GGH

Summary

GGH (gamma-glutamyl hydrolase, HGNC:4248) is a protein-coding gene on chromosome 8q12.3, encoding Gamma-glutamyl hydrolase (Q92820). Hydrolyzes the polyglutamate sidechains of pteroylpolyglutamates.

This gene catalyzes the hydrolysis of folylpoly-gamma-glutamates and antifolylpoly-gamma-glutamates by the removal of gamma-linked polyglutamates and glutamate.

Source: NCBI Gene 8836 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 52 total
• Druggable target: yes
• MANE Select transcript: NM_003878

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4248
Approved symbol	GGH
Name	gamma-glutamyl hydrolase
Location	8q12.3
Locus type	gene with protein product
Status	Approved
Aliases	GATD10
Ensembl gene	ENSG00000137563
Ensembl biotype	protein_coding
OMIM	601509
Entrez	8836

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 9 protein_coding, 7 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000260118, ENST00000518113, ENST00000518466, ENST00000518966, ENST00000520609, ENST00000522852, ENST00000523479, ENST00000523788, ENST00000677327, ENST00000677459, ENST00000677482, ENST00000677919, ENST00000678045, ENST00000678069, ENST00000679326, ENST00000899633, ENST00000899634, ENST00000899635, ENST00000899636, ENST00000899637

RefSeq mRNA: 2 — MANE Select: NM_003878 NM_001410926, NM_003878

CCDS: CCDS6177, CCDS94298

Canonical transcript exons

ENST00000260118 — 9 exons

Exon	Start	End
ENSE00001319126	63038660	63038806
ENSE00002133142	63015079	63015453
ENSE00003468727	63017493	63017630
ENSE00003479506	63027181	63027265
ENSE00003481094	63024080	63024186
ENSE00003530122	63035656	63035770
ENSE00003574598	63026158	63026296
ENSE00003590525	63023907	63023997
ENSE00003675532	63030167	63030217

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 97.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.5741 / max 675.4618, expressed in 1793 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93321	38.3068	1785
93320	0.8127	394
93326	0.3629	156
93325	0.0917	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	97.16	gold quality
nephron tubule	UBERON:0001231	97.15	gold quality
ventricular zone	UBERON:0003053	97.06	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.60	gold quality
mucosa of transverse colon	UBERON:0004991	96.56	gold quality
right lobe of liver	UBERON:0001114	96.38	gold quality
colonic mucosa	UBERON:0000317	96.04	gold quality
liver	UBERON:0002107	95.59	gold quality
cortical plate	UBERON:0005343	95.21	gold quality
penis	UBERON:0000989	94.84	gold quality
kidney epithelium	UBERON:0004819	94.62	gold quality
ganglionic eminence	UBERON:0004023	94.57	gold quality
tongue squamous epithelium	UBERON:0006919	93.84	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.50	gold quality
renal glomerulus	UBERON:0000074	93.02	gold quality
embryo	UBERON:0000922	92.87	gold quality
sperm	CL:0000019	92.75	gold quality
metanephric glomerulus	UBERON:0004736	92.30	gold quality
esophagus squamous epithelium	UBERON:0006920	91.69	gold quality
right testis	UBERON:0004534	91.54	gold quality
adult mammalian kidney	UBERON:0000082	91.48	gold quality
secondary oocyte	CL:0000655	91.32	gold quality
lower esophagus mucosa	UBERON:0035834	91.32	gold quality
left testis	UBERON:0004533	91.21	gold quality
squamous epithelium	UBERON:0006914	90.71	gold quality
placenta	UBERON:0001987	90.51	gold quality
testis	UBERON:0000473	90.50	gold quality
endothelial cell	CL:0000115	90.44	gold quality
gingival epithelium	UBERON:0001949	90.18	gold quality
male germ cell	CL:0000015	90.12	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-HCAD-32	yes	278.56
E-MTAB-6701	yes	122.91
E-MTAB-9467	yes	48.68
E-HCAD-1	yes	41.24
E-HCAD-10	yes	28.83
E-GEOD-125970	yes	25.17
E-HCAD-6	yes	22.31
E-CURD-122	yes	22.28
E-HCAD-13	yes	20.59
E-MTAB-6678	yes	8.36
E-MTAB-4850	no	325.44
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, TP53

Literature-anchored findings (GeneRIF, showing 31)

• Three-dimensional structure (PMID:11953431)
• cDNA microarray analysis led to the identification of 2 novel biomarkers that should facilitate molecular diagnosis and further study of pulmonary neuroendocrine tumors. (PMID:15492986)
• lack of dissociation of the dimer, large monomer-monomer interface, & presence of catalytically essential Tyr-36 in the homodimer interface sequences suggest that homodimer formation is required for hGH monomer to fold into an active conformation. (PMID:16945597)
• The genotype distribution and gene frequency of the GGH gene polymorphism was studied in a Japanese population. (PMID:17409534)
• CpG island methylator phenotype (CIMP+) in ColoRectal Cancer (CRC) is associated with low expression of GGH, suggesting involvement of the folate pathway in the development of this phenotype. (PMID:18414409)
• The genotypes of XRCC1 Arginine194Tryptophan and GGH-401Cytosine/Thymine were associated with the response to NAC in patients with cervical cancer. No SNP genotypes were associated with DFS. (PMID:18851872)
• Data revealed that high FPGS gene expression, low GGH gene expression and low ABCC1 gene expression in CRC tissues were predictive factors for a high reduced folate level after LV administration. (PMID:19636555)
• data implicate GGH as a novel biomarker for bladder cancer; suggest presence of GGH & diazepam-binding inhibitor in urine serves as a rationale for developing them as urinary markers of clinical outcomes for patients treated with neoadjuvant chemotherapy (PMID:19815704)
• The -401C/T polymorphism in the gamma-glutamyl hydrolase may be a factor involved in the generation of relapse to disease in patients with acute lymphoblastic leukemia. (PMID:20197200)
• Genotypes in GGH gene of acute lymphoblastic leukemia patients were evaluated (PMID:21538980)
• This is one of the first studies to assess FPGS and GGH genetic variants in relation to plasma homocysteine. (PMID:22018726)
• Genetic polymorphism of gamma-glutamyl hydrolase in Chinese acute leukemia children and identification of a novel double nonsynonymous mutation. (PMID:22568793)
• a SNP in the GGH gene remained associated with reduced CVD risk, with a stronger association in early onset CVD cases. (PMID:22649255)
• There was no significant difference in gamma-glutamyl hydrolase genotype or T allele frequency between the two groups (P> 0.05). (PMID:22678806)
• GG genotype of GGH -354 T > G polymorphism may have high predictive value for myelosuppression in methotrexate treated rheumatoid arthritis patients. (PMID:22763757)
• Genotyping of DHFR 829C>T and GGH -401C>T was performed using a polymerase chain reaction. (PMID:22994778)
• The results of our study suggested the potential interest of GGH -401C>T as a predictive factor of the outcome of cervical carcinoma treated with cisplatin-based chemoradiotherapy. (PMID:23107767)
• Suggest that GGH may serve as a potential biomarker of unfavorable clinical outcomes over short-term follow-up in breast cancer. (PMID:23374458)
• An interaction term, between FPGS rs7033913 heterozygotes and GGH rs11988534 homozygotes for the minor allele, had a p-value <0.0001 and may contribute to metotrexate toxicity in rheumatoid arthritis. (PMID:24447348)
• Polymorphism of GGH rs3758149 C>T is associated with response to therapy in acute lymphoblastic leukemia. (PMID:24908438)
• There were no other associations between single -nucleotide polymorphisms and the efficacy of MTX treatment. CONCLUSIONS: The MTHFR 677CC and GGH 401TT and CT genotypes were associated with a reduction in the number of MTX-related adverse events. (PMID:25599563)
• This study shows that polymorphisms on genes related to the metabolic pathway of pemetrexed, especially, ATIC and GGH genes, would have a therapeutic implication in pemetrexed-treated patients with lung adenocarcinoma (PMID:25823786)
• the highest expression of GGH and EGFR was noted in the left-sided colon; the highest expression of DHFR, FPGS, TOP1 and ERCC1 was noted in the rectosigmoid, whereas TYMP expression was approximately equivalent in the right-sided colon and rectum (PMID:26676887)
• These results indicate that elevated expressions of the tumor-related genes FPGS/GGH and VEGF are correlated with malignancy of thymic carcinoma and B3 thymoma tumors. (PMID:27387303)
• the results of our study identify GGH as an ERG subtype specific molecular marker with modest prognostic relevance, which may have clinical relevance if analyzed in combination with other molecular markers. (PMID:28146062)
• Either methylation of CpG1 or hypermethylation of CpG2 in GGH promoter region can significantly reduce GGH mRNA expression in pediatric patients with acute leukemia. (PMID:28278270)
• analysis of seven polymorphisms in genes of folate transport and (de)glutamation pathway on methotrexate polyglutamate levels and response in patients with rheumatoid arthritis: ABCB1, FPGS, GGH and RFC1 (PMID:30022368)
• The role of transcription factor Sp1 in the regulation of gamma-glutamyl hydrolase gene expression by the rs3758149 polymorphism in CEM/C1 cells. (PMID:31739835)
• Frequency distribution of five SNPs in human GGH gene and their effects on clinical outcomes of Chinese pediatric patients with acute lymphoblastic leukemia. (PMID:32295690)
• A gamma-glutamyl hydrolase lacking the signal peptide confers susceptibility to folates/antifolates in acute lymphoblastic leukemia cells. (PMID:35040120)
• Interaction between glycolysischolesterol synthesis axis and tumor microenvironment reveal that gamma-glutamyl hydrolase suppresses glycolysis in colon cancer. (PMID:36569910)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ggh	ENSDARG00000037176
mus_musculus	Ggh	ENSMUSG00000073987
rattus_norvegicus	Ggh	ENSRNOG00000007351
drosophila_melanogaster	l(3)72Dp	FBGN0263607
drosophila_melanogaster	l(3)72Dr	FBGN0263608

Protein

Protein identifiers

Gamma-glutamyl hydrolase — Q92820 (reviewed: Q92820)

Alternative names: Conjugase, GH, Gamma-Glu-X carboxypeptidase

All UniProt accessions (6): A0A7I2V431, A0A7I2V5M0, A0A7I2V5P2, A0A7I2V5X9, A0A7I2YQQ3, Q92820

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes the polyglutamate sidechains of pteroylpolyglutamates. Progressively removes gamma-glutamyl residues from pteroylpoly-gamma-glutamate to yield pteroyl-alpha-glutamate (folic acid) and free glutamate. May play an important role in the bioavailability of dietary pteroylpolyglutamates and in the metabolism of pteroylpolyglutamates and antifolates.

Subunit / interactions. Homodimer.

Subcellular location. Secreted. Extracellular space. Lysosome. Melanosome.

Similarity. Belongs to the peptidase C26 family.

RefSeq proteins (2): NP_001397855, NP_003869* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011697	Peptidase_C26	Family
IPR015527	Pept_C26_g-glut_hydrolase	Family
IPR029062	Class_I_gatase-like	Homologous_superfamily

Pfam: PF07722

Enzyme classification (BRENDA):

• EC 3.4.19.9 — folate gamma-glutamyl hydrolase (BRENDA: 17 organisms, 109 substrates, 59 inhibitors, 33 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PTEROYLTRIGLUTAMATE	0.0006–0.0287	8
METHOTREXATE DIGLUTAMATE	0.0214–0.049	7
P-AMINOBENZOYLPENTAGLUTAMATE	0.001–0.0019	4
FOLIC ACID PENTAGLUTAMATE	0.0012–0.0014	2
PTEROYLHEPTAGLUTAMATE	0.0002–0.0006	2
PTEROYLPENTAGLUTAMATE	0.0005–0.0008	2
5-FORMYLTETRAHYDROFOLATE TRIGLUTAMATE	0.057	1
5-L-GLUTAMYL-4-NITROANILIDE	0.0076	1
L-GLUTAMIC ACID GAMMA-(4-NITROANILIDE)	0.0076	1
N5-METHYLTETRAHYDROPTEROYLTETRAGLUTAMATE	0.0008	1
PTEROYLDIGLUTAMATE	0.0006	1
PTEROYLTETRAGLUTAMATE	6	1

Catalyzed reactions (Rhea), 1 shown:

• (6S)-5,6,7,8-tetrahydrofolyl-(gamma-L-Glu)(n) + (n-1) H2O = (6S)-5,6,7,8-tetrahydrofolate + (n-1) L-glutamate (RHEA:56784)

UniProt features (43 total): helix 12, strand 11, mutagenesis site 4, turn 4, glycosylation site 4, sequence variant 3, active site 2, signal peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1L9X	X-RAY DIFFRACTION	1.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92820-F1	94.01	0.92

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 (2): 134 (nucleophile); 244 (proton donor)

Glycosylation sites (4): 116, 163, 203, 307

Mutagenesis-validated functional residues (4):

Position	Phenotype
134	loss of activity.
195	reduces activity 250-fold.
244	loss of activity.
246	slightly reduced catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 292 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, MODULE_52, REACTOME_INNATE_IMMUNE_SYSTEM, XU_GH1_AUTOCRINE_TARGETS_UP, GOCC_SECRETORY_GRANULE, RIZKI_TUMOR_INVASIVENESS_3D_DN, MODULE_16, IWANAGA_E2F1_TARGETS_INDUCED_BY_SERUM, GOLDRATH_ANTIGEN_RESPONSE, MODULE_118, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOBP_PTERIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY

GO Biological Process (1): tetrahydrofolylpolyglutamate metabolic process (GO:0046900)

GO Molecular Function (5): exopeptidase activity (GO:0008238), omega peptidase activity (GO:0008242), gamma-glutamyl-peptidase activity (GO:0034722), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (10): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), vacuole (GO:0005773), azurophil granule lumen (GO:0035578), specific granule lumen (GO:0035580), melanosome (GO:0042470), extracellular exosome (GO:0070062), tertiary granule lumen (GO:1904724), lysosome (GO:0005764)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidase activity	2
intracellular membrane-bounded organelle	2
secretory granule lumen	2
folic acid-containing compound metabolic process	1
cysteine-type peptidase activity	1
omega peptidase activity	1
binding	1
catalytic activity	1
cellular anatomical structure	1
cytoplasm	1
vacuolar lumen	1
azurophil granule	1
specific granule	1
pigment granule	1
extracellular vesicle	1
intracellular organelle lumen	1
tertiary granule	1
lytic vacuole	1

Protein interactions and networks

STRING

1243 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GGH	SLC19A1	P41440	931
GGH	UEVLD	Q8IX04	898
GGH	TPMT	P51580	871
GGH	AUP1	Q9Y679	803
GGH	FPGS	Q05932	776
GGH	TSG101	Q99816	711
GGH	ATIC	P31939	706
GGH	UBE2I	P50550	696
GGH	TYMS	P04818	626
GGH	DHFR	P00374	623
GGH	DHFR2	Q86XF0	613
GGH	MTHFR	P42898	597
GGH	LDHC	P07864	561
GGH	SLC46A1	Q96NT5	547
GGH	SAE1	Q9UBE0	543

IntAct

63 interactions, top by confidence:

A	B	Type	Score
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
FKBP5	IKBKB	psi-mi:“MI:0914”(association)	0.640
SDF2L1	OLFM2	psi-mi:“MI:0914”(association)	0.640
GGH	SGTB	psi-mi:“MI:0915”(physical association)	0.560
	PLOD2	psi-mi:“MI:0914”(association)	0.530
GGH	UGDH	psi-mi:“MI:0914”(association)	0.530
ARID4B	GGH	psi-mi:“MI:0915”(physical association)	0.400
GGH	DHX9	psi-mi:“MI:0915”(physical association)	0.400
FBXL19	GGH	psi-mi:“MI:0915”(physical association)	0.400
ZNF770	GGH	psi-mi:“MI:0915”(physical association)	0.400
	FER1L5	psi-mi:“MI:0915”(physical association)	0.400
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
GGH		psi-mi:“MI:0915”(physical association)	0.370
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
UNC93B1		psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
GGH	TGOLN2	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
KDM4D	SMCHD1	psi-mi:“MI:0914”(association)	0.350
TRIM24	DDTL	psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
rep	BMPR1B	psi-mi:“MI:0914”(association)	0.350
	TOR1B	psi-mi:“MI:0914”(association)	0.350
OS9	RPN1	psi-mi:“MI:0914”(association)	0.350
NEK7	SUPT5H	psi-mi:“MI:0914”(association)	0.350
JAZF1	TNPO2	psi-mi:“MI:0914”(association)	0.350
MAP1LC3B		psi-mi:“MI:0914”(association)	0.350

BioGRID (274): GGH (Affinity Capture-MS), ZMYM3 (Affinity Capture-MS), TXNDC16 (Affinity Capture-MS), LRWD1 (Affinity Capture-MS), MKLN1 (Affinity Capture-MS), OS9 (Affinity Capture-MS), UGDH (Affinity Capture-MS), ATP2B2 (Affinity Capture-MS), DCAF8 (Affinity Capture-MS), CERCAM (Affinity Capture-MS), GPR98 (Affinity Capture-MS), TGOLN2 (Affinity Capture-MS), MICA (Affinity Capture-MS), GGH (Affinity Capture-MS), GGH (Affinity Capture-MS)

ESM2 similar proteins: A2AKK5, A3QVN2, A3QVN3, A3QVN4, A3QVN5, A3QVN6, A3QVN9, A3QVP0, A7YWG4, C3YWU0, J3S820, O65355, P04066, P06865, P14384, P17164, P29416, P31428, P31430, P48300, P58780, P93164, Q05A56, Q0V8R6, Q2KIM0, Q2M3T9, Q2VQV9, Q4QR71, Q5RC46, Q5RC84, Q5RFD6, Q5RFE4, Q60HF8, Q62867, Q63108, Q641X3, Q6AXR4, Q6AYS4, Q80V42, Q8R0W5

Diamond homologs: A7YWG4, O65355, P93164, Q54HL4, Q54LN4, Q62867, Q92820, Q9SYL6, Q9Z0L8, Q9ZV85

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SP1	“up-regulates quantity by expression”	GGH	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1176 predictions. Top by Δscore:

Variant	Effect	Δscore
8:63015454:C:CC	acceptor_gain	1.0000
8:63017489:TTA:T	donor_loss	1.0000
8:63017490:TA:T	donor_loss	1.0000
8:63017627:TATC:T	acceptor_gain	1.0000
8:63017628:ATC:A	acceptor_gain	1.0000
8:63017628:ATCC:A	acceptor_loss	1.0000
8:63017629:TC:T	acceptor_gain	1.0000
8:63017630:CC:C	acceptor_gain	1.0000
8:63017630:CCT:C	acceptor_loss	1.0000
8:63017631:C:CC	acceptor_gain	1.0000
8:63017632:T:C	acceptor_loss	1.0000
8:63023909:T:A	donor_gain	1.0000
8:63023998:C:CC	acceptor_gain	1.0000
8:63024079:CCT:C	donor_gain	1.0000
8:63026154:TTACC:T	donor_loss	1.0000
8:63026156:A:AC	donor_gain	1.0000
8:63026156:ACCT:A	donor_gain	1.0000
8:63026157:C:CC	donor_gain	1.0000
8:63026157:CCT:C	donor_gain	1.0000
8:63026157:CCTC:C	donor_gain	1.0000
8:63026292:AAACT:A	acceptor_gain	1.0000
8:63026293:AACT:A	acceptor_gain	1.0000
8:63026295:CT:C	acceptor_gain	1.0000
8:63026297:C:CC	acceptor_gain	1.0000
8:63026297:C:CG	acceptor_loss	1.0000
8:63026298:T:C	acceptor_gain	1.0000
8:63026299:T:C	acceptor_gain	1.0000
8:63026299:T:TC	acceptor_gain	1.0000
8:63026302:C:CT	acceptor_gain	1.0000
8:63026303:A:T	acceptor_gain	1.0000

AlphaMissense

2091 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:63017601:A:G	W243R	0.996
8:63017601:A:T	W243R	0.996
8:63017598:G:C	H244D	0.992
8:63023923:A:C	F227L	0.992
8:63023923:A:T	F227L	0.992
8:63023925:A:G	F227L	0.992
8:63024092:G:C	S198R	0.991
8:63024092:G:T	S198R	0.991
8:63024094:T:G	S198R	0.991
8:63024103:G:C	H195D	0.989
8:63026266:A:G	W131R	0.989
8:63026266:A:T	W131R	0.989
8:63015356:A:C	F311L	0.988
8:63015356:A:T	F311L	0.988
8:63015358:A:G	F311L	0.988
8:63026243:T:A	E138D	0.988
8:63026243:T:G	E138D	0.988
8:63035675:C:G	A69P	0.985
8:63017590:C:A	E246D	0.984
8:63017590:C:G	E246D	0.984
8:63017591:T:A	E246V	0.984
8:63017596:A:C	H244Q	0.983
8:63017596:A:T	H244Q	0.983
8:63026253:A:G	L135P	0.983
8:63035684:A:G	S66P	0.982
8:63035767:A:T	I38K	0.980
8:63027210:C:G	A111P	0.979
8:63035674:G:T	A69E	0.979
8:63035685:C:A	E65D	0.979
8:63035685:C:G	E65D	0.979

dbSNP variants (sampled 300 via entrez): RS1000018736 (8:63038515 C>T), RS1000117943 (8:63016851 T>G), RS1000376916 (8:63026830 C>T), RS1000399320 (8:63017208 A>G), RS1000673791 (8:63023263 C>A,T), RS1000762404 (8:63029646 T>A,C,G), RS1000980191 (8:63024901 T>G), RS1001262432 (8:63024883 C>A,T), RS1001442924 (8:63018445 A>G), RS1001695224 (8:63039539 T>A), RS1001731379 (8:63024464 G>A,T), RS1001773113 (8:63033762 T>C), RS1001914296 (8:63015207 A>C), RS1001950691 (8:63034009 TTATA>T,TTA,TTATATA,TTATATATA), RS1002003686 (8:63021157 T>C,G)

Disease associations

OMIM: gene MIM:601509 | 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
GCST006585_2155	Blood protein levels	2.000000e-56

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2223 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

11 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11545076	Efficacy	3	methotrexate	Acute lymphoblastic leukemia
rs11545077	Efficacy	3	methotrexate	Acute lymphoblastic leukemia
rs11545078	Toxicity	3	methotrexate	Acute lymphoblastic leukemia
rs11545078	Toxicity	3	pemetrexed	Non-Small Cell Lung Carcinoma
rs17279558	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity
rs1800909	Efficacy	3	methotrexate	Rheumatoid arthritis
rs3758149	Efficacy	3	methotrexate	Rheumatoid arthritis
rs3758149	Metabolism/PK	3	methotrexate	Acute lymphoblastic leukemia
rs3758149	Efficacy	3	methotrexate	Acute lymphoblastic leukemia
rs3780126	Efficacy	3	bevacizumab;pemetrexed	Non-Small Cell Lung Carcinoma
rs719235	Toxicity	3	methotrexate	Rheumatoid arthritis

PharmGKB variants

11 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs719235	GGH	3	2.50	1	methotrexate
rs1800909	GGH	3	2.50	1	methotrexate
rs3758149	GGH	3	3.75	3	methotrexate
rs3780126	GGH	3	1.50	1	bevacizumab;pemetrexed
rs11545077	GGH	3	2.50	1	methotrexate
rs11545078	GGH	3	3.00	2	methotrexate;pemetrexed
rs12681874	GGH		0.00	0
rs16930092	GGH		0.00	0
rs17279558	GGH	3	0.00	1	methylphenidate
rs11545076	GGH	3	2.50	1	methotrexate
rs10464903	GGH		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C26: Gamma-glutamyl hydrolase

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.03	Ki	0.93	nM	CHEMBL290594
9.02	Ki	0.95	nM	CHEMBL291301

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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
(2S)-2-[[hydroxy(methyl)phosphoryl]amino]pentanedioic acid	71582: Compound was tested for inhibitory potency against gamma-Glutamyl Hydrolase.	ki	0.0009	uM
(2S)-2-[[hydroxy(phenyl)phosphoryl]amino]pentanedioic acid	71582: Compound was tested for inhibitory potency against gamma-Glutamyl Hydrolase.	ki	0.0009	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects expression	5
Estradiol	affects cotreatment, decreases expression, increases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression	3
perfluorooctane sulfonic acid	decreases expression, increases expression	2
Folic Acid	affects expression, decreases expression	2
Methotrexate	affects response to substance, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cyclosporine	decreases expression	2
bisphenol F	increases expression	1
perfluorodecanesulfonic acid	increases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
lead acetate	increases expression	1
decabromobiphenyl ether	decreases expression	1
7-hydroxymethotrexate	decreases response to substance	1
tris(2-butoxyethyl) phosphate	affects expression	1
tetrahydropalmatine	increases expression	1
arsenite	affects binding, increases reaction	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
M-VAC protocol	affects cotreatment, increases response to substance	1
beta-methylcholine	affects expression	1
perfluoro-n-nonanoic acid	decreases expression	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL681828	Binding	Compound was tested for inhibitory potency against gamma-Glutamyl Hydrolase.	Evaluation of phosphorus-containing inhibitors of gamma-glutamyl hydrolase. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1MT	Abcam K-562 GGH KO	Cancer cell line	Female
CVCL_D2JD	Abcam Raji GGH KO	Cancer cell line	Male
CVCL_UQ60	Abcam Jurkat GGH KO	Cancer cell line	Male

Clinical trials (associated diseases)

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