GAD2

Summary

GAD2 (glutamate decarboxylase 2, HGNC:4093) is a protein-coding gene on chromosome 10p12.1, encoding Glutamate decarboxylase 2 (Q05329). Catalyzes the production of GABA.

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 autoantibody and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Alternative splicing results in multiple transcript variants that encode the same protein.

Source: NCBI Gene 2572 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 90 total
• Druggable target: yes
• MANE Select transcript: NM_001134366

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4093
Approved symbol	GAD2
Name	glutamate decarboxylase 2
Location	10p12.1
Locus type	gene with protein product
Status	Approved
Aliases	GAD65
Ensembl gene	ENSG00000136750
Ensembl biotype	protein_coding
OMIM	138275
Entrez	2572

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 1 retained_intron, 1 non_stop_decay

ENST00000259271, ENST00000376248, ENST00000376261, ENST00000428517, ENST00000648567

RefSeq mRNA: 2 — MANE Select: NM_001134366 NM_000818, NM_001134366

CCDS: CCDS7149

Canonical transcript exons

ENST00000376261 — 16 exons

Exon	Start	End
ENSE00000638362	26224539	26224651
ENSE00000816175	26229662	26229777
ENSE00000816179	26286345	26286494
ENSE00000816180	26292465	26292572
ENSE00000816181	26292902	26292991
ENSE00000926045	26217610	26217669
ENSE00000926046	26217842	26217991
ENSE00000926047	26245921	26246000
ENSE00000926048	26269119	26269173
ENSE00000926049	26270640	26270756
ENSE00000926050	26273636	26273700
ENSE00001470077	26216774	26216885
ENSE00001738920	26300788	26304558
ENSE00001769139	26223887	26223977
ENSE00001787496	26281009	26281087
ENSE00003556563	26219043	26219276

Expression profiles

Bgee: expression breadth ubiquitous, 113 present calls, max score 97.42.

FANTOM5 (CAGE): breadth broad, TPM avg 4.8224 / max 455.4268, expressed in 199 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104392	1.8470	111
104389	0.9749	114
104391	0.7497	101
104387	0.6653	124
104390	0.2823	74
104388	0.2791	84
104386	0.0241	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	97.42	gold quality
nucleus accumbens	UBERON:0001882	95.93	gold quality
type B pancreatic cell	CL:0000169	95.60	gold quality
putamen	UBERON:0001874	95.25	gold quality
caudate nucleus	UBERON:0001873	94.90	gold quality
endothelial cell	CL:0000115	94.73	gold quality
orbitofrontal cortex	UBERON:0004167	92.66	gold quality
lateral globus pallidus	UBERON:0002476	92.38	gold quality
middle frontal gyrus	UBERON:0002702	92.21	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.66	gold quality
middle temporal gyrus	UBERON:0002771	91.25	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.91	gold quality
Brodmann (1909) area 10	UBERON:0013541	90.60	gold quality
prefrontal cortex	UBERON:0000451	89.97	gold quality
primary visual cortex	UBERON:0002436	88.98	gold quality
hypothalamus	UBERON:0001898	88.28	gold quality
superior frontal gyrus	UBERON:0002661	88.16	gold quality
cingulate cortex	UBERON:0003027	87.81	gold quality
occipital lobe	UBERON:0002021	87.75	gold quality
anterior cingulate cortex	UBERON:0009835	87.69	gold quality
telencephalon	UBERON:0001893	87.60	gold quality
frontal cortex	UBERON:0001870	87.55	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.37	gold quality
neocortex	UBERON:0001950	87.14	gold quality
frontal pole	UBERON:0002795	86.90	gold quality
entorhinal cortex	UBERON:0002728	86.80	gold quality
cerebellar vermis	UBERON:0004720	86.76	gold quality
postcentral gyrus	UBERON:0002581	86.36	gold quality
lateral nuclear group of thalamus	UBERON:0002736	86.11	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.84	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-HCAD-31	yes	1558.51
E-MTAB-8894	yes	1143.91
E-HCAD-56	yes	858.41
E-HCAD-5	yes	719.39
E-GEOD-84465	yes	510.93
E-ENAD-27	yes	477.53
E-HCAD-35	yes	77.82
E-HCAD-25	yes	46.42
E-MTAB-5061	yes	18.46
E-GEOD-81547	yes	13.56
E-GEOD-93593	yes	11.80
E-GEOD-83139	yes	10.58
E-ANND-3	yes	9.81
E-MTAB-6108	no	154.52

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, DLX1, DLX2, ESR1, ESR2, SP1, TP53

miRNA regulators (miRDB)

67 targeting GAD2, 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-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-466	99.67	70.85	2863

Literature-anchored findings (GeneRIF, showing 40)

• Molecular mimicry in type 1 diabetes: immune cross-reactivity between islet autoantigen and human cytomegalovirus but not Coxsackie virus. (PMID:12021098)
• The PEVKEK region of the pyridoxal phosphate binding domain of GAD65 expresses a dominant B cell epitope for type 1 diabetes sera (PMID:12021103)
• GAD65-specific B cells and the antibodies they secrete appear to modulate the autoimmune T cell repertoire by down-regulating T cell epitopes in an immunodominant area while boosting epitopes in distant or cryptic regions. (PMID:12097368)
• GAD2 in type 1 diabetes. GAD2 does not play a major role in type 1 diabetes in these two European populations. (PMID:12196483)
• The effect of GAD65 on T-cell activation in stiff-man syndrome and cerebellar ataxia associated with polyendocrine autoimmunity was evaluated. (PMID:12197888)
• The alpha-helical secondary structure of the GAD65 C-terminus must be denatured to generate linear epitopes. The N-terminus is both surface-exposed and linear in the native structure. Masking membrane interactions must be broken for B-cell recognition. (PMID:12296864)
• 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)
• dinucleotide repeat polymorphism in GAD65 (PMID:12503190)
• results support the hypothesis that presentation of GAD autoantigen by islet endothelium in vivo could promote transmigration of circulating islet autoantigen-specific T-cells primed in regional lymph nodes against islet autoantigens (PMID:12606513)
• GAD antibodies in type I diabetes mellitus has unique N-terminal linear epitopes that are located on the anchoring domain of GAD65 molecules. (PMID:14557453)
• Data suggest that the conversion of full-length glutamate decarboxylase (GAD) to truncated GAD65 mediated by endogenous protease may represent an important mechanism in the regulation of GABA biosynthesis in the brain. (PMID:14576464)
• GAD2 is mapped to chromosome 10p12 and is a candidate gene for human obesity (PMID:14691540)
• The StyI polymorphism in intron 11 of GAD2 did not associate with schizophrenia or suicidal ideation/behavior. (PMID:15091314)
• 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)
• highly heterogeneous recognition of a multitude of INS and GAD65 peptide determinants occurred in the absence of protein recognition, and low functional avidity of the memory T cells (PMID:15163889)
• Among the type 1 diabetes children, increasing neutralising titres was associated positively with increasing antibody levels against GAD65. All siblings with antibodies against GAD 65 had significant titre increase against any of the CBV strains. (PMID:15170642)
• specificity and avidity of GAD65 reactive T-cell clones isolated from patients with type 1 diabetes (PMID:15277377)
• Conformation-dependent autoantibodies directed against GAD65 are markers of Type 1 diabetes. (PMID:15365614)
• GAD65 autoantibody response in the preclinical stage of type 1 diabetes is dynamic and related to the HLA genotypes that confer risk of diabetes. (PMID:15834701)
• Site-directed mutagenesis study validates that cysteine-446 (present in GAD65 as a free sulfhydryl group) plays an important role in GAD65 activity. (PMID:15836621)
• Out of 14 GAD2 markers screened in stage 1, only one met the threshold criteria for follow-up in a range of anxiety disorders and major depression (PMID:16718280)
• marginally significant (0.01 < P < 0.05) associations between four common variants of GAD2 and BMI were observed (PMID:16731858)
• The functional promoter GAD2 -243 A > G variant may influence risk for alcohol dependence (AD) in some populations, or its role may be limited to susceptibility to severe AD. (PMID:17034009)
• DPD-defined epitope specificity is correlated directly with preserved beta-cell functional reserve in GAD65Ab-positive patients and is associated with the milder clinical phenotype of A+B+ KPDM (PMID:17090641)
• We found glutamic acid decarboxylase (Gad65)antibodies in idiopathic generalized epilepsy and type 1 diabetes. (PMID:17167787)
• 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)
• GAD2-243A–>G polymorphism in a population of middle-aged White people associates with a modest reduction in body mass index and fasting and oral glucose tolerance test -related plasma glucose levels (PMID:17459095)
• Glutamate cysteine ligase catalytic suunit promoter polymorphisms may influence GAD65 autoantibody levels and influence the age of onset of type 1 diabetes. (PMID:17479437)
• Autoantibodies persist for 6 yearts after diagnosis of latent autoimmune diabetes in adultsbut levels and reactivity to different GAD65 epitopes are not associated with disease progression. (PMID:17657474)
• Differences in the epitope GAD65 binding between mother and child at birth are limited. The epitope pattern at type 1 diabetes diagnosis differed from that at birth, supporting the view that disease-associated epitopes develop between birth and diagnosis. (PMID:17992632)
• This study validates LIPS as a robust method to interrogate autoantibodies for the diagnosis of SPS and potentially other neurological diseases. (PMID:18047830)
• The proximity of B- and T-cell epitopes within the GAD65 structure suggests that antigen-antibody complexes may influence antigen processing by accessory cells and thereby T-cell reactivity. (PMID:18184926)
• conclude that masked GAD65Ab are present in the healthy population and that a lack of particular anti-Ids, rather than GAD65Ab per se, is a characteristic of type 1 diabetes. (PMID:18367670)
• SNP in the GAD2 gene was associated with increased BMI in late childhood and adolescence in this population of girls from western Pennsylvania. (PMID:18371956)
• We describe using intermittent prednisolone and finding autoantibodies to GAD65 in juvenile neuronal ceroid lipofuscinosis. (PMID:18378887)
• Patients with latent autoimmune diabetes in adults high GAD65(Ab) antibody titers resemble type 1 diabetic patients in their GAD65Ab epitope specificity. (PMID:18487477)
• These results suggest that GAD2 and GLUL do not play a major role in schizophrenia pathogenesis and there is no gene-gene interaction between the eight genes in the Japanese population. (PMID:19125103)
• behavioral inhibition-associated SNPs appear to be associated with differences in MYO3A- but not GAD2 lymphoblastoid-mRNA expression levels (PMID:19229853)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	gad2	ENSDARG00000015537
mus_musculus	Gad2	ENSMUSG00000026787
rattus_norvegicus	Apbb1ip	ENSRNOG00000017803
drosophila_melanogaster	Gad1	FBGN0004516
drosophila_melanogaster	Tdc2	FBGN0050446
caenorhabditis_elegans		WBGENE00006562
caenorhabditis_elegans		WBGENE00006762

Paralogs (7): GAD1 (ENSG00000128683), DDC (ENSG00000132437), CSAD (ENSG00000139631), HDC (ENSG00000140287), GADL1 (ENSG00000144644), SGPL1 (ENSG00000166224), PDXDC1 (ENSG00000179889)

Protein

Protein identifiers

Glutamate decarboxylase 2 — Q05329 (reviewed: Q05329)

Alternative names: 65 kDa glutamic acid decarboxylase, Glutamate decarboxylase 65 kDa isoform

All UniProt accessions (4): A0A3B3IU09, Q05329, Q5VZ30, Q5VZ31

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the production of GABA.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Cytosol. Cytoplasmic vesicle. Presynaptic cell membrane. Golgi apparatus membrane.

Post-translational modifications. Phosphorylated; which does not affect kinetic parameters or subcellular location. Palmitoylated; which is required for presynaptic clustering.

Similarity. Belongs to the group II decarboxylase family.

RefSeq proteins (2): NP_000809, NP_001127838* (*=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 (62 total): helix 25, strand 13, sequence variant 7, modified residue 5, turn 4, lipid moiety-binding region 2, binding site 2, chain 1, region of interest 1, mutagenesis site 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2OKK	X-RAY DIFFRACTION	2.3
1ES0	X-RAY DIFFRACTION	2.6
7LZ6	ELECTRON MICROSCOPY	7.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q05329-F1	90.62	0.86

Antibody-complex structures (SAbDab): 1 — 7LZ6

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): 181–183; 558

Post-translational modifications (7): 30, 45, 3, 6, 10, 13, 396

Mutagenesis-validated functional residues (1):

Position	Phenotype
3–13	no effect on glutamate decarboxylase activity.

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: 186 (showing top): BENPORATH_ES_WITH_H3K27ME3, MODULE_274, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_GLUTAMATE_METABOLIC_PROCESS, MODULE_563, MODULE_445, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CELL_CELL_SIGNALING, NKX61_01, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, LIU_VAV3_PROSTATE_CARCINOGENESIS_DN

GO Biological Process (4): GABA shunt (GO:0006540), chemical synaptic transmission (GO:0007268), GABA biosynthetic process (GO:0009449), carboxylic acid metabolic process (GO:0019752)

GO Molecular Function (6): glutamate decarboxylase activity (GO:0004351), pyridoxal phosphate binding (GO:0030170), protein binding (GO:0005515), lyase activity (GO:0016829), carbon-carbon lyase activity (GO:0016830), carboxy-lyase activity (GO:0016831)

GO Cellular Component (12): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), axon (GO:0030424), presynaptic membrane (GO:0042734), clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane (GO:0061202), Golgi apparatus (GO:0005794), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202)

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	4
cytoplasm	3
succinate metabolic process	1
glutamate 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
oxoacid metabolic process	1
carboxy-lyase activity	1
anion binding	1
vitamin B6 binding	1
binding	1
catalytic activity	1
lyase activity	1
carbon-carbon lyase activity	1
Golgi apparatus	1
bounding membrane of organelle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
neuron projection	1
synaptic membrane	1
presynapse	1
clathrin-coated vesicle membrane	1
clathrin-sculpted gamma-aminobutyric acid transport vesicle	1
endomembrane system	1
intracellular membrane-bounded organelle	1
intracellular vesicle	1
cell junction	1

Protein interactions and networks

STRING

3980 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GAD2	SLC32A1	Q9H598	967
GAD2	PTPRN	Q16849	962
GAD2	SLC30A8	Q8IWU4	889
GAD2	INS	P01308	883
GAD2	SLC30A10	Q6XR72	877
GAD2	AMPH	P49418	856
GAD2	SLC17A7	Q9P2U7	855
GAD2	SLC6A1	P30531	826
GAD2	CNTNAP2	Q9UHC6	814
GAD2	SLC17A6	Q9P2U8	806
GAD2	TNFRSF10A	O00220	805
GAD2	PVALB	P20472	801
GAD2	BIN1	O00499	796
GAD2	LGI1	O95970	790
GAD2	CD4	P01730	785

IntAct

138 interactions, top by confidence:

A	B	Type	Score
ARL6IP1	GAD2	psi-mi:“MI:0915”(physical association)	0.720
MAL2	GAD2	psi-mi:“MI:0915”(physical association)	0.720
GAD2	LDAF1	psi-mi:“MI:0915”(physical association)	0.720
GAD2	ARL6IP1	psi-mi:“MI:0915”(physical association)	0.720
GAD2	MAL2	psi-mi:“MI:0915”(physical association)	0.720
AGTRAP	GAD2	psi-mi:“MI:0915”(physical association)	0.560
GAD2	CMTM5	psi-mi:“MI:0915”(physical association)	0.560
CMTM5	GAD2	psi-mi:“MI:0915”(physical association)	0.560
GAD2	ARMC12	psi-mi:“MI:0915”(physical association)	0.560
GAD2	DERL3	psi-mi:“MI:0915”(physical association)	0.560
GAD2	APOC4	psi-mi:“MI:0915”(physical association)	0.560
GAD2	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
GAD2	DGAT2L6	psi-mi:“MI:0915”(physical association)	0.560
SMPD2	GAD2	psi-mi:“MI:0915”(physical association)	0.560
HIGD1C	GAD2	psi-mi:“MI:0915”(physical association)	0.560
GAD2	RPRM	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (54): ARL6IP1 (Two-hybrid), AGTRAP (Two-hybrid), TMEM159 (Two-hybrid), MAL2 (Two-hybrid), CMTM5 (Two-hybrid), GAD2 (Biochemical Activity), GAD2 (Biochemical Activity), GAD2 (Two-hybrid), GAD2 (Two-hybrid), GAD2 (Two-hybrid), GAD2 (Two-hybrid), GAD2 (Two-hybrid), GAD2 (Two-hybrid), GAD2 (Two-hybrid), GAD2 (Two-hybrid)

ESM2 similar proteins: A0A2H5AIY0, A0A2H5AIY2, A0A2I6B3P0, A0AA51Z3J4, A6QM00, A8XKT0, O82415, O88533, O96567, O96569, O96571, P05031, P14173, P17770, P18486, P20228, P20711, P22781, P27718, P48320, P48321, P48861, P54768, P54769, P54770, P54771, P80041, P81893, P93082, P93083, Q05329, Q05683, Q06085, Q06086, Q06087, Q06088, Q0VCA1, Q0ZQX0, Q0ZS27, Q16S21

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, Q9Z3R1, A0A481NV25, I1RV23, O96571, P71362, Q0W498, Q43908, A0A0A2IDH4, Q8TV92, Q05733, A7B1V0, A0B9M9, A4G060, A6VIC0, A7IAB9

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
GAD2	“down-regulates quantity”	L-glutamate(1-)	“chemical modification”
GAD2	“up-regulates quantity”	“gamma-aminobutyric acid”	“chemical modification”
PKC	“up-regulates activity”	GAD2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	78
Likely benign	3
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

2151 predictions. Top by Δscore:

Variant	Effect	Δscore
10:26217991:GGT:G	donor_loss	1.0000
10:26217992:G:GA	donor_loss	1.0000
10:26217993:T:A	donor_loss	1.0000
10:26223882:TTCA:T	acceptor_loss	1.0000
10:26223885:A:AC	acceptor_loss	1.0000
10:26223885:A:AG	acceptor_gain	1.0000
10:26223885:AG:A	acceptor_gain	1.0000
10:26223885:AGG:A	acceptor_gain	1.0000
10:26223886:G:GG	acceptor_gain	1.0000
10:26223886:GG:G	acceptor_gain	1.0000
10:26223886:GGG:G	acceptor_gain	1.0000
10:26223886:GGGC:G	acceptor_gain	1.0000
10:26223973:AACAT:A	donor_gain	1.0000
10:26223974:ACAT:A	donor_gain	1.0000
10:26223975:CAT:C	donor_gain	1.0000
10:26223975:CATG:C	donor_loss	1.0000
10:26223976:AT:A	donor_gain	1.0000
10:26223976:ATGT:A	donor_loss	1.0000
10:26223977:TGTA:T	donor_loss	1.0000
10:26223978:G:GG	donor_gain	1.0000
10:26223978:GTAA:G	donor_loss	1.0000
10:26223979:T:G	donor_loss	1.0000
10:26229778:G:GG	donor_gain	1.0000
10:26269170:GAAA:G	donor_gain	1.0000
10:26269171:AAAGT:A	donor_loss	1.0000
10:26269172:AAG:A	donor_loss	1.0000
10:26269173:AGTAA:A	donor_loss	1.0000
10:26269174:G:A	donor_loss	1.0000
10:26269174:G:GG	donor_gain	1.0000
10:26269175:TAAGT:T	donor_loss	1.0000

AlphaMissense

3880 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:26224540:T:C	F205L	1.000
10:26224542:C:A	F205L	1.000
10:26224542:C:G	F205L	1.000
10:26281025:T:A	W392R	1.000
10:26281025:T:C	W392R	1.000
10:26286483:T:A	W459R	1.000
10:26286483:T:C	W459R	1.000
10:26219085:T:C	F110S	0.999
10:26219159:T:C	F135L	0.999
10:26219161:C:A	F135L	0.999
10:26219161:C:G	F135L	0.999
10:26219243:T:C	C163R	0.999
10:26219256:T:C	L167P	0.999
10:26223934:G:A	G190R	0.999
10:26223934:G:C	G190R	0.999
10:26223935:G:A	G190E	0.999
10:26223949:T:A	W195R	0.999
10:26223949:T:C	W195R	0.999
10:26223953:T:C	L196P	0.999
10:26223969:T:A	N201K	0.999
10:26223969:T:G	N201K	0.999
10:26223975:C:A	N203K	0.999
10:26223975:C:G	N203K	0.999
10:26224546:T:G	Y207D	0.999
10:26224555:G:C	A210P	0.999
10:26224577:A:T	E217V	0.999
10:26229662:G:A	G242D	0.999
10:26229770:C:T	S278F	0.999
10:26245924:C:G	H282D	0.999
10:26245926:T:A	H282Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000033242 (10:26243749 T>C,G), RS1000058908 (10:26250176 G>C), RS1000079364 (10:26295645 T>C), RS1000104601 (10:26241218 G>A,C), RS1000155282 (10:26269610 C>G), RS1000170777 (10:26244096 A>T), RS1000184215 (10:26285656 T>C,G), RS1000229848 (10:26239441 G>A), RS1000242263 (10:26279167 G>A), RS1000242336 (10:26234011 A>G), RS1000323149 (10:26238425 G>A,C), RS1000344047 (10:26233181 G>A), RS1000378141 (10:26266777 C>T), RS1000408142 (10:26272936 G>T), RS1000423469 (10:26295399 T>C)

Disease associations

OMIM: gene MIM:138275 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008153_7	Lean body mass	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004995	lean body mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2952 (SINGLE PROTEIN)

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2236418	GAD2		0.00	0
rs2839669	GAD2		0.00	0
rs2839670	GAD2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Decarboxylases

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Pyridoxal Phosphate	affects binding, increases metabolic processing	4
Valproic Acid	affects cotreatment, decreases expression	4
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
bisphenol F	decreases methylation	1
novichok	affects binding	1
mipafox	affects binding	1
tabun	affects binding	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects binding	1
VX-agent	affects binding	1
ethyl-p-hydroxybenzoate	decreases expression	1
arsenite	increases methylation	1
phenylsaligenin cyclic phosphate	affects binding	1
phenyl di-n-pentylphosphinate	affects binding	1
2-palmitoylglycerol	increases expression	1
entinostat	decreases expression	1
S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate	affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
Panobinostat	affects cotreatment, decreases expression	1
Glyphosate	affects binding	1
Ethanol	decreases expression, affects cotreatment	1
Allylglycine	decreases activity, affects binding	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Diazinon	affects binding	1
Chlorpyrifos	affects binding	1
Ethylmaleimide	decreases activity	1
Folic Acid	affects cotreatment, decreases expression	1
Isoflurophate	affects binding	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
CHEMBL1116773	Binding	Inhibition of human brain Gad65 expressed in Escherichia coli at 2.7 mM	Ginkgo biloba and ginkgotoxin. — J Nat Prod

Clinical trials (associated diseases)

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