GCLM

Summary

GCLM (glutamate-cysteine ligase modifier subunit, HGNC:4312) is a protein-coding gene on chromosome 1p22.1, encoding Glutamate–cysteine ligase regulatory subunit (P48507).

Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase, is the first rate limiting enzyme of glutathione synthesis. The enzyme consists of two subunits, a heavy catalytic subunit and a light regulatory subunit. Gamma glutamylcysteine synthetase deficiency has been implicated in some forms of hemolytic anemia. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 2730 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 25 total
• Druggable target: yes
• MANE Select transcript: NM_002061

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4312
Approved symbol	GCLM
Name	glutamate-cysteine ligase modifier subunit
Location	1p22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000023909
Ensembl biotype	protein_coding
OMIM	601176
Entrez	2730

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000370238, ENST00000462183, ENST00000467772, ENST00000615724, ENST00000871361, ENST00000871362, ENST00000871363, ENST00000871364, ENST00000967006

RefSeq mRNA: 2 — MANE Select: NM_002061 NM_001308253, NM_002061

CCDS: CCDS746, CCDS81352

Canonical transcript exons

ENST00000370238 — 7 exons

Exon	Start	End
ENSE00000621419	93894614	93894728
ENSE00000831178	93909038	93909430
ENSE00001452131	93885199	93889159
ENSE00003497900	93896618	93896820
ENSE00003571837	93904523	93904588
ENSE00003571988	93901585	93901669
ENSE00003654966	93897839	93897898

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 96.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.8809 / max 456.5103, expressed in 1815 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13350	18.7817	1704
13351	5.4781	1637
13355	1.1294	676
13352	0.8784	525
13353	0.7225	451
13356	0.6935	438
13349	0.4477	216
13354	0.3858	223
13357	0.3638	196

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	96.38	gold quality
islet of Langerhans	UBERON:0000006	96.14	gold quality
epithelium of bronchus	UBERON:0002031	95.15	gold quality
bronchus	UBERON:0002185	95.15	gold quality
jejunal mucosa	UBERON:0000399	94.50	gold quality
hair follicle	UBERON:0002073	94.01	gold quality
secondary oocyte	CL:0000655	93.74	gold quality
cartilage tissue	UBERON:0002418	93.28	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.09	gold quality
epithelium of nasopharynx	UBERON:0001951	92.70	gold quality
duodenum	UBERON:0002114	92.20	gold quality
adrenal tissue	UBERON:0018303	92.13	gold quality
trabecular bone tissue	UBERON:0002483	91.91	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.86	gold quality
nasal cavity mucosa	UBERON:0001826	91.73	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.65	gold quality
biceps brachii	UBERON:0001507	91.40	gold quality
jejunum	UBERON:0002115	91.31	gold quality
nasal cavity epithelium	UBERON:0005384	91.11	gold quality
bone marrow	UBERON:0002371	90.45	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.45	gold quality
liver	UBERON:0002107	89.55	gold quality
tongue squamous epithelium	UBERON:0006919	89.20	gold quality
body of tongue	UBERON:0011876	89.17	gold quality
tongue	UBERON:0001723	89.16	gold quality
left adrenal gland	UBERON:0001234	89.15	gold quality
caput epididymis	UBERON:0004358	88.99	gold quality
right adrenal gland	UBERON:0001233	88.71	gold quality
diaphragm	UBERON:0001103	88.65	gold quality
adrenal gland	UBERON:0002369	88.48	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ENAD-21	yes	1199.16
E-ANND-3	yes	9.50
E-MTAB-6386	no	184.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN, JUND, NFE2L2, NKRF, PARK7

miRNA regulators (miRDB)

133 targeting GCLM, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1468-3P	99.96	72.74	3797

Literature-anchored findings (GeneRIF, showing 38)

• Polymorphism in the 5’-flanking region is associated with myocardial infarction (PMID:12081989)
• A -588T polymorphism of the GCLM gene causes a decrease in endothelial NO bioactivity, causing impairment of endothelium-dependent vasomotor function in large and resistance coronary arteries. The GCL-GSH-NO axis may defend against coronary artery disease (PMID:12975258)
• GCLM has a role in cisplatin (CDDP)-resistance in lung cancer (PMID:14532974)
• Review. The most important element in both Gclc and Gclm expression is the electrophile response element in their promoters. (PMID:15451055)
• Reduction-oxidation regulation of gamma-GCSh expression is mediated by p38 mitogen-activated protein kinase signaling. (PMID:15946948)
• in most tissues, glutanmate-cysteine ligase modifier submit (GCLM) is limiting, suggesting an increase in GCLM alone would increase gamma-GC synthesis; in kidney, gamma-GC synthesis may be controlled post-translationally (PMID:16081425)
• The polymorphism of GCLM -588C/T and -23G/T sites were associated with susceptibility to COPD. (PMID:16677451)
• The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study. (PMID:16909399)
• upregulation of gamma-glutamate-cysteine ligase as part of the long-term adaptation process to iron accumulation in neurons (PMID:17344309)
• the present data strongly indicates that, in spite of its functional impact, the GCLM C-588T polymorphism is - at least in a German cohort - not an independent risk indicator of coronary artery disease and myocardial infarction (PMID:17924854)
• Results suggest that a common genetic variation in the GCLM gene might not contribute to the risk of methamphetamine-use disorder and schizophrenia in the Japanese population. (PMID:18991850)
• Overexpression of GCL in granulosa cells can augment glutathione synthesis and ameliorate various sequelae associated with exposure to oxidative stress and irradiation. (PMID:19153097)
• It is unlikely that functional mutations in the GCLM gene could play a major role in genetic predisposition to schizophrenia. (PMID:19455074)
• association study in the Chinese population yielded no supportive evidence for GCLM as a susceptible gene in schizophrenia (PMID:19584774)
• Data show that induction of HO-1, GCLM, and NQO1 by OA-NO2 Is Nrf2-dependent. (PMID:19808663)
• To further investigate the role of the GCLM locus in schizophrenia susceptibility, we studied three SNPs and haplotypes in the region of GCLM using Han Chinese case-control samples. (PMID:20061124)
• Posttranslational modification and regulation of glutamate-cysteine ligase by the alpha,beta-unsaturated aldehyde 4-hydroxy-2-nonenal. (PMID:20970495)
• SNPs not associted with schizophrenia in Japanese individuals (PMID:21105962)
• SNPs not associated with self-reported depression (PMID:21277635)
• When eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury were divided into tertiles, GCLM-588 TT genotype individuals showed a lower risk than CC genotype; however, there were few TT carriers and the results were not statistically significant. (PMID:21504558)
• GCLM is a functional target gene of the BACH1 transcription factor according to ChIP-seq and knockdown analysis in HEK 293 cells. (PMID:21555518)
• TP is expressed at high levels in human GBM tumors and shRNA knockdown of TP in U87 GBM cells results in a significant increase in cellular GCL enzymatic activity (PMID:23743623)
• Ten of the 17 maternal SNPs and 2 of the 17 fetal SNPs were found within the GCLM gene conotruncal heart defect cases. (PMID:24535845)
• Upregulation of both GCLC and GLCM mRNA levels in response to cysteine deprivation was dependent on new protein synthesis. (PMID:24557597)
• miR-320a has a role in modulating the induction of HO-1, GCLM and OKL38 by oxidized phospholipids in endothelial cells (PMID:24786516)
• miR-433 targets both catalytic (GCLc) and regulatory (GCLm) subunits of GCL. (PMID:25353619)
• Knockdown of glutamate cysteine ligase catalytic subunit by siRNA causes the gold nanoparticles-induced cytotoxicity in lung cancer cells. (PMID:25789740)
• This study demonstrated that Tuberous sclerosis complex neuropathology requires glutamate-cysteine ligase. (PMID:26220190)
• Data suggest expression of hepatocyte GCLC and GCLM can be regulated by dietary component; alpha-lipoic acid, a vitamin B complex nutrient, protects against oxidative stress/cytotoxicity induced by cadmium via restoration of GCLC and GCLM expression. (PMID:26365678)
• Data suggest gene expression in vascular endothelium is altered by dietary factors; aged garlic extract induces expression of HMOX1 (heme oxygenase-1) and GCLM via activation of NRF2-ARE (nuclear factor erythroid 2-antioxidant response element) signaling. (PMID:26507778)
• Glutaminolysis is activated in ES2 and OVCAR3, though ES2 exclusively synthesizes amino acids and GSH. ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH production by BSO sensitizes ES2 to carboplatin. HNF1beta regulates the expression of GCLC, but not GCLM, and consequently GSH production in ES2 (PMID:26520442)
• High GCLM expression is associated with chemotherapy resistance in breast cancer. (PMID:26894974)
• Two promoter polymorphisms of GCLM (-588C/T) and GCLC (-128T/C) are associated with an increased risk of ischemic heart disease in Kazakhstan population. (PMID:28757675)
• Glutathione biosynthesis during the lipopolysaccharide-induced inflammatory response in THP-1 macrophages is tightly and differentially regulated via GCLC and GCLM subunits of glutamate cysteine ligase. (PMID:28993271)
• Genetic variants in glutamate cysteine ligase confer protection against type 2 diabetes. (PMID:32715377)
• Association of glutamate cystein ligase (GCL) activity Peroxiredoxin 4 (prxR4) and apelin levels in women with preeclampsia. (PMID:33421846)
• Association of Polymorphisms of Glutamate Cysteine Ligase Genes GCLC C-129 T and GCLM C-588 T with Risk of Polycystic Ovary Syndrome in Chinese Women. (PMID:34642912)
• Glutamate-cysteine ligase catalytic and its modifier function as novel immunotargets in gastric adenocarcinoma. (PMID:35241341)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gclm	ENSDARG00000018953
mus_musculus	Gclm	ENSMUSG00000028124
rattus_norvegicus	Gclm	ENSRNOG00000013409
drosophila_melanogaster	Gclm	FBGN0046114
caenorhabditis_elegans	E01A2.1	WBGENE00017084

Protein

Protein identifiers

Glutamate–cysteine ligase regulatory subunit — P48507 (reviewed: P48507)

Alternative names: GCS light chain, Gamma-ECS regulatory subunit, Gamma-glutamylcysteine synthetase regulatory subunit, Glutamate–cysteine ligase modifier subunit

All UniProt accessions (1): P48507

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Heterodimer of a catalytic heavy chain and a regulatory light chain.

Tissue specificity. In all tissues examined. Highest levels in skeletal muscle.

Pathway. Sulfur metabolism; glutathione biosynthesis; glutathione from L-cysteine and L-glutamate: step 1/2.

Similarity. Belongs to the aldo/keto reductase family. Glutamate–cysteine ligase light chain subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P48507-1	1	yes
P48507-2	2

RefSeq proteins (2): NP_001295182, NP_002052* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR023210	NADP_OxRdtase_dom	Domain
IPR032963	Gclm	Family
IPR036812	NAD(P)_OxRdtase_dom_sf	Homologous_superfamily

Pfam: PF00248

Enzyme classification (BRENDA):

• EC 6.3.2.2 — glutamate-cysteine ligase (BRENDA: 68 organisms, 284 substrates, 218 inhibitors, 346 Km, 118 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.0001–45	80
L-GLUTAMATE	0.0032–1755.4	68
L-CYSTEINE	0.0001–2.7	48
L-GLU	0.03–229	42
L-CYS	0.05–57.3	32
L-ALPHA-AMINOBUTYRATE	0.25–380	18
L-2-AMINOBUTANOATE	0.14–10.4	14
L-2-AMINOBUTYRATE	0.8–5	6
2-AMINOBUTYRATE	0.32–10.4	4
4-AMINOBUTYRATE	1.3–150	3
GLUTAMATE	0.75–9.1	3
CYSTEINE	0.3–2.7	2
GAMMA-L-GLU-L-CYS	0.86–1.3	2
L-2-AMINOBUTYRIC ACID	5.4–6.1	2
(R)-BETA-AMINO-ISO-BUTYRATE	7.3	1

UniProt features (4 total): chain 1, modified residue 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48507-F1	91.24	0.76

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 263

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-174403	Glutathione synthesis and recycling
R-HSA-5578999	Defective GCLC causes HAGGSD
R-HSA-9818027	NFE2L2 regulating anti-oxidant/detoxification enzymes

MSigDB gene sets: 395 (showing top): GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, LIANG_HEMATOPOIESIS_STEM_CELL_NUMBER_SMALL_VS_HUGE_UP, REACTOME_BIOLOGICAL_OXIDATIONS, GNF2_PRDX2, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_RESPONSE_TO_PEPTIDE, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_GLUTAMATE_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP

GO Biological Process (22): obsolete cysteine metabolic process (GO:0006534), glutamate metabolic process (GO:0006536), glutathione biosynthetic process (GO:0006750), response to oxidative stress (GO:0006979), response to nutrient (GO:0007584), apoptotic mitochondrial changes (GO:0008637), response to xenobiotic stimulus (GO:0009410), response to activity (GO:0014823), cellular response to hepatocyte growth factor stimulus (GO:0035729), hepatic stellate cell activation (GO:0035733), negative regulation of neuron apoptotic process (GO:0043524), cellular response to fibroblast growth factor stimulus (GO:0044344), response to human chorionic gonadotropin (GO:0044752), response to nitrosative stress (GO:0051409), regulation of mitochondrial depolarization (GO:0051900), cellular response to glucose stimulus (GO:0071333), cellular response to follicle-stimulating hormone stimulus (GO:0071372), cellular response to thyroxine stimulus (GO:0097069), blood vessel diameter maintenance (GO:0097746), cellular response to leukemia inhibitory factor (GO:1990830), negative regulation of extrinsic apoptotic signaling pathway (GO:2001237), glutathione metabolic process (GO:0006749)

GO Molecular Function (5): glutamate-cysteine ligase activity (GO:0004357), glutamate-cysteine ligase catalytic subunit binding (GO:0035226), protein-containing complex binding (GO:0044877), glutamate-cysteine ligase regulator activity (GO:1990609), protein binding (GO:0005515)

GO Cellular Component (2): cytosol (GO:0005829), glutamate-cysteine ligase complex (GO:0017109)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Glutathione conjugation	1
Metabolic disorders of biological oxidation enzymes	1
Nuclear events mediated by NFE2L2	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stress	2
response to chemical	2
cellular response to growth factor stimulus	2
binding	2
cytoplasm	2
amino acid metabolic process	1
dicarboxylic acid metabolic process	1
glutathione metabolic process	1
nonribosomal peptide biosynthetic process	1
modified amino acid biosynthetic process	1
sulfur compound biosynthetic process	1
response to nutrient levels	1
apoptotic process	1
mitochondrion organization	1
response to stimulus	1
response to hepatocyte growth factor	1
fibroblast activation	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
response to fibroblast growth factor	1
response to gonadotropin	1
regulation of membrane depolarization	1
regulation of mitochondrial membrane potential	1
mitochondrial depolarization	1
intracellular glucose homeostasis	1
response to glucose	1
cellular response to hexose stimulus	1
response to follicle-stimulating hormone	1
cellular response to gonadotropin stimulus	1
cellular response to amino acid stimulus	1
cellular response to thyroid hormone stimulus	1
response to thyroxine	1
cellular response to oxygen-containing compound	1
cellular response to L-phenylalanine derivative	1
vascular process in circulatory system	1
blood circulation	1
regulation of tube diameter	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1

Protein interactions and networks

STRING

2002 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GCLM	GCLC	P48506	999
GCLM	NQO1	P15559	941
GCLM	KEAP1	Q14145	932
GCLM	HMOX1	P09601	908
GCLM	NFE2L2	Q16236	906
GCLM	GSR	P00390	766
GCLM	GSS	P48637	761
GCLM	TXNRD1	Q16881	761
GCLM	SRXN1	Q9BYN0	754
GCLM	GPX4	P36969	748
GCLM	CRYZ	Q08257	711
GCLM	SAT1	P21673	692
GCLM	GPX2	P18283	678
GCLM	ATF4	P18848	660
GCLM	SLC7A11	Q9UPY5	650
GCLM	TXN	P10599	650

IntAct

56 interactions, top by confidence:

A	B	Type	Score
GCLC	GCLM	psi-mi:“MI:0914”(association)	0.790
GCLM	GCLC	psi-mi:“MI:0407”(direct interaction)	0.790
GCLC	GCLM	psi-mi:“MI:0915”(physical association)	0.790
MLF1	DNAJB6	psi-mi:“MI:0914”(association)	0.750
GNPDA2	GNPDA1	psi-mi:“MI:0914”(association)	0.640
GCLM	OSGIN1	psi-mi:“MI:0915”(physical association)	0.560
PRKCA	DUSP11	psi-mi:“MI:0914”(association)	0.530
Mgu	GCLM	psi-mi:“MI:0914”(association)	0.530
PARP12	GCLM	psi-mi:“MI:0914”(association)	0.530
GCLM	PRKCA	psi-mi:“MI:0914”(association)	0.530
BSG	BTAF1	psi-mi:“MI:0914”(association)	0.530
GCLM	PCBP3	psi-mi:“MI:0915”(physical association)	0.400
GCLM	CALM1	psi-mi:“MI:0915”(physical association)	0.370
GCLM	IRF7	psi-mi:“MI:0915”(physical association)	0.370
GCLM	STOX1	psi-mi:“MI:0915”(physical association)	0.370
GCLM	CFTR	psi-mi:“MI:0915”(physical association)	0.370
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
RRP1B	ZNF785	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
DNA2	TARSL2	psi-mi:“MI:0914”(association)	0.350
PLAUR	DDX11L8	psi-mi:“MI:0914”(association)	0.350
TRPV5	CREB1	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (79): GCLM (Affinity Capture-MS), GCLM (Affinity Capture-MS), GCLM (Affinity Capture-MS), GCLM (Affinity Capture-MS), CPNE3 (Co-fractionation), GCLC (Co-fractionation), GCLM (Affinity Capture-MS), GCLM (Affinity Capture-MS), GCLM (Affinity Capture-MS), GCLM (Affinity Capture-MS), GCLM (Affinity Capture-MS), GCLM (Affinity Capture-MS), GCLM (Affinity Capture-MS), GCLM (Affinity Capture-MS), GCLM (Proximity Label-MS)

ESM2 similar proteins: A6QLH6, B0KWT6, B1MTV8, B2GV38, B2KIK3, B5X9S9, B5XFI8, B7NZQ9, C1BGZ8, C9J798, O09172, O14908, O43374, O70422, P0CL18, P11441, P21126, P41214, P48507, P48508, P60027, Q0P5I8, Q2T9Y6, Q2TBN5, Q32LP0, Q3B7U9, Q58CR3, Q5R4T1, Q5R812, Q5RA63, Q5RB75, Q5RCR8, Q5ZMQ0, Q66H91, Q68FF6, Q7ZWB2, Q8BPA8, Q8IVD9, Q8R1T1, Q8WUX9

Diamond homologs: O09172, P48507, P48508, Q2T9Y6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NFE2L2	“up-regulates quantity by expression”	GCLM	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1020 predictions. Top by Δscore:

Variant	Effect	Δscore
1:93889041:T:TA	donor_gain	1.0000
1:93889091:A:AC	donor_gain	1.0000
1:93889092:C:CC	donor_gain	1.0000
1:93894609:TTTA:T	donor_loss	1.0000
1:93894610:TTACC:T	donor_loss	1.0000
1:93894611:TACCT:T	donor_loss	1.0000
1:93894613:C:CG	donor_loss	1.0000
1:93894724:TTTAC:T	acceptor_gain	1.0000
1:93894725:TTAC:T	acceptor_gain	1.0000
1:93894726:TAC:T	acceptor_gain	1.0000
1:93894727:ACCTA:A	acceptor_loss	1.0000
1:93894728:CCTAG:C	acceptor_loss	1.0000
1:93894729:C:CC	acceptor_gain	1.0000
1:93894729:C:CG	acceptor_loss	1.0000
1:93894735:G:C	acceptor_gain	1.0000
1:93896712:T:TA	donor_gain	1.0000
1:93896754:C:CA	donor_gain	1.0000
1:93897895:TTTG:T	acceptor_gain	1.0000
1:93897896:TTG:T	acceptor_gain	1.0000
1:93897897:TG:T	acceptor_gain	1.0000
1:93897899:C:CC	acceptor_gain	1.0000
1:93909033:CTCA:C	donor_loss	1.0000
1:93909034:TCACC:T	donor_loss	1.0000
1:93909035:CACCT:C	donor_loss	1.0000
1:93909036:A:C	donor_loss	1.0000
1:93909036:ACCT:A	donor_gain	1.0000
1:93909037:C:CA	donor_loss	1.0000
1:93909037:CCTC:C	donor_gain	1.0000
1:93909039:T:TA	donor_gain	1.0000
1:93889009:G:C	donor_gain	0.9900

AlphaMissense

1786 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:93894637:A:G	L211P	0.999
1:93894658:G:T	A204D	0.999
1:93889069:C:G	R249P	0.998
1:93889091:A:G	W242R	0.998
1:93889091:A:T	W242R	0.998
1:93894637:A:T	L211Q	0.998
1:93894659:C:G	A204P	0.998
1:93894721:G:T	P183Q	0.998
1:93896658:A:G	L167P	0.998
1:93896717:C:A	W147C	0.998
1:93896717:C:G	W147C	0.998
1:93896719:A:G	W147R	0.998
1:93896719:A:T	W147R	0.998
1:93889026:T:A	K263N	0.997
1:93889026:T:G	K263N	0.997
1:93889042:C:T	G258E	0.997
1:93889064:A:G	S251P	0.997
1:93889072:A:G	L248P	0.997
1:93894627:G:C	H214Q	0.997
1:93894627:G:T	H214Q	0.997
1:93894629:G:C	H214D	0.997
1:93894643:A:T	I209K	0.997
1:93894706:A:T	V188D	0.997
1:93894721:G:C	P183R	0.997
1:93894722:G:A	P183S	0.997
1:93896634:A:G	L175P	0.997
1:93896788:A:G	S124P	0.997
1:93897894:T:A	K94N	0.997
1:93897894:T:G	K94N	0.997
1:93889024:C:T	G264D	0.996

dbSNP variants (sampled 300 via entrez): RS1000112976 (1:93885401 T>A), RS1000302861 (1:93893147 T>C), RS1000432721 (1:93886089 G>A), RS1000641800 (1:93890978 T>C), RS1000854855 (1:93905826 A>G), RS1000872921 (1:93905552 T>C), RS1001487104 (1:93891959 G>A), RS1001495773 (1:93898829 G>A), RS1001603160 (1:93899859 A>G), RS1001726602 (1:93885211 T>A,C), RS1001731097 (1:93905411 A>C), RS1001765520 (1:93892222 A>C), RS1001820971 (1:93890328 G>A), RS1001943930 (1:93900055 G>C), RS1002102568 (1:93890684 C>G,T)

Disease associations

OMIM: gene MIM:601176 | disease phenotypes: MIM:608446

GenCC curated gene-disease

Mondo (1): myocardial infarction, susceptibility to (MONDO:0012039)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001859_29	Thiazide-induced adverse metabolic effects in hypertensive patients	1.000000e-06
GCST007239_1	Ovarian cancer	5.000000e-06
GCST009391_1274	Metabolite levels	1.000000e-06
GCST010002_363	Refractive error	3.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0010546	uridine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295765 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects reaction, affects cotreatment, decreases expression, increases abundance, decreases reaction (+2 more)	32
Arsenic Trioxide	decreases reaction, increases expression, increases reaction, decreases expression, increases abundance	11
sulforaphane	increases expression, decreases expression, affects reaction	9
Arsenic	increases expression, increases abundance, decreases reaction, affects reaction, increases reaction (+1 more)	9
Benzo(a)pyrene	affects methylation, increases expression	9
Acetaminophen	increases expression, decreases reaction, affects cotreatment	8
Tetrachlorodibenzodioxin	affects expression, increases expression	8
Valproic Acid	affects cotreatment, increases expression	8
Hydrogen Peroxide	affects cotreatment, increases expression, increases reaction, decreases expression, affects reaction (+1 more)	7
Tobacco Smoke Pollution	increases expression	7
cinnamaldehyde	increases activity, increases expression	6
Curcumin	increases expression, decreases reaction	6
Quercetin	increases expression, decreases reaction, decreases expression, affects cotreatment	6
Particulate Matter	affects cotreatment, increases abundance, increases expression, decreases expression	6
2-tert-butylhydroquinone	affects cotreatment, increases expression, increases reaction, decreases expression	5
Cisplatin	increases reaction, affects binding, increases expression	5
Cyclosporine	increases expression	5
Cadmium Chloride	increases abundance, increases expression, increases reaction, increases localization	5
methylmercuric chloride	increases expression, affects cotreatment	4
arsenite	increases expression, affects reaction, increases abundance	4
salvin	increases reaction, decreases expression, decreases reaction, increases expression	4
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases expression, decreases activity, decreases expression	4
Air Pollutants	increases abundance, increases expression, decreases expression	4
Cadmium	increases abundance, increases expression	4
Dinitrochlorobenzene	increases expression, affects reaction	4
Eugenol	increases expression	4
Mercury	affects abundance, affects metabolic processing, decreases expression	4
Oxygen	decreases expression, increases expression	4
Silver	affects reaction, increases expression	4
Thiram	increases expression	4

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118752	Binding	Binding affinity to GCLM in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1WG	Abcam A-549 GCLM KO	Cancer cell line	Male
CVCL_D2AV	Abcam HCT 116 GCLM KO	Cancer cell line	Male
CVCL_D2NE	Abcam THP-1 GCLM KO	Cancer cell line	Male
CVCL_SP83	HAP1 GCLM (-) 1	Cancer cell line	Male
CVCL_SP84	HAP1 GCLM (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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