GAD1

Summary

GAD1 (glutamate decarboxylase 1, HGNC:4092) is a protein-coding gene on chromosome 2q31.1, encoding Glutamate decarboxylase 1 (Q99259). Catalyzes the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) with pyridoxal 5’-phosphate as cofactor.

This gene encodes one of several forms of glutamic acid decarboxylase, identified as a major autoantigen in insulin-dependent diabetes. The enzyme encoded is responsible for catalyzing the production of gamma-aminobutyric acid from L-glutamic acid. A pathogenic role for this enzyme has been identified in the human pancreas since it has been identified as an autoantigen and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Deficiency in this enzyme has been shown to lead to pyridoxine dependency with seizures. Alternative splicing of this gene results in two products, the predominant 67-kD form and a less-frequent 25-kD form.

Source: NCBI Gene 2571 — RefSeq curated summary.

At a glance

• Gene–disease (curated): obsolete early infantile epileptic encephalopathy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 309 total — 10 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 48
• Druggable target: yes
• MANE Select transcript: NM_000817

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4092
Approved symbol	GAD1
Name	glutamate decarboxylase 1
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000128683
Ensembl biotype	protein_coding
OMIM	605363
Entrez	2571

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 10 protein_coding, 5 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000344257, ENST00000358196, ENST00000375272, ENST00000414527, ENST00000429023, ENST00000445006, ENST00000454603, ENST00000455008, ENST00000456864, ENST00000462739, ENST00000478562, ENST00000485013, ENST00000486850, ENST00000488724, ENST00000493270, ENST00000493875, ENST00000625689, ENST00000883273

RefSeq mRNA: 2 — MANE Select: NM_000817 NM_000817, NM_013445

CCDS: CCDS2239, CCDS2240

Canonical transcript exons

ENST00000358196 — 17 exons

Exon	Start	End
ENSE00001338054	170818529	170818673
ENSE00003464789	170844045	170844157
ENSE00003468499	170829475	170829633
ENSE00003481722	170859709	170861151
ENSE00003518424	170836793	170836883
ENSE00003518871	170845706	170845785
ENSE00003521438	170857018	170857125
ENSE00003523708	170849286	170849350
ENSE00003622484	170847676	170847792
ENSE00003622500	170852714	170852792
ENSE00003626505	170846009	170846063
ENSE00003629902	170845506	170845621
ENSE00003632226	170830950	170831192
ENSE00003679612	170858804	170858893
ENSE00003684011	170853873	170854022
ENSE00003699191	170822087	170822149
ENSE00003849098	170816887	170817048

Expression profiles

Bgee: expression breadth ubiquitous, 199 present calls, max score 99.26.

FANTOM5 (CAGE): breadth broad, TPM avg 9.6018 / max 229.6578, expressed in 853 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23634	7.0316	783
23633	0.4975	233
23636	0.4513	207
23632	0.3971	122
202469	0.3269	170
23631	0.2540	108
23635	0.2095	103
202468	0.2073	96
23637	0.1631	74
23630	0.0636	41

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.26	gold quality
middle temporal gyrus	UBERON:0002771	97.96	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.92	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.63	gold quality
lateral globus pallidus	UBERON:0002476	97.61	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.22	gold quality
primary visual cortex	UBERON:0002436	96.72	gold quality
occipital lobe	UBERON:0002021	96.62	gold quality
frontal pole	UBERON:0002795	96.49	gold quality
orbitofrontal cortex	UBERON:0004167	96.44	gold quality
paraflocculus	UBERON:0005351	96.23	gold quality
superior frontal gyrus	UBERON:0002661	95.72	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.52	gold quality
secondary oocyte	CL:0000655	95.45	gold quality
prefrontal cortex	UBERON:0000451	95.34	gold quality
nucleus accumbens	UBERON:0001882	95.00	gold quality
parietal lobe	UBERON:0001872	94.85	gold quality
cingulate cortex	UBERON:0003027	94.84	gold quality
superior vestibular nucleus	UBERON:0007227	94.81	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.76	gold quality
anterior cingulate cortex	UBERON:0009835	94.76	gold quality
frontal cortex	UBERON:0001870	94.75	gold quality
postcentral gyrus	UBERON:0002581	94.71	gold quality
middle frontal gyrus	UBERON:0002702	94.54	gold quality
neocortex	UBERON:0001950	94.41	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.12	gold quality
hypothalamus	UBERON:0001898	93.98	gold quality
entorhinal cortex	UBERON:0002728	93.89	gold quality
cerebellar vermis	UBERON:0004720	93.86	gold quality
oocyte	CL:0000023	93.77	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	2162.76
E-MTAB-7316	yes	1907.12
E-GEOD-93593	yes	1592.35
E-GEOD-84465	yes	1231.81
E-MTAB-8894	yes	800.90
E-HCAD-25	yes	534.27
E-GEOD-109979	yes	407.87
E-GEOD-75688	yes	269.21
E-MTAB-8205	yes	173.01
E-MTAB-7008	yes	96.62
E-HCAD-5	yes	16.16
E-GEOD-137537	yes	6.60
E-ANND-3	yes	4.12

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ARNT, ASCL1, CREB1, CTNNB1, DLX1, DLX2, DNMT1, EGR1, HDAC1, LMX1B, MECP2, PHOX2B, PITX2, SIX3, SPI1, XBP1, ZNF263, ZNF699

miRNA regulators (miRDB)

83 targeting GAD1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-10393-5P	99.65	68.01	1368

Literature-anchored findings (GeneRIF, showing 40)

• GAD gene transfer into glutamatergic excitatory neurons leading to an inhibitory bias with altered network activity and a neuroprotective phenotype holds potential for treatment of Parkinson’s disease (PMID:12376704)
• autoreactivity to GAD25 is rare in newly diagnosed type 1 diabetes and does not underlie GAD67 reactivity (PMID:12515288)
• The activity of GAD was reduced in patients with multiple sclerosis. (PMID:12774663)
• In the human cerebellar cortex some types of ’non-traditional’ large neurons are GAD-immunoreactive, in addition to those neurons already known to be GABAergic (i.e., stellate, basket, Purkinje and Golgi neurons). (PMID:15014985)
• The silent C661T substitution in GAD1 did not associated with schizophrenia or suicidal ideation/behavior. (PMID:15091314)
• Single nucleotide polymorphisms of the GAD67 gene are associated with nonsyndromic cleft lip with or without cleft palate. (PMID:15103710)
• Expression of GAD65 and GAD67 mRNA in the (dorsolateral prefrontal cortex) DLPFC and in the occipital cortex was significantly elevated in patients with schizophrenia, whereas the expression of the corresponding proteins and GAT-1 mRNA was unchanged. (PMID:15114630)
• Results describe the effect of phosphorylation on the two well-defined glutamic acid decarboxylase (GAD) isoforms, namely, GAD65 and GAD67, using highly purified preparations of recombinant human brain GAD65 and GAD67. (PMID:15147202)
• Three adjacent SNPs in the 5-prime upstream region of GAD1 showed a positive pairwise association with childhood-onset schizophrenia. Significant transmission distortion of 4-SNP haplotypes was also observed. (PMID:15505639)
• no evidence for significant allelic association between autism and GAD1 (PMID:15542242)
• Auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. (PMID:15571623)
• Results from the association studies indicate that GAD1 promoter variants are of importance for the Danish bipolar affective disorder. (PMID:15806582)
• Site-directed mutagenesis study validates that cysteine-455 (present in GAD67 as a free sulfhydryl group) plays an important role in GAD67 activity. (PMID:15836621)
• variations in the GAD1 gene may contribute to individual differences in N and impact susceptibility across a range of anxiety disorders and major depression (PMID:16718280)
• GAD67 is localized in the dermis and is potentially involved in variety of skin activities. (PMID:17113713)
• The results indicate that GAD67 mRNA level was reduced by 40% in the autistic group, suggesting that reduced Purkinje cell GABA input to the cerebellar nuclei. (PMID:17235515)
• conclusion is that GAD1 does not play a major role in schizophrenia in the Japanese population (PMID:17303389)
• All 24 children who developed diabetes had high-affinity glutamte decarboxylase autoantibodies before diabetes onset. (PMID:17325256)
• The structure of GAD67 shows a tethered loop covering the active site, providing a catalytic environment that sustains GABA production. In contrast, the same catalytic loop is inherently mobile in GAD65. (PMID:17384644)
• study suggests that the GABRB2 and GAD1 genes individually, as well as the combined effects of the polymorphism in the GAD1, GAD2 and GABRB2 genes, are associated with schizophrenia in the Chinese population (PMID:17412563)
• Subjects with schizophrenia exhibited expression deficits in GAD67. (PMID:17471287)
• GAD67 expression increase was marked in schizophrenics. (PMID:17553960)
• Expression of GAD67 splice variants may be related to human fetal pancreas development. (PMID:17652798)
• Subjects with schizophrenia showed a significant, on average 8-fold deficit in repressive chromatin-associated DNA methylation at the GAD1 promoter. (PMID:17726539)
• Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. (PMID:17767149)
• Expression of GAD67 mRNA in basket cells was significantly up-regulated in eight autistic brains compared with that in eight control brains respectively. Stellate cells showed a trend toward a small increase in GAD67 mRNA levels. (PMID:17918742)
• This study validates LIPS as a robust method to interrogate autoantibodies for the diagnosis of SPS and potentially other neurological diseases. (PMID:18047830)
• GAD1 single nucleotide polymorphism is in linkage disequilibrium with a child bipolar I disorder phenotype. (PMID:18294085)
• abruption of GAD1 gene is important to the risk of schizophrenia. (PMID:18335162)
• Data show that the expression of FEZ1,GAD1, and RGS4 are high correlated with one another in the prefrontal cortex of postmortem brain samples. (PMID:18470533)
• Autism may be caused by epigenetic changes in the gene encoding GAD1. (PMID:18783896)
• found evidence of a possible association between GAD67 and oral clefts in Caucasians (PMID:18837046)
• Nine single nucleotide polymorphisms comprising the GAD1 gene and the microsatellite marker D2S2381 are examined for association with autism. We found no association between childhood autism and any single marker or 2-5 marker haplotypes. (PMID:19139806)
• Decreased glutamic acid decarboxylase(67) mRNA expression in multiple brain areas of patients with schizophrenia and mood disorders. (PMID:19321177)
• glutamic acid decarboxylase autoimmunity may be associated with some forms of epilepsy (PMID:19428124)
• The structural features that distinguish GAD65 from GAD67 as a B cell autoantigen are related to functional requirements for its enzymatic mechanism. (PMID:19783309)
• The overall amount of GAD-67 was significantly reduced (-34%) in depressed subjects compared to matched controls. (PMID:20236554)
• These results support the importance of genetic variation in GAD1 in regulating prefrontal cortical GABA function. (PMID:20357758)
• results highlight a statistical association between one SNP of GAD67 (rs 11542313) and the condition of alcohol dependence. (PMID:20598486)
• Analysis of expression data from a microarray study performed in samples from Brodmann area 9 confirms that GAD67 expression is decreased in Parkinson’s disease (PMID:20832408)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	gad1b	ENSDARG00000027419
danio_rerio	gad1a	ENSDARG00000093411
mus_musculus	Gad1	ENSMUSG00000070880
rattus_norvegicus	Gad1	ENSRNOG00000000007
drosophila_melanogaster	Gad1	FBGN0004516
drosophila_melanogaster	Tdc2	FBGN0050446
caenorhabditis_elegans		WBGENE00006562
caenorhabditis_elegans		WBGENE00006762

Paralogs (7): DDC (ENSG00000132437), GAD2 (ENSG00000136750), CSAD (ENSG00000139631), HDC (ENSG00000140287), GADL1 (ENSG00000144644), SGPL1 (ENSG00000166224), PDXDC1 (ENSG00000179889)

Protein

Protein identifiers

Glutamate decarboxylase 1 — Q99259 (reviewed: Q99259)

Alternative names: 67 kDa glutamic acid decarboxylase, Glutamate decarboxylase 67 kDa isoform

All UniProt accessions (8): Q99259, A0A0S2Z3V5, C9J6C9, C9JLZ7, C9JN45, C9JT43, F8WD43, U3KQR2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) with pyridoxal 5’-phosphate as cofactor. Enzymatically inactive as glutamate decarboxylase.

Subunit / interactions. Homodimer.

Tissue specificity. Expressed in brain. Expressed in pancreatic islets, testis, adrenal cortex, and perhaps other endocrine tissues, but not in brain.

Disease relevance. Developmental and epileptic encephalopathy 89 (DEE89) [MIM:619124] A form of epileptic encephalopathy, a heterogeneous group of early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE89 is an autosomal recessive severe form characterized by profound global developmental delay with impaired intellectual development, absent speech, inability to sit or walk due to axial hypotonia and spastic quadriparesis, and onset of seizures in the first days or months of life. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the group II decarboxylase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q99259-1	1, GAD67	yes
Q99259-2	2
Q99259-3	3, GAD25
Q99259-4	4

RefSeq proteins (2): NP_000808, NP_038473 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002129	PyrdxlP-dep_de-COase	Domain
IPR015421	PyrdxlP-dep_Trfase_major	Homologous_superfamily
IPR015424	PyrdxlP-dep_Trfase	Homologous_superfamily
IPR021115	Pyridoxal-P_BS	Binding_site

Pfam: PF00282

Enzyme classification (BRENDA):

• EC 4.1.1.15 — glutamate decarboxylase (BRENDA: 66 organisms, 124 substrates, 254 inhibitors, 101 Km, 34 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-GLUTAMATE	0.0274–137.1	64
L-GLU	0.174–22	26
CYSTEINE SULFINIC ACID	5.2	1
L-ALPHA-METHYLGLUTAMATE	1.04	1
L-CYSTEIC ACID	5.4	1

Catalyzed reactions (Rhea), 1 shown:

• L-glutamate + H(+) = 4-aminobutanoate + CO2 (RHEA:17785)

UniProt features (79 total): helix 23, sequence conflict 17, strand 16, sequence variant 8, splice variant 4, turn 4, binding site 2, modified residue 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3VP6	X-RAY DIFFRACTION	2.1
2OKJ	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99259-F1	89.05	0.84

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 (2): 190–192; 567

Post-translational modifications (2): 78, 405

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-888568	GABA synthesis
R-HSA-888590	GABA synthesis, release, reuptake and degradation
R-HSA-9022927	MECP2 regulates transcription of genes involved in GABA signaling

MSigDB gene sets: 388 (showing top): GNF2_RTN1, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, MODULE_274, GOBP_BEHAVIOR, NKX25_02, LFA1_Q6, TTTGTAG_MIR520D, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, ATACCTC_MIR202, GOBP_GLUTAMATE_METABOLIC_PROCESS, GOZGIT_ESR1_TARGETS_DN, MODULE_563, AREB6_01, GTTAAAG_MIR302B, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS

GO Biological Process (7): L-glutamate catabolic process (GO:0006538), GABA shunt (GO:0006540), chemical synaptic transmission (GO:0007268), GABA biosynthetic process (GO:0009449), social behavior (GO:0035176), locomotory exploration behavior (GO:0035641), carboxylic acid metabolic process (GO:0019752)

GO Molecular Function (7): glutamate decarboxylase activity (GO:0004351), pyridoxal phosphate binding (GO:0030170), identical protein binding (GO:0042802), protein binding (GO:0005515), lyase activity (GO:0016829), carbon-carbon lyase activity (GO:0016830), carboxy-lyase activity (GO:0016831)

GO Cellular Component (14): cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell cortex (GO:0005938), vesicle membrane (GO:0012506), axon terminus (GO:0043679), perinuclear region of cytoplasm (GO:0048471), presynaptic active zone (GO:0048786), inhibitory synapse (GO:0060077), clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane (GO:0061202), GABA-ergic synapse (GO:0098982), axon (GO:0030424), neuron projection terminus (GO:0044306), synapse (GO:0045202), presynapse (GO:0098793)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
GABA synthesis, release, reuptake and degradation	1
Neurotransmitter release cycle	1
Transcriptional Regulation by MECP2	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
synapse	3
glutamate metabolic process	2
cell periphery	2
cytoplasm	2
presynapse	2
neuron projection	2
dicarboxylic acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
succinate metabolic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
anterograde trans-synaptic signaling	1
amino acid biosynthetic process	1
non-proteinogenic amino acid biosynthetic process	1
behavior	1
biological process involved in intraspecies interaction between organisms	1
locomotory behavior	1
exploration behavior	1
oxoacid metabolic process	1
carboxy-lyase activity	1
anion binding	1
vitamin B6 binding	1
protein binding	1
binding	1
catalytic activity	1
lyase activity	1
carbon-carbon lyase activity	1
intracellular anatomical structure	1
membrane	1
organelle membrane	1
vesicle	1
neuron projection terminus	1
distal axon	1
clathrin-coated vesicle membrane	1
clathrin-sculpted gamma-aminobutyric acid transport vesicle	1
cell junction	1

Protein interactions and networks

STRING

4274 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GAD1	PVALB	P20472	963
GAD1	SLC32A1	Q9H598	946
GAD1	SLC17A6	Q9P2U8	874
GAD1	SST	P01166	859
GAD1	CALB1	P05937	854
GAD1	MECP2	P51608	838
GAD1	SLC17A7	Q9P2U7	833
GAD1	CALB2	P22676	803
GAD1	SLC6A1	P30531	797
GAD1	GABRB3	P28472	792
GAD1	RBFOX3	A6NFN3	766
GAD1	GABRA1	P14867	742
GAD1	DLX5	P56178	714
GAD1	SLC6A5	Q9Y345	713
GAD1	TH	P07101	700

IntAct

49 interactions, top by confidence:

A	B	Type	Score
HAAO	GAD1	psi-mi:“MI:0915”(physical association)	0.830
GAD1	HAAO	psi-mi:“MI:0915”(physical association)	0.830
GAD1	MAL2	psi-mi:“MI:0915”(physical association)	0.720
GAD1	AGTRAP	psi-mi:“MI:0915”(physical association)	0.720
GAD1	CMTM5	psi-mi:“MI:0915”(physical association)	0.720
CMTM5	GAD1	psi-mi:“MI:0915”(physical association)	0.720
MAL2	GAD1	psi-mi:“MI:0915”(physical association)	0.720
AGTRAP	GAD1	psi-mi:“MI:0915”(physical association)	0.720
CMTM5	GAD1	psi-mi:“MI:0915”(physical association)	0.670
GAD1	STK3	psi-mi:“MI:0915”(physical association)	0.560
GAD1	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
STK3	GAD1	psi-mi:“MI:0915”(physical association)	0.560
HIS2	GAD1	psi-mi:“MI:0915”(physical association)	0.560
GAD1	HIS2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (39): STK3 (Two-hybrid), HAAO (Two-hybrid), AGTRAP (Two-hybrid), CMTM5 (Two-hybrid), HAAO (Two-hybrid), GAD1 (Two-hybrid), FGFR1 (Affinity Capture-MS), GAD1 (Two-hybrid), AGTRAP (Two-hybrid), MAL2 (Two-hybrid), CMTM5 (Two-hybrid), TRIM23 (Two-hybrid), KRT31 (Two-hybrid), TRIP6 (Two-hybrid), KRTAP3-2 (Two-hybrid)

ESM2 similar proteins: A0AA51Z3J4, A0PA85, A6QM00, B0B804, B0BC69, I1RV23, O84439, P14748, P16453, P18088, P19113, P20228, P23738, P34897, P48318, P48319, P48320, P48321, P48861, P49357, P49358, P50432, P54769, P54770, Q04792, Q05329, Q05683, Q06087, Q0VCA1, Q10104, Q16S21, Q28D99, Q3KLR8, Q3SZ20, Q4PRC2, Q5EA83, Q5IS68, Q5R7S7, Q6ZQY3, Q758F0

Diamond homologs: A0PA85, A2STQ3, A6QM00, E9FCP7, P14748, P18088, P20228, P48318, P48319, P48320, P48321, Q05329, Q05683, Q0VCA1, Q28D99, Q2FSD2, Q4PRC2, Q5IS68, Q5R7S7, Q64611, Q6ZQY3, Q80WP8, Q99259, Q9DBE0, Q9Y600, A0B9M9, A1AWM1, A3CWM4, A4G060, A5CWM6, A5ULW4, A6URB4, A6UVR4, A6VIC0, A7IAB9, A8EYH9, A8GNU0, A8GWB2, B0R349, B8DZS1

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
DNMT1	“down-regulates quantity by repression”	GAD1	“transcriptional regulation”
HDAC1	“down-regulates quantity by repression”	GAD1	“transcriptional regulation”
MECP2	“down-regulates quantity by repression”	GAD1	“transcriptional regulation”
GAD1	“down-regulates quantity”	L-glutamate(1-)	“chemical modification”
GAD1	“up-regulates quantity”	“gamma-aminobutyric acid”	“chemical modification”
PKA	“down-regulates activity”	GAD1	phosphorylation
PRKCE	“down-regulates activity”	GAD1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	8
Uncertain significance	131
Likely benign	106
Benign	31

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1327513	NM_000817.3(GAD1):c.1691A>G (p.Asn564Ser)	Pathogenic
1327514	NM_000817.3(GAD1):c.639-1445del	Pathogenic
1327515	NM_000817.3(GAD1):c.87C>G (p.Tyr29Ter)	Pathogenic
1327516	NM_000817.3(GAD1):c.1119+1G>A	Pathogenic
4683079	NM_000817.3(GAD1):c.87C>A (p.Tyr29Ter)	Pathogenic
565722	NM_000817.3(GAD1):c.865C>T (p.Gln289Ter)	Pathogenic
988956	NM_000817.3(GAD1):c.1414-1G>C	Pathogenic
988957	NM_000817.3(GAD1):c.692AGA[1] (p.Lys232del)	Pathogenic
988958	NM_000817.3(GAD1):c.812_816del (p.Val271fs)	Pathogenic
988959	NM_000817.3(GAD1):c.1591C>T (p.Arg531Ter)	Pathogenic
1803976	NM_000817.3(GAD1):c.1370G>A (p.Arg457His)	Likely pathogenic
2129735	NM_000817.3(GAD1):c.548-2A>C	Likely pathogenic
2501091	NM_000817.3(GAD1):c.1297G>T (p.Gly433Ter)	Likely pathogenic
3064894	NM_000817.3(GAD1):c.703_706del (p.Arg234_Glu235insTer)	Likely pathogenic
3584960	NM_000817.3(GAD1):c.719C>G (p.Ser240Ter)	Likely pathogenic
4528921	NM_000817.3(GAD1):c.611G>A (p.Trp204Ter)	Likely pathogenic
4725966	NM_000817.3(GAD1):c.1264-350_1289delinsGAGGTATCCAGCACATCCTGGCTG	Likely pathogenic
800908	NM_000817.3(GAD1):c.1402T>G (p.Trp468Gly)	Likely pathogenic

SpliceAI

2679 predictions. Top by Δscore:

Variant	Effect	Δscore
2:170818674:G:GG	donor_gain	1.0000
2:170822079:C:A	acceptor_gain	1.0000
2:170822083:CTAGC:C	acceptor_loss	1.0000
2:170822084:TAGC:T	acceptor_loss	1.0000
2:170822085:A:AG	acceptor_gain	1.0000
2:170822085:A:AT	acceptor_loss	1.0000
2:170822085:AGC:A	acceptor_gain	1.0000
2:170822086:G:GG	acceptor_gain	1.0000
2:170822086:GC:G	acceptor_gain	1.0000
2:170822086:GCG:G	acceptor_gain	1.0000
2:170822086:GCGT:G	acceptor_gain	1.0000
2:170822147:GCG:G	donor_gain	1.0000
2:170822148:CGGT:C	donor_loss	1.0000
2:170822150:G:GG	donor_gain	1.0000
2:170822150:GTA:G	donor_loss	1.0000
2:170822151:T:G	donor_loss	1.0000
2:170827498:G:GT	donor_gain	1.0000
2:170831173:G:GT	donor_gain	1.0000
2:170831192:GGTA:G	donor_loss	1.0000
2:170836790:TA:T	acceptor_loss	1.0000
2:170836791:A:AC	acceptor_loss	1.0000
2:170836791:A:AG	acceptor_gain	1.0000
2:170836792:G:A	acceptor_loss	1.0000
2:170836792:G:GA	acceptor_gain	1.0000
2:170836792:GGTC:G	acceptor_gain	1.0000
2:170836879:AACAT:A	donor_gain	1.0000
2:170836880:ACAT:A	donor_gain	1.0000
2:170836881:CAT:C	donor_gain	1.0000
2:170836882:AT:A	donor_gain	1.0000
2:170836882:ATGTA:A	donor_loss	1.0000

AlphaMissense

3943 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:170836850:G:A	G202E	1.000
2:170836855:T:A	W204R	1.000
2:170836855:T:C	W204R	1.000
2:170836859:T:C	L205P	1.000
2:170836881:C:A	N212K	1.000
2:170836881:C:G	N212K	1.000
2:170844046:T:C	F214L	1.000
2:170844048:T:A	F214L	1.000
2:170844048:T:G	F214L	1.000
2:170844061:G:C	A219P	1.000
2:170852730:T:A	W401R	1.000
2:170852730:T:C	W401R	1.000
2:170852743:A:T	K405M	1.000
2:170852744:G:C	K405N	1.000
2:170852744:G:T	K405N	1.000
2:170853909:T:C	Y434H	1.000
2:170853913:T:A	L435H	1.000
2:170853913:T:C	L435P	1.000
2:170853915:T:C	F436L	1.000
2:170853916:T:C	F436S	1.000
2:170853917:C:A	F436L	1.000
2:170853917:C:G	F436L	1.000
2:170853948:G:C	D447H	1.000
2:170853949:A:T	D447V	1.000
2:170853954:G:T	G449W	1.000
2:170853955:G:A	G449E	1.000
2:170853972:T:C	C455R	1.000
2:170853973:G:A	C455Y	1.000
2:170853976:G:A	G456D	1.000
2:170853978:C:A	R457S	1.000

dbSNP variants (sampled 300 via entrez): RS1000037893 (2:170833255 AG>A), RS1000049650 (2:170826621 G>A,C), RS1000175219 (2:170846172 T>G), RS1000322108 (2:170833031 G>C), RS1000411471 (2:170837464 C>T), RS1000504038 (2:170824211 T>G), RS1000671041 (2:170853807 A>G), RS1000759654 (2:170847303 T>C), RS1000832195 (2:170826880 C>G), RS1000899121 (2:170832637 G>C,T), RS1000931340 (2:170832354 T>C), RS1000971113 (2:170813711 C>A,T), RS1001066832 (2:170818846 G>A,C,T), RS1001118169 (2:170859750 G>A), RS1001130994 (2:170855710 A>C,T)

Disease associations

OMIM: gene MIM:605363 | disease phenotypes: MIM:603513, MIM:619026, MIM:619124, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
early infantile epileptic encephalopathy	Definitive	Autosomal recessive
developmental and epileptic encephalopathy 89	Strong	Autosomal recessive
spastic quadriplegic cerebral palsy	Supportive	Autosomal recessive
cerebral palsy, spastic quadriplegic, 1	Limited	Autosomal recessive
neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
obsolete early infantile epileptic encephalopathy	Definitive	AR

Mondo (7): neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (MONDO:0033613), developmental and epileptic encephalopathy 89 (MONDO:0030856), hereditary spastic paraplegia (MONDO:0019064), pyridoxine-dependent epilepsy (MONDO:0009945), (MONDO:0011329), (MONDO:0016021), spastic quadriplegic cerebral palsy (MONDO:0016215)

Orphanet (4): Inherited congenital spastic tetraplegia (Orphanet:210141), Infantile neurodegeneration-progressive spasticity-intellectual disability-white matter lesions syndrome (Orphanet:641353), Hereditary spastic paraplegia (Orphanet:685), Pyridoxine-dependent-developmental and epileptic encephalopathy (Orphanet:3006)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000059	Hypoplastic labia majora
HP:0000064	Hypoplastic labia minora
HP:0000175	Cleft palate
HP:0000219	Thin upper lip vermilion
HP:0000256	Macrocephaly
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000494	Downslanted palpebral fissures
HP:0000582	Upslanted palpebral fissure
HP:0000774	Narrow chest
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture
HP:0001539	Omphalocele
HP:0001762	Talipes equinovarus
HP:0002059	Cerebral atrophy
HP:0002079	Hypoplasia of the corpus callosum
HP:0002187	Profound intellectual disability
HP:0002273	Tetraparesis
HP:0002487	Hyperkinetic movements

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005312_34	Menopause (age at onset)	3.000000e-19

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C567853	Cerebral Palsy, Spastic Quadriplegic, 1 (supp.)
C536254	Pyridoxine-dependent epilepsy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2614 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3749034	Dosage	3	methadone	Heroin Dependence
rs3762555	Dosage	3	methadone	Heroin Dependence
rs3762556	Dosage	3	methadone	Heroin Dependence
rs769404	Dosage	3	methadone	Heroin Dependence

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3762555	GAD1	3	3.00	1	methadone
rs3762556	GAD1	3	3.00	1	methadone
rs3791878	GAD1		0.00	0
rs3749034	GAD1	3	3.00	1	methadone
rs769395	GAD1		0.00	0
rs769404	GAD1	3	0.50	1	methadone

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Decarboxylases

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	7
Valproic Acid	affects expression, decreases expression, increases expression	6
Tetrachlorodibenzodioxin	decreases expression, increases expression	4
methylmercuric chloride	increases expression, affects cotreatment	3
trichostatin A	increases expression, affects cotreatment	3
sodium arsenite	increases expression	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
belinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Estradiol	increases reaction, increases expression	2
Hydrogen Peroxide	decreases response to substance, affects expression	2
Methotrexate	affects response to substance, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Pyridoxal Phosphate	affects binding, increases metabolic processing	2
Particulate Matter	increases abundance, increases expression	2
novichok	affects binding	1
sotorasib	affects cotreatment, decreases expression	1
methyleugenol	increases expression	1
mipafox	affects binding	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
tabun	affects binding	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects binding	1
VX-agent	affects binding	1
terbufos	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1116774	Binding	Inhibition of human Gad67	Ginkgo biloba and ginkgotoxin. — J Nat Prod

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1SP	Abcam U-87MG GAD1 KO	Cancer cell line	Male
CVCL_D1WF	Abcam A-549 GAD1 KO	Cancer cell line	Male
CVCL_D2AU	Abcam HCT 116 GAD1 KO	Cancer cell line	Male
CVCL_SP47	HAP1 GAD1 (-) 1	Cancer cell line	Male
CVCL_XP03	HAP1 GAD1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT05432999	Not specified	COMPLETED	Extracorporeal Shockwave Therapy for Spasticity in People With Spinal Cord Injury
NCT07433647	Not specified	RECRUITING	Evaluation of Brain MRI Changes in Cerebral Palsy Patients
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)
NCT05354622	Not specified	RECRUITING	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)
NCT05373082	Not specified	COMPLETED	Identification of Modifying Factors in Hereditary Spastic Paraplegia
NCT05411627	Not specified	WITHDRAWN	A Pilot Study of Shockwave Therapy in HSP
NCT05613114	Not specified	COMPLETED	Effect of Dalfampridine in Patients With Hereditary Spastic Paraplegia
NCT05767268	Not specified	COMPLETED	Assessment of the Psychophysical State During Rehabilitation Treatment With Lokomat
NCT05848271	Not specified	RECRUITING	Natural History Study of Patients with HPDL Mutations
NCT06156813	Not specified	RECRUITING	Turkish Lower-Extremity Motor Activity Log (LE-MAL)
NCT06229626	Not specified	RECRUITING	Evaluation of an Intensive Training Program for Patients with Hereditary Spastic Paraparesis SPG4/Spast
NCT06260982	Not specified	UNKNOWN	Cognitive Disorders in Hereditary Spastic Paraplegia Type 4
NCT06553976	Not specified	RECRUITING	Spastic Paraplegia - Centers of Excellence Research Network
NCT06572046	Not specified	RECRUITING	STOP-HSP.Net: a Registry for Hereditary Spastic Paraplegia as an Integration Tool for Future Therapeutic Strategies
NCT06573866	Not specified	RECRUITING	Enhancement of Quality of Work And Life