ligand-gated monoatomic anion channel activity	2
transmitter-gated monoatomic ion channel activity	2
cellular anatomical structure	2
synapse	2
synaptic membrane	2
G protein-coupled receptor signaling pathway	1
monoatomic ion transport	1
transmembrane transport	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
response to amino acid	1
cellular response to acid chemical	1
response to zinc ion	1
cellular response to metal ion	1
response to ethanol	1
cellular response to alcohol	1
chloride transport	1
monoatomic anion transmembrane transport	1
transport	1
monoatomic anion transport	1
inorganic anion transport	1
regulation of 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
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
transmitter-gated channel activity	1
membrane	1

Protein interactions and networks

STRING

1136 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLRA2	NOVA1	P51513	845
GLRA2	GARS1	P41250	684
GLRA2	GRPR	P30550	674
GLRA2	NTNG2	Q96CW9	672
GLRA2	NTNG1	Q9Y2I2	669
GLRA2	GPM6B	Q13491	650
GLRA2	NOVA2	Q9UNW9	600
GLRA2	GDI1	P31150	592
GLRA2	FAM107B	Q9H098	557
GLRA2	GLUD2	P49448	550
GLRA2	HCCS	P53701	548
GLRA2	CDKL5	O76039	521
GLRA2	OR8D2	Q9GZM6	509
GLRA2	PHEX	P78562	495
GLRA2	GPHN	Q9NQX3	471

IntAct

8 interactions, top by confidence:

A	B	Type	Score
GDI2	GLRA2	psi-mi:“MI:0915”(physical association)	0.370
GLRA2	SEC23A	psi-mi:“MI:0915”(physical association)	0.370
GLRA2	DDX24	psi-mi:“MI:0915”(physical association)	0.370
GLRA2	MARCHF6	psi-mi:“MI:0914”(association)	0.350
GLRA2	BAG6	psi-mi:“MI:0915”(physical association)	0.000
GLRA2	GPR108	psi-mi:“MI:0915”(physical association)	0.000
PSD	GLRA2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (49): TF (Affinity Capture-MS), BLK (Affinity Capture-MS), TMEM87A (Affinity Capture-MS), COPG1 (Affinity Capture-MS), PKD2 (Affinity Capture-MS), SCAP (Affinity Capture-MS), SGCB (Affinity Capture-MS), UBR3 (Affinity Capture-MS), CNNM1 (Affinity Capture-MS), NUP35 (Affinity Capture-MS), SYVN1 (Affinity Capture-MS), SLC39A6 (Affinity Capture-MS), EXTL3 (Affinity Capture-MS), KCTD17 (Affinity Capture-MS), C16orf58 (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

2 interactions.

A	Effect	B	Mechanism
glycine	“up-regulates activity”	GLRA2	“chemical activation”
ethanol	“up-regulates activity”	GLRA2	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	4
Uncertain significance	39
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
148339	GRCh38/hg38 Xp22.33-11.23(chrX:10701-49071220)x1	Pathogenic
1686857	NM_002063.4(GLRA2):c.407A>G (p.Asn136Ser)	Pathogenic
1686858	NC_000023.10:g.14693216_14836199del	Pathogenic
1686859	NM_002063.4(GLRA2):c.458G>A (p.Arg153Gln)	Pathogenic
810510	NM_002063.4(GLRA2):c.887C>T (p.Thr296Met)	Pathogenic
1334140	NM_002063.4(GLRA2):c.140T>C (p.Phe47Ser)	Likely pathogenic
1334408	NM_002063.4(GLRA2):c.777C>G (p.Ile259Met)	Likely pathogenic
4536752	NM_002063.4(GLRA2):c.494G>C (p.Arg165Thr)	Likely pathogenic
4755488	NM_002063.4(GLRA2):c.392A>G (p.Asp131Gly)	Likely pathogenic

SpliceAI

1856 predictions. Top by Δscore:

Variant	Effect	Δscore
X:14581406:GGTAA:G	donor_loss	1.0000
X:14581407:G:GA	donor_loss	1.0000
X:14581408:T:G	donor_loss	1.0000
X:14604304:T:A	acceptor_gain	1.0000
X:14604313:A:G	acceptor_gain	1.0000
X:14604393:GAGTT:G	donor_gain	1.0000
X:14604395:GTT:G	donor_gain	1.0000
X:14604398:G:GG	donor_gain	1.0000
X:14607124:A:AG	acceptor_gain	1.0000
X:14607127:TCAG:T	acceptor_loss	1.0000
X:14607128:CAGTT:C	acceptor_loss	1.0000
X:14607129:A:AG	acceptor_gain	1.0000
X:14607129:AGT:A	acceptor_loss	1.0000
X:14607129:AGTT:A	acceptor_gain	1.0000
X:14607129:AGTTG:A	acceptor_gain	1.0000
X:14607130:G:GG	acceptor_gain	1.0000
X:14607130:GT:G	acceptor_gain	1.0000
X:14607130:GTT:G	acceptor_gain	1.0000
X:14607130:GTTG:G	acceptor_gain	1.0000
X:14607130:GTTGG:G	acceptor_gain	1.0000
X:14608990:GGAAA:G	acceptor_gain	1.0000
X:14690705:CTCA:C	acceptor_loss	1.0000
X:14690708:A:AG	acceptor_gain	1.0000
X:14690708:AG:A	acceptor_gain	1.0000
X:14690709:G:GC	acceptor_loss	1.0000
X:14690709:G:GT	acceptor_gain	1.0000
X:14690709:GG:G	acceptor_gain	1.0000
X:14690709:GGT:G	acceptor_gain	1.0000
X:14690709:GGTC:G	acceptor_gain	1.0000
X:14690709:GGTCT:G	acceptor_gain	1.0000

AlphaMissense

3003 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:14532345:G:C	D59H	1.000
X:14532346:A:G	D59G	1.000
X:14532352:G:T	R61I	1.000
X:14532357:A:G	R63G	1.000
X:14532358:G:C	R63T	1.000
X:14532358:G:T	R63M	1.000
X:14532359:G:C	R63S	1.000
X:14532359:G:T	R63S	1.000
X:14532360:C:A	P64T	1.000
X:14532360:C:T	P64S	1.000
X:14532361:C:A	P64Q	1.000
X:14581205:T:C	L98P	1.000
X:14581211:A:C	Q100P	1.000
X:14581216:T:A	W102R	1.000
X:14581216:T:C	W102R	1.000
X:14581217:G:C	W102S	1.000
X:14581217:G:T	W102L	1.000
X:14581218:G:C	W102C	1.000
X:14581218:G:T	W102C	1.000
X:14581222:G:C	D104H	1.000
X:14581223:A:G	D104G	1.000
X:14581228:C:G	R106G	1.000
X:14581228:C:T	R106W	1.000
X:14581229:G:C	R106P	1.000
X:14581232:T:A	L107Q	1.000
X:14581232:T:C	L107P	1.000
X:14581262:T:C	L117P	1.000
X:14581292:T:A	I127N	1.000
X:14581294:T:A	W128R	1.000
X:14581294:T:C	W128R	1.000

dbSNP variants (sampled 300 via entrez): RS1000004573 (X:14465434 G>A), RS1000006240 (X:14497850 T>C), RS1000013699 (X:14519696 G>A), RS1000017229 (X:14675222 T>C), RS1000026371 (X:14713130 T>C), RS1000030199 (X:14650146 C>A,G,T), RS1000048586 (X:14674767 T>G), RS1000059212 (X:14585919 A>T), RS1000059937 (X:14649777 C>T), RS1000088482 (X:14451602 C>T), RS1000101566 (X:14492142 T>C), RS1000119606 (X:14593979 A>C), RS1000132568 (X:14608574 T>A), RS1000185251 (X:14608075 TCCAACAG>T), RS1000192550 (X:14660012 C>T)

Disease associations

OMIM: gene MIM:305990 | disease phenotypes: MIM:301076, MIM:160700

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder, X-linked, syndromic, Pilorge type	Strong	X-linked

Mondo (2): intellectual developmental disorder, X-linked, syndromic, Pilorge type (MONDO:0024772), myopia (MONDO:0001384)

Orphanet (0):

HPO phenotypes

11 total (12 of 11 shown, HPO-id order):

HPO	Term
HP:0000403	Recurrent otitis media
HP:0000717	Autism
HP:0000732	Inflexible adherence to routines
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001256	Mild intellectual disability
HP:0001417	X-linked inheritance
HP:0002033	Poor suck
HP:0002069	Bilateral tonic-clonic seizure
HP:0011003	High myopia
HP:0011463	Childhood onset
HP:0000545	Myopia

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009216	Myopia	C11.744.636

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4296075 (PROTEIN COMPLEX), CHEMBL5871 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 26,379 (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
CHEMBL190461	CANNABIDIOL	4	26,379

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 (17 total), top 17:

Ligand	Action	Affinity	Parameter
HU-210	Antagonist	7.0	pIC50
WIN55212-2	Antagonist	6.7	pIC50
picrotoxinin	Channel blocker	6.4	pIC50
Δ9-tetrahydrocannabinol	Potentiation	6.0	pEC50
onternabez	Antagonist	6.0	pIC50
picrotoxin	Channel blocker	5.6	pIC50
ginkgolide X	Antagonist	5.6	pIC50
ginkgolide B	Channel blocker	5.4	pIC50
pregnenolone sulphate	Antagonist	5.3	pKi
bilobalide	Antagonist	5.1	pIC50
tropisetron	Antagonist	4.9	pKi
picrotin	Channel blocker	4.9	pIC50
Cu2+	Inhibition	4.8	pIC50
cyanotriphenylborate	Channel blocker	4.7	pIC50
colchicine	Antagonist	4.2	pIC50
5,7-dichlorokynurenic acid	Antagonist	3.7	pIC50
Zn2+	Inhibition	3.4	pIC50

ChEMBL bioactivities

15 potent at pChembl≥5 of 24 total, top 15 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.90	IC50	1259	nM	GINKGOLIDE M
5.89	IC50	1300	nM	GINKGOLIDE M
5.70	IC50	1995	nM	GINKGOLIDE A
5.68	IC50	2100	nM	GINKGOLIDE A
5.57	IC50	2700	nM	CANNABIDIOL
5.43	IC50	3700	nM	GINKOLIDE B
5.40	IC50	3981	nM	GINKOLIDE B
5.34	IC50	4600	nM	CHEMBL426556
5.30	IC50	5012	nM	CHEMBL426556
5.11	IC50	7800	nM	CHEMBL221823
5.10	IC50	7943	nM	CHEMBL221823
5.10	IC50	7943	nM	GINKGOLIDE C
5.09	IC50	8200	nM	GINKGOLIDE C
5.02	IC50	9500	nM	3,14-DIDEHYDROGINKGOLIDE A
5.00	IC50	1e+04	nM	3,14-DIDEHYDROGINKGOLIDE A

PubChem BioAssay actives

15 with measured affinity, of 52 total; 8 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
(1S,6R,8S,9R,11R,12R,13R,16S,17S)-8-tert-butyl-6,9,12-trihydroxy-16-methyl-2,4,14,19-tetraoxahexacyclo[8.7.2.01,11.03,7.07,11.013,17]nonadecane-5,15,18-trione	281249: Activity at human alpha-2GlyR expressed in HEK293 cells by FMP assay	ic50	1.2589	uM
(1R,3R,6R,7S,8S,10R,11S,13S,16S,17R)-8-tert-butyl-6,17-dihydroxy-16-methyl-2,4,14,19-tetraoxahexacyclo[8.7.2.01,11.03,7.07,11.013,17]nonadecane-5,15,18-trione	281249: Activity at human alpha-2GlyR expressed in HEK293 cells by FMP assay	ic50	1.9953	uM
Cannabidiol	2090857: Inhibition of human strychnine-insensitive glycine receptor alpha 2 expressed in HEK293 cells	ic50	2.7000	uM
(1R,3R,6R,7S,8S,10R,11R,12R,13S,16S,17R)-8-tert-butyl-6,12,17-trihydroxy-16-methyl-2,4,14,19-tetraoxahexacyclo[8.7.2.01,11.03,7.07,11.013,17]nonadecane-5,15,18-trione	281249: Activity at human alpha-2GlyR expressed in HEK293 cells by FMP assay	ic50	3.7000	uM
(1R,3R,6R,7S,8S,9S,10R,11R,12R,13S,16S,17R)-8-tert-butyl-9-fluoro-6,12,17-trihydroxy-16-methyl-2,4,14,18-tetraoxahexacyclo[8.7.2.01,11.03,7.07,11.013,17]nonadecane-5,15,19-trione	281249: Activity at human alpha-2GlyR expressed in HEK293 cells by FMP assay	ic50	4.6000	uM
(1R,3R,6R,7S,8S,9R,10S,11R,12R,13S,16S,17R)-8-tert-butyl-9,12,17-trihydroxy-6-methoxy-16-methyl-2,4,14,18-tetraoxahexacyclo[8.7.2.01,11.03,7.07,11.013,17]nonadecane-5,15,19-trione	281249: Activity at human alpha-2GlyR expressed in HEK293 cells by FMP assay	ic50	7.8000	uM
(1R,3R,6R,7S,8S,9S,11S,12S,13S,16S,17S)-8-tert-butyl-6,9,12,17-tetrahydroxy-13-methyl-2,4,15,19-tetraoxahexacyclo[8.7.2.01,11.03,7.07,11.012,16]nonadecane-5,14,18-trione	281249: Activity at human alpha-2GlyR expressed in HEK293 cells by FMP assay	ic50	7.9433	uM
(1R,3R,6R,7S,8S,10R,11S,13S)-8-tert-butyl-6-hydroxy-16-methyl-2,4,14,18-tetraoxahexacyclo[8.7.2.01,11.03,7.07,11.013,17]nonadec-16-ene-5,15,19-trione	281249: Activity at human alpha-2GlyR expressed in HEK293 cells by FMP assay	ic50	9.5000	uM

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases methylation	1
fipronil	decreases activity	1
Resveratrol	affects cotreatment, decreases expression	1
Hexachlorocyclohexane	decreases activity	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Copper	affects cotreatment, decreases expression	1
Metribolone	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 3 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4219612	Binding	Inhibition of recombinant human glycine receptor alpha2beta expressed in HEK293 cells	Progress in the discovery of small molecule modulators of the Cys-loop superfamily receptors. — Bioorg Med Chem Lett
CHEMBL1113521	Functional	Antagonist activity at human recombinant alpha 2 GlyR expressed in HEK293 cells assessed as inhibition of glycine current influx at 10 uM by whole cell patch clamp assay	Ircinialactams: subunit-selective glycine receptor modulators from Australian sponges of the family Irciniidae. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00347204	PHASE4	COMPLETED	Comparison of Acular LS Versus Nevanac for Pain Control in Eyes Undergoing PRK
NCT00349843	PHASE4	COMPLETED	Investigation of Multi-Purpose Solution-Based Corneal Staining and Ocular Comfort
NCT00349882	PHASE4	COMPLETED	Effects of Contact Lens Care Regimens on the Corneal Epithelium
NCT00350246	PHASE4	COMPLETED	Long-term Effects of Laser Refractive Surgery
NCT00404105	PHASE4	COMPLETED	A Comparison of PRK and LASIK for Correction of Myopia
NCT00455455	PHASE4	COMPLETED	Corneal and Conjunctival Sensitivity and Staining Study
NCT00541177	PHASE4	UNKNOWN	Study of Myopia Prevention in Children With Low Concentration of Atropine
NCT00627302	PHASE4	COMPLETED	Efficacy of PEG-400 and Systane Artificial Tears (Alcon) on Quality of Vision
NCT00640341	PHASE4	COMPLETED	Comparative Performance of PureVision, Acuvue Oasys and O2Optix
NCT00770094	PHASE4	UNKNOWN	Multi Laser Platform Comparison Study for LASIK
NCT00821236	PHASE4	COMPLETED	Contralateral Comparison of Three Excimer Laser Systems in Performing LASIK
NCT00889941	PHASE4	COMPLETED	Effect of Preoperative Pupil Size on Quality of Vision After Wavefront-Guided LASIK
NCT00937105	PHASE4	COMPLETED	Daily Wear Corneal Infiltrative Event Study
NCT01173198	PHASE4	COMPLETED	An Evaluation of Outcomes Following Wavefront Optimized or Wavefront Guided Lasik Procedure in Low to Moderate Myopic Patients
NCT01250925	PHASE4	COMPLETED	Effect of Contact Lens Wear on Immune Cell Density and Morphology of the Ocular Surface
NCT01387360	PHASE4	COMPLETED	Presbyopic Supracor Treatment for Near Myopic/Hyperopic Pseudophakic Eyes
NCT01454843	PHASE4	COMPLETED	LASIK Using the Alcon Allegretto Wavefront-Guided Excimer Laser vs AMO Visx Wavefront-Guided Excimer Laser
NCT01693939	PHASE4	COMPLETED	Evaluation of the Post-LASIK Flap Thickness of the FS200 Femtosecond Laser Flap
NCT01706237	PHASE4	WITHDRAWN	Visual Outcomes And Contrast Sensitivity After Myopic Wavefront-Optimized Lasik With Nexisvision Shield Or Bandage Contact Lens
NCT01746589	PHASE4	COMPLETED	Visual Outcomes and Contrast Sensitivity After Myopic LASIK
NCT01977807	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser in Asian Eyes Using LASIK
NCT02071576	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser Using LASIK
NCT02112968	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of a New High Repetition Rate Excimer Laser Using LASIK for the Correction of Ammetropia and Presbyopia
NCT02186184	PHASE4	COMPLETED	Effect of Orthokeratology Versus Spectacles on Myopia Progression in Chinese Children: A Crossover Trial
NCT02544529	PHASE4	WITHDRAWN	Echothiophate Iodide for the Prevention of Progression of Myopia
NCT03001401	PHASE4	UNKNOWN	Comparison of Next Generation Laser Techniques of Myopia Correction: iDesign vs. SMILE
NCT03158142	PHASE4	COMPLETED	The Influence of Atropine on Choroidal Thickness
NCT03544827	PHASE4	COMPLETED	The Effects of Low Dose Atropine on Choroidal Thickness
NCT03881670	PHASE4	COMPLETED	On-Eye Optical Quality of Lotrafilcon B Lenses Over 12 Hours
NCT03949101	PHASE4	UNKNOWN	Atropine for Children and Adolescent Myopia Progression Study
NCT04208750	PHASE4	COMPLETED	Clinical Investigation of the Vision-R800 Device.
NCT04283331	PHASE4	UNKNOWN	Anesthetic Impregnated Bandage Soft Contact Lens (BSCL) in Pain Management After Photorefractive Keratectomy (PRK)
NCT05357326	PHASE4	UNKNOWN	Myopia Intervention in Children and Adolescents and Establishment of a Precise Intervention Model
NCT05448989	PHASE4	UNKNOWN	Efficacy and Safety of 1% Atropine 5+3 Regimen in Children and Adolescents Controlling Myopia
NCT05449015	PHASE4	UNKNOWN	Study on the Effect of Two Ways of Cycloplegia on Biological Parameters of Ciliary Muscle
NCT05733741	PHASE4	COMPLETED	Preservative-free Topical Anesthetics for Post-PRK Pain
NCT05803863	PHASE4	UNKNOWN	Efficacy Comparison of 2 Low-dose Atropine Eye Drops in Vietnamese Children Myopia Management
NCT06431841	PHASE4	ACTIVE_NOT_RECRUITING	Atropine and Spectacle Combination Treatment (ASPECT): 12-month Results of a Randomized Clinical Trial for Myopia Control
NCT06450132	PHASE4	ACTIVE_NOT_RECRUITING	Changes in Eye Shape With Myopia Management Interventions
NCT06553404	PHASE4	ACTIVE_NOT_RECRUITING	Myoslow Lens Study to Control Myopia in Children