GLUD2

Summary

GLUD2 (glutamate dehydrogenase 2, HGNC:4336) is a protein-coding gene on chromosome Xq24, encoding Glutamate dehydrogenase 2, mitochondrial (P49448). Important for recycling the chief excitatory neurotransmitter, glutamate, during neurotransmission.

The protein encoded by this gene is localized to the mitochondrion and acts as a homohexamer to recycle glutamate during neurotransmission. The encoded enzyme catalyzes the reversible oxidative deamination of glutamate to alpha-ketoglutarate. This gene is intronless.

Source: NCBI Gene 2747 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 73 total — 1 likely-pathogenic
• MANE Select transcript: NM_012084

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4336
Approved symbol	GLUD2
Name	glutamate dehydrogenase 2
Location	Xq24
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000182890
Ensembl biotype	protein_coding
OMIM	300144
Entrez	2747

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000328078

RefSeq mRNA: 1 — MANE Select: NM_012084 NM_012084

CCDS: CCDS14603

Canonical transcript exons

ENST00000328078 — 1 exons

Exon	Start	End
ENSE00001309101	121047610	121050094

Expression profiles

Bgee: expression breadth ubiquitous, 122 present calls, max score 83.26.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9894 / max 27.0833, expressed in 480 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197437	0.9894	480

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	83.26	gold quality
testis	UBERON:0000473	82.15	gold quality
left testis	UBERON:0004533	81.77	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.62	gold quality
placenta	UBERON:0001987	67.94	gold quality
right adrenal gland	UBERON:0001233	67.56	gold quality
right adrenal gland cortex	UBERON:0035827	67.43	gold quality
liver	UBERON:0002107	66.44	gold quality
right lobe of liver	UBERON:0001114	65.44	gold quality
adult mammalian kidney	UBERON:0000082	64.81	gold quality
left adrenal gland	UBERON:0001234	64.74	gold quality
adrenal gland	UBERON:0002369	64.10	gold quality
left adrenal gland cortex	UBERON:0035825	63.63	gold quality
omental fat pad	UBERON:0010414	62.90	gold quality
islet of Langerhans	UBERON:0000006	62.49	gold quality
kidney	UBERON:0002113	61.62	gold quality
prefrontal cortex	UBERON:0000451	61.54	gold quality
adipose tissue	UBERON:0001013	61.37	gold quality
endometrium	UBERON:0001295	61.25	gold quality
adrenal tissue	UBERON:0018303	61.01	gold quality
subcutaneous adipose tissue	UBERON:0002190	59.88	gold quality
gall bladder	UBERON:0002110	59.75	gold quality
superior frontal gyrus	UBERON:0002661	59.31	gold quality
pancreas	UBERON:0001264	58.10	gold quality
corpus callosum	UBERON:0002336	58.02	gold quality
frontal cortex	UBERON:0001870	57.51	gold quality
ventricular zone	UBERON:0003053	57.48	gold quality
smooth muscle tissue	UBERON:0001135	56.40	gold quality
thoracic mammary gland	UBERON:0005200	56.34	gold quality
body of pancreas	UBERON:0001150	56.02	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.43

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting GLUD2, 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-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
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-6885-3P	99.75	70.36	3187
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-26A-1-3P	99.64	66.81	788
HSA-MIR-26A-2-3P	99.64	66.82	786
HSA-MIR-298	99.63	67.56	1916

Literature-anchored findings (GeneRIF, showing 32)

• identify the structural basis for allosteric differences of GlUD1 and GLUD2 (PMID:11950837)
• These results suggest that the Ser443 residue plays an important role in the different thermal stability of human glutamate dehydrogenase isozymes (hGDH1 and hGDH2). (PMID:15044002)
• GLUD2 originated by retroposition from GLUD1 in the hominoid ancestor less than 23 million years ago. (PMID:15378063)
• results suggest that cysteine 323 plays an important role in catalysis by human GDH isozymes; C323 is not directly involved in allosteric regulation. (PMID:15750346)
• amino acid changes, acting in concert with Arg443Ser and Gly456Ala, ought to be responsible the unique properties of the brain-specific human isoenzyme (PMID:17924438)
• Mitochondrial targeting specificity of GLUD2 is due to an amino acid substitution in the mitochondrial targeting sequence soon after the duplication event in the hominoid ancestor approximately 18-25 million years ago. (PMID:18688271)
• study of molecular mechanisms regulating hGDH2 function by creating & analyzing mutants with single amino acid substitutions in the regulatory domain (antenna, pivot helix) of the protein (PMID:19393024)
• GDH2 localizes mainly to mitochondria and to a lesser extent to the endoplasmic reticulum of cells (PMID:19428807)
• Hence, while most of the hGDHs translocate into the mitochondria (a process associated with cleavage of the signal sequence), part of the protein localizes to the endoplasmic reticulum, probably serving additional functions (PMID:19448744)
• A gain-of-function rare polymorphism in hGDH2 hastens the onset of Parkinson’s disease in hemizygous subjects. (PMID:19826450)
• GLUD2 glutamate dehydrogenase is expressed in neural and testicular supporting cells (PMID:20194501)
• [review] Whereas GDH2 in most mammals is encoded by a single functional GLUD1 gene expressed widely, humans have acquired through retroposition an X-linked GLUD2 gene that encodes a highly homologous isoenzyme GDH2 expressed in testis and brain. (PMID:21420458)
• Human GDH1 appears to act like bovine GDH1, but human GDH2 does not show the same enhancement of branched chain alpha-keto acid dehydrogenase complex enzyme activities. (PMID:21621574)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• first N-terminal alpha helical structure is crucial for the mitochondrial import of hGDH2 and these findings may have implications in understanding the evolutionary mechanisms that led to the large mitochondrial targeting signals of human GDHs (PMID:22658952)
• first N-terminal alpha helical structure is crucial for the mitochondrial import of hGDH2 and these findings may have implications in understanding the evolutionary mechanisms that led to the large mitochondrial targeting signals of human GDHs (PMID:22709669)
• hGDH2 can operate efficiently in the relatively acidic environment that prevails in astrocytes following glutamate uptake [review] (PMID:24352816)
• IDH1(R132H) exhibits a growth-inhibitory effect that is abrogated in the presence of glutamate dehydrogenase 2 (GLUD2), a hominoid-specific enzyme purportedly optimized to facilitate glutamate turnover in human forebrain. (PMID:25225364)
• Study of the expression of the GDH1/2 in human steroidogenic organs revealed that, while GDH2 was expressed specifically in steroid-synthesizing cells, GDH1 was expressed both in the cells that produce steroids and in those that lack endocrine function. (PMID:26241911)
• hGDH2 evolution bestowed large human neurons with enhanced glutamate metabolizing capacity, thus strengthening cortical excitatory transmission. (PMID:26399640)
• Notably, the introduction of GLUD2 did not affect glutamate levels in mice, consistent with observations in the primates. Instead, the metabolic effects of GLUD2 center on the tricarboxylic acid cycle, suggesting that GLUD2 affects carbon flux during early brain development, possibly supporting lipid biosynthesis. (PMID:27118840)
• The expression of GLUD2 was identified in the cellular and subcellular compartments of numerous tissues. (PMID:27422263)
• This study demonstrated that hGDH2 expression increases capacity for uptake and oxidative metabolism of glutamate, particularly during increased workload and hypoglycemia. (PMID:28032919)
• This proliferation requires glutamate dehydrogenase 2, which synthesizes glutamate from ammonia and alpha-ketoglutarate and is expressed in MCF7 and T47D cells. Our findings provide insight into how cancer cells survive under glutamine deprivation conditions and thus contribute to elucidating the mechanisms of tumor growth. (PMID:29146184)
• In HEK293 cell lines GDH2 and GDH1 were over-expressed and found to be co-localized in subcellular fractions. (PMID:29943084)
• The autoantibodies to GluD2 are common in patients with OMAS, bind to surface determinants, and are potentially pathogenic. (PMID:30045961)
• GLUD2 overexpression inhibited Glioblastoma (GBM) cell growth suggesting a novel potential drug target for control of GBM progression. The possibility to enhance GLUD2 activity in GBM could result in a blocked/reduced proliferation of GBM cells without affecting the survival of the surrounding neurons. (PMID:30314897)
• present data, showing that GLUD2 expression in Tg mice improves in vivo glucose homeostasis by boosting fasting serum insulin levels, suggest that evolutionary adaptation of hGDH2 has enabled humans to achieve narrow-range euglycemia by regulating glutamate-mediated basal insulin secretion (PMID:31400387)
• Ammonia inhibits energy metabolism in astrocytes in a rapid and glutamate dehydrogenase 2-dependent manner. (PMID:32917661)
• Functional validation of a human GLUD2 variant in a murine model of Parkinson’s disease. (PMID:33093440)
• Crystal structure of glutamate dehydrogenase 2, a positively selected novel human enzyme involved in brain biology and cancer pathophysiology. (PMID:33421122)
• Lack of evidence for direct ligand-gated ion channel activity of GluD receptors. (PMID:39052831)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	glud1a	ENSDARG00000008816
mus_musculus	Glud1	ENSMUSG00000021794
rattus_norvegicus	Glud1	ENSRNOG00000057367
drosophila_melanogaster	Gdh	FBGN0001098
drosophila_melanogaster	bb8	FBGN0039071
caenorhabditis_elegans		WBGENE00014095

Paralogs (1): GLUD1 (ENSG00000148672)

Protein

Protein identifiers

Glutamate dehydrogenase 2, mitochondrial — P49448 (reviewed: P49448)

All UniProt accessions (2): A0A140VK14, P49448

UniProt curated annotations — full annotation on UniProt →

Function. Important for recycling the chief excitatory neurotransmitter, glutamate, during neurotransmission.

Subunit / interactions. Homohexamer.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Expressed in retina, testis and, at a lower level, brain.

Post-translational modifications. Stoichiometry shows that ADP-ribosylation occurs in one subunit per catalytically active homohexamer.

Similarity. Belongs to the Glu/Leu/Phe/Val dehydrogenases family.

RefSeq proteins (1): NP_036216* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006095	Glu/Leu/Phe/Val/Trp_DH	Family
IPR006096	Glu/Leu/Phe/Val/Trp_DH_C	Domain
IPR006097	Glu/Leu/Phe/Val/Trp_DH_dimer	Domain
IPR033524	Glu/Leu/Phe/Val_DH_AS	Active_site
IPR033922	NAD_bind_Glu_DH	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR046346	Aminoacid_DH-like_N_sf	Homologous_superfamily

Pfam: PF00208, PF02812

Enzyme classification (BRENDA):

• EC 1.4.1.3 — glutamate dehydrogenase [NAD(P)+] (BRENDA: 48 organisms, 64 substrates, 129 inhibitors, 445 Km, 127 kcat entries)

Substrate kinetics (BRENDA)

17 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2-OXOGLUTARATE	0.0051–14	116
NADH	0.0002–0.98	88
L-GLUTAMATE	0.24–52	53
NAD+	0.014–10.01	43
NH3	0.38–100	36
NH4+	0.0424–160	35
NADPH	0.006–0.78	31
NADP+	0.004–0.637	15
GLUTAMATE	0.25–23.8	14
ALPHA-KETOGLUTARATE	0.0029	1
N6-(2-AMINOETHYL)-NAD+	0.291	1
N6-(2-AMINOETHYL)-NADP+	0.273	1
N6-(2-HYDROXY-3-TRIMETHYLAMMONIUMPROPYL)-NAD+	0.148	1
N6-(3-SULFONATOPROPYL)-NAD+	0.052	1
NORVALINE	49	1

Catalyzed reactions (Rhea), 2 shown:

• L-glutamate + NADP(+) + H2O = 2-oxoglutarate + NH4(+) + NADPH + H(+) (RHEA:11612)
• L-glutamate + NAD(+) + H2O = 2-oxoglutarate + NH4(+) + NADH + H(+) (RHEA:15133)

UniProt features (47 total): helix 21, strand 15, turn 4, transit peptide 1, chain 1, active site 1, binding site 1, modified residue 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6G2U	X-RAY DIFFRACTION	2.93

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49448-F1	90.67	0.87

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): 183

Ligand- & substrate-binding residues (1): 84

Post-translational modifications (1): 172

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-8964539	Glutamate and glutamine metabolism

MSigDB gene sets: 82 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_GLUTAMATE_METABOLIC_PROCESS, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_DICARBOXYLIC_ACID_BIOSYNTHETIC_PROCESS, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, WTGAAAT_UNKNOWN

GO Biological Process (4): glutamate metabolic process (GO:0006536), obsolete glutamate biosynthetic process (GO:0006537), L-glutamate catabolic process (GO:0006538), amino acid metabolic process (GO:0006520)

GO Molecular Function (9): L-glutamate dehydrogenase (NAD+) activity (GO:0004352), L-glutamate dehydrogenase [NAD(P)+] activity (GO:0004353), L-glutamate dehydrogenase (NADP+) activity (GO:0004354), GTP binding (GO:0005525), ADP binding (GO:0043531), L-leucine binding (GO:0070728), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-NH2 group of donors, NAD or NADP as acceptor (GO:0016639)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Mitochondrial biogenesis	1
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
L-glutamate dehydrogenase [NAD(P)+] activity	2
amino acid metabolic process	1
dicarboxylic acid metabolic process	1
glutamate metabolic process	1
dicarboxylic acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
primary metabolic process	1
amino-acid dehydrogenase [NAD(P)+] activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
adenyl ribonucleotide binding	1
anion binding	1
amino acid binding	1
carboxylic acid binding	1
cation binding	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on the CH-NH2 group of donors	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1964 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLUD2	SHMT2	P34897	750
GLUD2	PDHA2	P29803	739
GLUD2	SHMT1	P34896	693
GLUD2	NTNG2	Q96CW9	648
GLUD2	GPM6B	Q13491	647
GLUD2	GLUL	P15104	646
GLUD2	GDI1	P31150	643
GLUD2	ASPM	Q8IZT6	640
GLUD2	NTNG1	Q9Y2I2	638
GLUD2	GAPDHS	O14556	624
GLUD2	PGK2	P07205	620
GLUD2	GOT1	P17174	618
GLUD2	GOT1L1	Q8NHS2	612
GLUD2	PDHA1	P08559	602
GLUD2	RNASE1	P07998	588

IntAct

23 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
TSPAN5	ADAM10	psi-mi:“MI:0914”(association)	0.800
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
GLUD2	GLUD1	psi-mi:“MI:0915”(physical association)	0.590
	TK2	psi-mi:“MI:0915”(physical association)	0.400
BCAR1	MYO1C	psi-mi:“MI:0914”(association)	0.350
SH3GL3	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
RFPL4B	POTEF	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
ATF2	CLIC1	psi-mi:“MI:0914”(association)	0.350
VCP	FAM171A2	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
CLPP	NDUFA4	psi-mi:“MI:2364”(proximity)	0.270
CEP164	RBFOX2	psi-mi:“MI:2364”(proximity)	0.270
CEP135	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
TRMT10C	PRORP	psi-mi:“MI:0915”(physical association)	0.000
GLUD2	MYC	psi-mi:“MI:0915”(physical association)	0.000
GLUD2	TOM1L1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (44): GLUD2 (Affinity Capture-RNA), GLUD2 (Affinity Capture-RNA), GLUD2 (Affinity Capture-MS), GLUD1 (Affinity Capture-MS), GLUD2 (Affinity Capture-MS), GLUD2 (Proximity Label-MS), GLUD2 (Proximity Label-MS), GLUD2 (Affinity Capture-MS), GLUD2 (Affinity Capture-MS), GLUD2 (Affinity Capture-MS), GLUD2 (Affinity Capture-MS), GLUD1 (Affinity Capture-MS), GLUD2 (Affinity Capture-MS), TOM1L1 (Two-hybrid), GLUD2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1S4CL59, A0A1S4D475, A0A1S4DF18, A0A1S4DFD3, A7SG73, A8XKG6, B2RFS9, B2RFT0, O04015, O04226, O65361, O65595, P00366, P00908, P10860, P22200, P26443, P32296, P43619, P47860, P49448, P54887, P54888, Q0E671, Q0IZS0, Q18164, Q2QS13, Q2QS14, Q3SZM5, Q42806, Q42954, Q55664, Q55FT1, Q64428, Q64HZ8, Q64I00, Q64I01, Q6STH5, Q8YNK2, Q90WG6

Diamond homologs: A2XMV1, A2XW22, A3MUY9, A3MWK6, F2Z610, O04937, O59650, O74024, P00366, P00367, P00368, P00369, P00370, P0CL72, P0CL73, P0DMG3, P0DMG4, P10860, P13154, P15111, P24295, P26443, P27346, P28997, P28998, P29051, P29507, P31026, P39475, P39633, P39708, P42174, P43793, P49448, P50735, P52596, P54385, P54386, P54531, P80053

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SIRT4	“down-regulates activity”	GLUD2	glycosylation
GLUD2	“up-regulates quantity”	2-oxoglutarate(2-)	“chemical modification”
GLUD2	“down-regulates quantity”	“glutamic acid”	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by Receptor Tyrosine Kinases	5	12.3×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	62
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2690949	NM_012084.4(GLUD2):c.412C>T (p.Gln138Ter)	Likely pathogenic

SpliceAI

11 predictions. Top by Δscore:

Variant	Effect	Δscore
X:121048452:T:A	acceptor_gain	0.4500
X:121048760:TGGGC:T	acceptor_gain	0.3100
X:121048653:T:TA	acceptor_gain	0.2900
X:121048761:G:A	acceptor_gain	0.2600
X:121048771:A:AC	acceptor_gain	0.2600
X:121048127:G:T	donor_gain	0.2500
X:121048760:T:TA	acceptor_gain	0.2300
X:121048674:T:A	acceptor_gain	0.2200
X:121048683:T:TA	acceptor_gain	0.2100
X:121048761:GGGC:G	acceptor_gain	0.2100
X:121048762:G:T	acceptor_gain	0.2000

AlphaMissense

3676 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:121048241:T:A	V186D	0.999
X:121048292:G:C	R203T	0.999
X:121048292:G:T	R203M	0.999
X:121048293:G:C	R203S	0.999
X:121048293:G:T	R203S	0.999
X:121048310:T:C	L209P	0.999
X:121048357:G:C	D225H	0.999
X:121048084:G:C	G134R	0.998
X:121048094:C:A	A137D	0.998
X:121048136:G:C	R151P	0.998
X:121048238:G:A	G185D	0.998
X:121048289:C:A	T202K	0.998
X:121048289:C:G	T202R	0.998
X:121048358:A:G	D225G	0.998
X:121048358:A:T	D225V	0.998
X:121048359:C:A	D225E	0.998
X:121048359:C:G	D225E	0.998
X:121048904:G:A	G407E	0.998
X:121048085:G:A	G134D	0.997
X:121048234:G:C	A184P	0.997
X:121048387:T:A	W235R	0.997
X:121048387:T:C	W235R	0.997
X:121048031:T:C	L116P	0.996
X:121048043:T:C	F120S	0.996
X:121048232:A:T	K183I	0.996
X:121048291:A:G	R203G	0.996
X:121048310:T:G	L209R	0.996
X:121048358:A:C	D225A	0.996
X:121048903:G:T	G407W	0.996
X:121048907:C:A	P408Q	0.996

dbSNP variants (sampled 300 via entrez): RS1000038005 (X:121047455 T>C,G), RS1002142070 (X:121047892 G>A), RS1003134479 (X:121048515 C>T), RS1008883661 (X:121047452 G>A,T), RS1008914834 (X:121046575 C>T), RS1010368484 (X:121045832 G>T), RS1010571738 (X:121046362 G>A), RS1010713886 (X:121046210 C>A,T), RS1010943222 (X:121045801 C>A,T), RS1011693968 (X:121049295 T>C), RS1011837503 (X:121049995 A>C), RS1014489604 (X:121048026 T>A,C), RS1015893520 (X:121048675 G>C), RS1019044022 (X:121045883 C>G), RS1019381220 (X:121049449 T>C,G)

Disease associations

OMIM: gene MIM:300144 | disease phenotypes: MIM:168600

GenCC curated gene-disease

Mondo (1): late-onset Parkinson disease (MONDO:0008199)

Orphanet (2): Hereditary late-onset Parkinson disease (Orphanet:411602), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003212_1	Fibrinogen levels in ischemic stroke	5.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	4
trichostatin A	affects cotreatment, decreases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	3
bisphenol A	affects expression, affects binding, increases reaction	2
entinostat	decreases expression, affects cotreatment	2
Acetaminophen	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	decreases expression	1
terbufos	increases methylation	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
tamibarotene	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression, affects cotreatment	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Calcitriol	increases expression, affects cotreatment	1
Carbamazepine	affects expression	1
Fonofos	increases methylation	1
Manganese	increases expression, affects cotreatment, increases abundance	1
Parathion	increases methylation	1
Quercetin	decreases expression	1
Dihydrotestosterone	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C6NX	ICGi044-A	Induced pluripotent stem cell	Male
CVCL_C6NY	ICGi044-B	Induced pluripotent stem cell	Male
CVCL_C6NZ	ICGi044-C	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT01807481	PHASE4	UNKNOWN	Phase IV Study to Evaluate the Efficacy and Safety of Mircera in PD
NCT07015671	PHASE3	COMPLETED	Bioavailability and Bioequivalence Study of ER Torsemide and Spironolactone FDC Tablet in Healthy Subjects
NCT03942458	PHASE1	COMPLETED	Pharmacokinetics and Pharmacodynamics of Vicagrel in Healthy Adult Subjects of Different CYP2C19
NCT07195825	PHASE1	RECRUITING	A Clinical Study to Evaluate the Safety, and Tolerability of BBM-P002 in the Treatment of Parkinson’s Disease
NCT04093349	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Gene Transfer Study for Late-Onset Pompe Disease (RESOLUTE)
NCT07282847	PHASE1/PHASE2	RECRUITING	A Study to Evaluate Safety, Tolerability, and Efficacy of AB-1009 Gene Therapy (GAA Gene) in Adult Participants With Late Onset Pompe Disease (PROGRESS-GT LOPD)
NCT00105131	Not specified	COMPLETED	Genetic Characterization of Parkinson’s Disease
NCT03021408	Not specified	UNKNOWN	Effectiveness of Different Approaches for the Rehabilitation of Gait in Patients With Parkinson’s Disease
NCT03893240	Not specified	COMPLETED	Neutralizing Antibody Seroprevalence Study With a Retrospective Component in Participants With Late-Onset Pompe Disease
NCT05810454	Not specified	NOT_YET_RECRUITING	iPACES v3 MCI NIA Protocol Copied for iPACES v4 PD NINDS