GSTM3

Summary

GSTM3 (glutathione S-transferase mu 3, HGNC:4635) is a protein-coding gene on chromosome 1p13.3, encoding Glutathione S-transferase Mu 3 (P21266). Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.

Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual’s susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Mutations of this class mu gene have been linked with a slight increase in a number of cancers, likely due to exposure with environmental toxins. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2947 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cystic fibrosis (Supportive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 36 total
• Phenotypes (HPO): 35
• Druggable target: yes
• MANE Select transcript: NM_000849

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4635
Approved symbol	GSTM3
Name	glutathione S-transferase mu 3
Location	1p13.3
Locus type	gene with protein product
Status	Approved
Aliases	GST5, GSTM3TV2
Ensembl gene	ENSG00000134202
Ensembl biotype	protein_coding
OMIM	138390
Entrez	2947

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000256594, ENST00000361066, ENST00000476321, ENST00000486823, ENST00000488824, ENST00000872817, ENST00000944483

RefSeq mRNA: 1 — MANE Select: NM_000849 NM_000849

CCDS: CCDS812

Canonical transcript exons

ENST00000361066 — 9 exons

Exon	Start	End
ENSE00000913154	109739833	109739908
ENSE00001192281	109740953	109741038
ENSE00001192318	109740240	109740511
ENSE00001417282	109733937	109737169
ENSE00003478810	109737457	109737567
ENSE00003484421	109737656	109737751
ENSE00003592814	109739429	109739493
ENSE00003629107	109738285	109738366
ENSE00003671980	109738091	109738191

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.8277 / max 862.8769, expressed in 1663 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13720	41.8277	1663

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	99.88	gold quality
right testis	UBERON:0004534	99.88	gold quality
adult organism	UBERON:0007023	99.43	gold quality
male germ cell	CL:0000015	99.30	gold quality
sperm	CL:0000019	99.24	gold quality
seminal vesicle	UBERON:0000998	98.88	gold quality
corpus epididymis	UBERON:0004359	98.79	gold quality
renal medulla	UBERON:0000362	98.69	gold quality
testis	UBERON:0000473	98.54	gold quality
right ovary	UBERON:0002118	98.47	gold quality
left ovary	UBERON:0002119	98.35	gold quality
apex of heart	UBERON:0002098	98.30	gold quality
metanephros cortex	UBERON:0010533	98.21	gold quality
nucleus accumbens	UBERON:0001882	97.77	gold quality
smooth muscle tissue	UBERON:0001135	97.74	gold quality
caudate nucleus	UBERON:0001873	97.73	gold quality
body of stomach	UBERON:0001161	97.69	gold quality
mucosa of stomach	UBERON:0001199	97.66	gold quality
skin of hip	UBERON:0001554	97.61	gold quality
right atrium auricular region	UBERON:0006631	97.47	gold quality
stromal cell of endometrium	CL:0002255	97.34	gold quality
heart right ventricle	UBERON:0002080	97.32	gold quality
putamen	UBERON:0001874	97.30	gold quality
amygdala	UBERON:0001876	97.22	gold quality
triceps brachii	UBERON:0001509	97.14	gold quality
adult mammalian kidney	UBERON:0000082	96.96	gold quality
ovary	UBERON:0000992	96.88	gold quality
choroid plexus epithelium	UBERON:0003911	96.87	gold quality
heart left ventricle	UBERON:0002084	96.86	gold quality
cardiac ventricle	UBERON:0002082	96.81	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-124472	yes	751.89
E-HCAD-10	yes	26.80
E-MTAB-9388	yes	13.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

133 targeting GSTM3, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• polymorphism of and susceptibility to oral cancer in an Indian population (PMID:12016153)
• No increased prostate scancer risk for men carrying any of the GSTM1 or GSTT1 genotypes. (PMID:14968442)
• Glutathione S-transferase hGSTM3 has a role in ageing-associated neurodegeneration (PMID:15621212)
• GSTM3 -63C allele strongly affects gene expression and suggests that individuals who carry the low expression allele may be deficient in glutathione transferase catalyzed biological functions. (PMID:15665284)
• To find out the association of GST variants with risk of gallbladder cancer, the distribution of polymorphisms in the GST family of genes (GSTT1, GSTM1, GSTP1, and GSTM3) were studied in 106 cancer patients and 201 healthy controls. (PMID:16760134)
• Polymorphisms affecting GSTP1, GST alpha 1 and GSTM3 genes are probably not related to the risk of developing hepatocellular carcinoma in a population of white Spanish patients. (PMID:17716224)
• Single marker association analyses revealed that the AGG/AGG genotype of the GSTM3 rs1799735 (del/AGG) polymorphism was associated with an increased risk of AD (p=0.05), especially in the group of APOE4-allele non-carriers (p=0.004; OR=2.07). (PMID:17904251)
• distribution of -63A/C polymorphism of human glutathione S-transferase M3(GSTM3) gene in Chinese Han population and the association of -63A/C polymorphism with essential hypertension (PMID:17922434)
• Diminished GSTM3 mRNA levels correlated with decreased minichromosome maintenance deficient 3 (MCM3) mRNA levels in a diagnostic and SNP-dependent fashion in Alzheimer disease. (PMID:18423940)
• The GSTM3*A/*A genotype was 76% in cancer cases versus 74% in controls; a significant association between smoking status and GSTM3 genotype was not detected. (PMID:18569590)
• Our results suggested GSTM3 (AB + BB) genotype to be significantly associated with prostate cancer risk. (PMID:18668224)
• GSTM1null, GSTM3AB, and CYP2E1c1c2 genotypes modulate the risk of gastric cancer (PMID:19521675)
• GST-M3 activity is possibly involved in protection against mucosal atrophy caused by H. pylori as the levels of IgG titer and pepsinogen I are linked to mucosal status. (PMID:19696791)
• The researchers found evidence of an increased risk for non-Hodgkin’s lymphoma in women who used hair dye before 1980 and who were carriers of the GSTM3 intron 6 deletion. (PMID:19822571)
• single-nucleotide polymorphisms/haplotypes in the GSTM3 gene within the GSTMs gene cluster are likely to contribute to breast cancer risk when the GSTM1 is absent (PMID:19856098)
• The presence of the GSTM3*B allele appears to associated with a reduced risk of laryngeal squamous cell carcinoma. (PMID:19922706)
• Polymorphisms in GSTM1, GSTM3, GSTT1, and GSTP1 do not influence the risk of primary glioma, at least in this population in Rio de Janeiro, Brazil. (PMID:20391338)
• In individuals from Angola, Mozambique and the Sao Tome e Principe islands, the GSTM3*B allele was three times more frequent (0.74-0.78) than the GSTM3*A allele (0.22-0.26), with no significant differences in allele frequency across the three groups. (PMID:20549140)
• This study aims to investigate the genotype frequencies of GSTM1, GSTT1 and GSTM3 genes in 80 osteosarcoma patients and 160 normal control participants, and also the influence of these polymorphisms in the clinical outcome of osteosarcoma patients. (PMID:20577141)
• There were no significant differences in distribution of 3-bp deletion polymorphism in intron 6 variant allele in Glutathione-S-transferase M3 between chronic obstructive pulmonary disease patients and controls in a north Indian population. (PMID:21513434)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• All three markers correlated significantly with regional lymph node metastasis: FXYD3 (p = 0.0110), S100A11 (p = 0.0071), and GSTM3 (p = 0.0173) in colon cancer lymphatic metastasis. (PMID:22430872)
• Methylation of GSTM3 promoter may contribute to oxidative stress-associated liver damage and correlate with the disease severity in Acute-on-chronic hepatitis B liver failure. (PMID:22976281)
• In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the epsilon4 allele of apolipoprotein E genotype, and geographic region. (PMID:23036584)
• The GSTM3 A/B gene polymorphism is not associated with lung cancer susceptibility. (PMID:23167362)
• rs1332018 genetic variants in the GSTM3 promoter predispose the host to downregulating GSTM3 expression in kidney, facilitate carcinogenesis, and predict an unfavourable postoperative prognosis of renal cell carcinoma. (PMID:24157827)
• This meta-analysis suggests that the GSTM3 A/B polymorphism may be an important protective factor for head and neck cancer, especially of laryngeal cancer and Caucasian populations. (PMID:24416175)
• This meta-analysis suggested that the GSTT1 and GSTM3 polymorphisms might influence osteosarcoma risk. (PMID:24689813)
• To identify the genotypes of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 in a case-control study. (PMID:25040976)
• NSD1 interacted with RNAPII and bound to GSTM3 -63A/C TATA box. (PMID:25193115)
• No associations between the GSTT1, GSTP1, and GSTM3 genotypes and neoplasia risk were observed. In conclusion, we determined the genotype distribution of GST polymorphisms in control subjects and breast cancer patients from northeastern Mexico. (PMID:26125851)
• The individuals carrying the deletions of GSTM1 and GSTT1 were at risk for Neurocysticercosis (NCC). Genetic variants of GSTM3 and GSTP1 were not associated with NCC. (PMID:27021019)
• Expression of GSTM3 might be regulated by epigenetic changes in lens tissue. Hypermethylation in GSTM3 promoter and altered histone modification might have a role in the ARC formation. (PMID:27607418)
• Differential activity of antioxidant enzymes caused by the polymorphism in GSTM3 may contribute to resistance to hormonal therapy through oxidative stress. The GSTM3 rs7483 polymorphism may be a promising biomarker for prostate cancer patients treated with androgen-deprivation therapy (ADT) (PMID:27993795)
• this study indicated that a functional polymorphism of GSTM3 -rs1055259 reduced susceptibility of clear cell renal cell carcinoma in the Chinese population. It influenced GSTM3 protein synthesis by interfering miR-556 binding, subsequently suppressed ROS activity and clear cell renal cell carcinoma progression. . (PMID:29569387)
• ROS production is one mechanism by which cancer drugs kill tumour cells, and according to our evidence, GSTM3 may play an important role in preventing breast cancer treatment-induced cellular cytotoxicity (PMID:30054830)
• High GSTM3 expression is associated with glioma. (PMID:31172354)
• GSTM3 variant is a novel genetic modifier in Brugada syndrome, a disease with risk of sudden cardiac death. (PMID:32645615)
• Whole-proteome analysis of mesonephric-derived cancers describes new potential biomarkers. (PMID:33121982)
• Low GSTM3 expression is associated with poor disease-free survival in resected esophageal squamous cell carcinoma. (PMID:33482859)

Cross-species orthologs

42 orthologs

Organism	Symbol	Gene ID
danio_rerio	gstm.2	ENSDARG00000029473
danio_rerio	gstm.1	ENSDARG00000042533
danio_rerio	gstm.3	ENSDARG00000088116
mus_musculus	Gstm5	ENSMUSG00000004032
rattus_norvegicus	Gstm5	ENSRNOG00000049743
caenorhabditis_elegans		WBGENE00001750
caenorhabditis_elegans		WBGENE00001751
caenorhabditis_elegans		WBGENE00001752
caenorhabditis_elegans		WBGENE00001753
caenorhabditis_elegans		WBGENE00001754
caenorhabditis_elegans		WBGENE00001755
caenorhabditis_elegans		WBGENE00001756
caenorhabditis_elegans		WBGENE00001757
caenorhabditis_elegans		WBGENE00001758
caenorhabditis_elegans		WBGENE00001759
caenorhabditis_elegans		WBGENE00001760
caenorhabditis_elegans		WBGENE00001761
caenorhabditis_elegans		WBGENE00001762
caenorhabditis_elegans		WBGENE00001764
caenorhabditis_elegans		WBGENE00001765
caenorhabditis_elegans		WBGENE00001766
caenorhabditis_elegans		WBGENE00001767
caenorhabditis_elegans		WBGENE00001769
caenorhabditis_elegans		WBGENE00001770
caenorhabditis_elegans		WBGENE00001772
caenorhabditis_elegans		WBGENE00001774
caenorhabditis_elegans		WBGENE00001775
caenorhabditis_elegans		WBGENE00001776
caenorhabditis_elegans		WBGENE00001777
caenorhabditis_elegans		WBGENE00001779
caenorhabditis_elegans		WBGENE00001780
caenorhabditis_elegans		WBGENE00001781
caenorhabditis_elegans		WBGENE00001782
caenorhabditis_elegans		WBGENE00001783
caenorhabditis_elegans		WBGENE00001785
caenorhabditis_elegans		WBGENE00001786
caenorhabditis_elegans		WBGENE00001787
caenorhabditis_elegans		WBGENE00001789
caenorhabditis_elegans		WBGENE00018911
caenorhabditis_elegans		WBGENE00018912
caenorhabditis_elegans	W10C8.4	WBGENE00021127
caenorhabditis_elegans		WBGENE00021566

Paralogs (11): GSTP1 (ENSG00000084207), GSTM1 (ENSG00000134184), GSTM5 (ENSG00000134201), HPGDS (ENSG00000163106), GSTM4 (ENSG00000168765), GSTA4 (ENSG00000170899), GSTA3 (ENSG00000174156), GSTA5 (ENSG00000182793), GSTM2 (ENSG00000213366), GSTA1 (ENSG00000243955), GSTA2 (ENSG00000244067)

Protein

Protein identifiers

Glutathione S-transferase Mu 3 — P21266 (reviewed: P21266)

Alternative names: GST class-mu 3, GSTM3-3

All UniProt accessions (2): P21266, Q6FGJ9

UniProt curated annotations — full annotation on UniProt →

Function. Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. May govern uptake and detoxification of both endogenous compounds and xenobiotics at the testis and brain blood barriers.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Tissue specificity. Testis and brain.

Post-translational modifications. The N-terminus is blocked.

Similarity. Belongs to the GST superfamily. Mu family.

RefSeq proteins (1): NP_000840* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003081	GST_mu	Family
IPR004045	Glutathione_S-Trfase_N	Domain
IPR004046	GST_C	Domain
IPR010987	Glutathione-S-Trfase_C-like	Domain
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR036282	Glutathione-S-Trfase_C_sf	Homologous_superfamily
IPR040079	Glutathione_S-Trfase	Family
IPR050213	GST_superfamily	Family

Pfam: PF00043, PF02798

Enzyme classification (BRENDA):

• EC 2.5.1.18 — glutathione transferase (BRENDA: 178 organisms, 548 substrates, 680 inhibitors, 878 Km, 525 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
1-CHLORO-2,4-DINITROBENZENE	0.0003–223.6	289
GLUTATHIONE	0.0002–532.43	253
GSH	0.0003–37.4	62
REDUCED GLUTATHIONE	0.017–11.4	24
ETHACRYNIC ACID	0.0001–2.43	19
CUMENE HYDROPEROXIDE	0.038–14.3	10
(+)-2-BROMO-3-(4-NITROPHENYL)PROPANOIC ACID	0.023–0.417	8
MONOCHLOROBIMANE	0.004–0.25	8
4-CHLORO-7-NITROBENZO-2-OXA-1,3-DIAZOLE	0.324–3.866	7
1-IODOHEXANE	0.009–0.059	6
ALACHLOR	0.042–7.23	6
PHENETHYL ISOTHIOCYANATE	0.0065–0.14	6
STYRENE 7,8-OXIDE	0.064–0.365	6
1,2-DICHLORO-4-NITROBENZENE	0.27–1.4	5
1-CHLORO-2,3-DINITROBENZOATE	0.21–20.7	5

Catalyzed reactions (Rhea), 1 shown:

• RX + glutathione = an S-substituted glutathione + a halide anion + H(+) (RHEA:16437)

UniProt features (35 total): helix 11, strand 8, binding site 5, mutagenesis site 4, domain 2, cross-link 2, chain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3GTU	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P21266-F1	96.62	0.97

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 (5): 11–12; 50–54; 63–64; 76–77; 120

Post-translational modifications (2): 54, 73

Mutagenesis-validated functional residues (4):

Position	Phenotype
120	no effect.
120	strongly increased catalytic activity.
213	strongly increased catalytic activity.
213	no effect.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-156590	Glutathione conjugation

MSigDB gene sets: 314 (showing top): GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_BIOLOGICAL_OXIDATIONS, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOMF_GLUTATHIONE_TRANSFERASE_ACTIVITY, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, SMID_BREAST_CANCER_LUMINAL_B_UP, GOBP_AMIDE_METABOLIC_PROCESS, ENGELMANN_CANCER_PROGENITORS_UP, DELYS_THYROID_CANCER_DN, GOBP_ENDOTHELIUM_DEVELOPMENT, MODULE_99

GO Biological Process (6): glutathione metabolic process (GO:0006749), establishment of blood-nerve barrier (GO:0008065), nitrobenzene metabolic process (GO:0018916), xenobiotic catabolic process (GO:0042178), response to estrogen (GO:0043627), cellular detoxification of nitrogen compound (GO:0070458)

GO Molecular Function (7): glutathione transferase activity (GO:0004364), enzyme binding (GO:0019899), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), glutathione binding (GO:0043295), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), sperm fibrous sheath (GO:0035686), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Phase II - Conjugation of compounds	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein binding	2
modified amino acid metabolic process	1
sulfur compound metabolic process	1
endothelial cell development	1
peripheral nervous system development	1
benzene-containing compound metabolic process	1
xenobiotic metabolic process	1
catabolic process	1
response to hormone	1
cellular response to stress	1
detoxification of nitrogen compound	1
cellular detoxification	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
identical protein binding	1
protein dimerization activity	1
anion binding	1
modified amino acid binding	1
oligopeptide binding	1
sulfur compound binding	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
sperm flagellum	1
extracellular vesicle	1

Protein interactions and networks

STRING

1174 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GSTM3	GSTZ1	O43708	853
GSTM3	SLCO6A1	Q86UG4	804
GSTM3	GSTA4	O15217	659
GSTM3	GSTT2B	P0CG30	649
GSTM3	GSTO1	P78417	649
GSTM3	NFE2L1	Q14494	614
GSTM3	EPHX1	P07099	570
GSTM3	GSTK1	Q9Y2Q3	540
GSTM3	GSTO2	Q9H4Y5	530
GSTM3	CYP1A1	P04798	512
GSTM3	CYP2C19	P33259	501
GSTM3	HHAT	Q5VTY9	492
GSTM3	GCLC	P48506	488
GSTM3	ABCB1	P08183	487
GSTM3	NQO1	P15559	486

IntAct

76 interactions, top by confidence:

A	B	Type	Score
GSTM3	GSTM3	psi-mi:“MI:0915”(physical association)	0.860
GSTM5	GSTM3	psi-mi:“MI:0914”(association)	0.830
GSTM3	GSTM5	psi-mi:“MI:0915”(physical association)	0.830
GSTM5	GSTM3	psi-mi:“MI:0915”(physical association)	0.830
GSTM4	GSTM3	psi-mi:“MI:0915”(physical association)	0.740
GSTM3	GSTM4	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
GSTM3	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
GSTM2	GSTM3	psi-mi:“MI:0914”(association)	0.530
GSTM3	ECT2L	psi-mi:“MI:0914”(association)	0.530
GSTM3	GSTM2	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
ZP4	GSTM3	psi-mi:“MI:0915”(physical association)	0.520
ZP3	GSTM3	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (191): GSTM3 (Two-hybrid), GSTM4 (Two-hybrid), GSTM5 (Two-hybrid), GSTM3 (Affinity Capture-RNA), GSTM3 (Affinity Capture-RNA), GSTM3 (Affinity Capture-RNA), GSTM3 (Affinity Capture-MS), GSTM3 (Two-hybrid), GSTM3 (Affinity Capture-MS), GSTM4 (Affinity Capture-MS), PLS1 (Affinity Capture-MS), LANCL2 (Affinity Capture-MS), GNB1L (Affinity Capture-MS), TPX2 (Affinity Capture-MS), HNRNPLL (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2PR19, A6QQZ0, O09131, O65857, O76483, O88741, P09488, P0CG29, P0CG30, P21266, P28161, P28342, P30109, P30568, P30713, P42760, P46409, P46430, P46439, P46440, P48774, P57108, P78417, Q01579, Q03013, Q03425, Q03662, Q4V8E6, Q5BK56, Q5R8E8, Q61133, Q64471, Q84TK0, Q8R5I6, Q8TB36, Q9BEA9, Q9BEB0, Q9C6C8, Q9D4P7, Q9FE46

Diamond homologs: M1RIR6, O35543, O35660, P00502, P04905, P08009, P08010, P08515, P09488, P10649, P15626, P15964, P16413, P19639, P20136, P21266, P28161, P30112, P30116, P31670, P31671, P35661, P46409, P46419, P46427, P46436, P46439, P48774, P51781, P56598, P86214, Q00285, Q03013, Q5BK56, Q5R8E8, Q80W21, Q8JFZ2, Q8R5I6, Q9BEA9, Q9BEB0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 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.

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of gene expression	6	9.9×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

833 predictions. Top by Δscore:

Variant	Effect	Δscore
1:109737564:TGAG:T	acceptor_gain	1.0000
1:109737568:C:CC	acceptor_gain	1.0000
1:109737650:TCCTA:T	donor_loss	1.0000
1:109737653:TA:T	donor_loss	1.0000
1:109737654:A:AG	donor_loss	1.0000
1:109737655:CC:C	donor_loss	1.0000
1:109737748:TTTC:T	acceptor_gain	1.0000
1:109737749:TTCCT:T	acceptor_loss	1.0000
1:109737750:TCCTG:T	acceptor_loss	1.0000
1:109737751:CCTG:C	acceptor_loss	1.0000
1:109737752:C:CA	acceptor_loss	1.0000
1:109737752:C:CC	acceptor_gain	1.0000
1:109738083:AAACT:A	donor_loss	1.0000
1:109738084:AACTC:A	donor_loss	1.0000
1:109738086:CTCA:C	donor_loss	1.0000
1:109738087:TCAC:T	donor_loss	1.0000
1:109738089:A:AC	donor_gain	1.0000
1:109738089:A:AT	donor_loss	1.0000
1:109738090:C:CA	donor_gain	1.0000
1:109738090:CGTG:C	donor_gain	1.0000
1:109738090:CGTGG:C	donor_gain	1.0000
1:109738117:T:C	donor_gain	1.0000
1:109738187:ACCAC:A	acceptor_gain	1.0000
1:109738188:CCAC:C	acceptor_gain	1.0000
1:109738188:CCACC:C	acceptor_gain	1.0000
1:109738189:CAC:C	acceptor_gain	1.0000
1:109738189:CACC:C	acceptor_gain	1.0000
1:109738190:AC:A	acceptor_gain	1.0000
1:109738191:CC:C	acceptor_gain	1.0000
1:109738192:C:CC	acceptor_gain	1.0000

AlphaMissense

1507 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:109739470:A:G	W50R	0.998
1:109739470:A:T	W50R	0.998
1:109739468:C:A	W50C	0.997
1:109739468:C:G	W50C	0.997
1:109738128:C:G	R112P	0.996
1:109738302:G:T	A85D	0.996
1:109738311:C:G	R82P	0.996
1:109738356:A:G	L67P	0.996
1:109738363:G:A	P65S	0.996
1:109739469:C:G	W50S	0.996
1:109740252:C:A	W12C	0.996
1:109740252:C:G	W12C	0.996
1:109740254:A:G	W12R	0.996
1:109740254:A:T	W12R	0.996
1:109740257:A:G	Y11H	0.996
1:109737555:C:G	D161H	0.995
1:109738365:A:G	L64P	0.995
1:109740241:C:T	G16E	0.995
1:109740242:C:G	G16R	0.995
1:109740242:C:T	G16R	0.995
1:109738299:C:G	R86P	0.994
1:109738362:G:T	P65H	0.994
1:109738365:A:T	L64Q	0.994
1:109740245:G:T	R15S	0.994
1:109739456:T:A	K54N	0.993
1:109739456:T:G	K54N	0.993
1:109737551:A:G	F162S	0.992
1:109737554:T:A	D161V	0.992
1:109737554:T:G	D161A	0.992
1:109738325:G:C	S77R	0.992

dbSNP variants (sampled 300 via entrez): RS1000122012 (1:109740224 T>C), RS1000489495 (1:109739973 G>A), RS1000802567 (1:109735808 A>G), RS1001095643 (1:109741117 C>T), RS1001450001 (1:109742202 C>T), RS1001531923 (1:109741466 G>A,T), RS1001974124 (1:109736608 C>A,G,T), RS1002505352 (1:109742587 T>C), RS1003862863 (1:109742529 G>A), RS1004373826 (1:109735832 G>A), RS1004979185 (1:109739011 CTTGGGAGGCTGAG>C), RS1005356269 (1:109738656 T>C,G), RS1005668023 (1:109741802 G>A), RS1005710910 (1:109739529 T>C), RS1006035103 (1:109734601 C>A,T)

Disease associations

OMIM: gene MIM:138390 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
cystic fibrosis	Supportive	Autosomal recessive

Mondo (1): cystic fibrosis (MONDO:0009061)

Orphanet (0):

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000246	Sinusitis
HP:0000365	Hearing impairment
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000787	Nephrolithiasis
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0001392	Abnormality of the liver
HP:0001394	Cirrhosis
HP:0001508	Failure to thrive
HP:0001738	Exocrine pancreatic insufficiency
HP:0002020	Gastroesophageal reflux
HP:0002024	Malabsorption
HP:0002035	Rectal prolapse
HP:0002099	Asthma
HP:0002105	Hemoptysis
HP:0002107	Pneumothorax
HP:0002110	Bronchiectasis
HP:0002205	Recurrent respiratory infections
HP:0002570	Steatorrhea
HP:0002724	Recurrent Aspergillus infections
HP:0002726	Recurrent Staphylococcus aureus infections
HP:0002783	Recurrent lower respiratory tract infections
HP:0002842	Recurrent Burkholderia cepacia infections
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003251	Male infertility
HP:0004401	Meconium ileus
HP:0005376	Recurrent Haemophilus influenzae infections
HP:0006536	Airway obstruction
HP:0012236	Elevated sweat chloride

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_350	Blood protein levels	3.000000e-15
GCST011955_7	Alcohol dependence	9.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003550	Cystic Fibrosis	C06.689.202; C08.381.187; C16.320.190; C16.614.213

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2242 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1799735	Toxicity	3	cisplatin;cyclophosphamide	Ovarian Neoplasms
rs1799735	Metabolism/PK	3	olanzapine
rs36120609	Toxicity	3	cisplatin;cyclophosphamide	Drug Toxicity
rs36120609	Metabolism/PK	3	olanzapine

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7483	GSTM3		0.00	0
rs12059276	GSTM3		0.00	0
rs1799735	GSTM3	3	2.75	2	cisplatin;cyclophosphamide;olanzapine
rs36120609	GSTM3	3	4.25	2	cisplatin;cyclophosphamide;olanzapine

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, increases abundance, increases expression	7
Valproic Acid	affects cotreatment, increases expression	5
ochratoxin A	decreases expression, increases acetylation, increases expression	3
Arsenic	increases expression, increases abundance, affects methylation	3
Benzo(a)pyrene	decreases methylation, increases expression, decreases reaction, decreases expression	3
Carmustine	affects metabolic processing, decreases activity, decreases nitrosation	3
Cisplatin	increases expression, affects response to substance	3
Nickel	affects expression, decreases expression, decreases reaction	3
trichostatin A	affects expression, decreases reaction, increases expression	2
monomethylarsonous acid	increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Cadmium	increases expression, decreases expression	2
Dinitrochlorobenzene	decreases metabolic processing, increases metabolic processing, affects metabolic processing	2
Methionine	affects cotreatment, affects expression, decreases expression, decreases reaction	2
Polycyclic Aromatic Hydrocarbons	increases response to substance	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	increases expression	2
Okadaic Acid	increases expression	2
Nanotubes, Carbon	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	increases expression	1
fluorotelomer sulfonic acids	increases expression	1
dicrotophos	decreases expression	1
bismuth tripotassium dicitrate	increases expression	1
2,4,6-tribromophenol	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
cumene hydroperoxide	decreases metabolic processing, increases metabolic processing	1

ChEMBL screening assays

1 unique, capped per target: 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1743229	ADMET	Substrates for human cytosolic glutathione transferase GSTM3	Casarett and Doull’s Toxicology The Basic Science of Poisons, 7th edition

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00157690	PHASE4	COMPLETED	Study of Alendronate to Prevent and Treat Osteoporosis in Cystic Fibrosis Patients
NCT00208078	PHASE4	TERMINATED	Effect of Non-Invasive Ventilation in Cystic Fibrosis Patient With Chronic Respiratory Failure.
NCT00244270	PHASE4	COMPLETED	Cystic Fibrosis and Totally Implantable Vascular Access Devices
NCT00333385	PHASE4	TERMINATED	Continuous Versus Short Infusions of Ceftazidime in Cystic Fibrosis
NCT00411736	PHASE4	COMPLETED	Scandinavian Cystic Fibrosis Azithromycin Study
NCT00418470	PHASE4	TERMINATED	Prolonging the Duration of Peripheral Venous Catheters in Cystic Fibrosis People
NCT00431964	PHASE4	COMPLETED	Effect of Azithromycin on Lung Function in 6-18 Year-olds With Cystic Fibrosis (CF) Not Infected With P. Aeruginosa
NCT00434278	PHASE4	TERMINATED	A Trial of Pulmozyme Withdrawal on Exercise Tolerance in Cystic Fibrosis Subjects With Severe Lung Disease (TOPIC)
NCT00483769	PHASE4	COMPLETED	One Year Glargine Treatment in CFRD Children and Adolescents
NCT00528190	PHASE4	COMPLETED	Treatment of Aspergillus Fumigatus (a Fungal Infection) in Patients With Cystic Fibrosis
NCT00557089	PHASE4	COMPLETED	The Effect of rhDNase on Ventilation Inhomogeneity in Patients With Cystic Fibrosis
NCT00572975	PHASE4	COMPLETED	Malabsorption Blood Test:Toward a Novel Approach to Quantify Steatorrhea
NCT00680316	PHASE4	TERMINATED	A Study of Pulmozyme® (Dornase Alpha) in 3- to 5-Year-Old Patients With Cystic Fibrosis
NCT00685035	PHASE4	COMPLETED	Comparison of Airway Clearance Therapy in Cystic Fibrosis Using the Same VEST Therapy Device But With Different Settings
NCT00744250	PHASE4	TERMINATED	Intraduodenal Aspiration Study to Assess the Bioavailability of Oral Pancrecarb® Compared to Placebo Control
NCT00787917	PHASE4	TERMINATED	An Exploratory Study to Assess Multiple Doses of Omalizumab in Patients With Cystic Fibrosis Complicated by Acute Bronchopulmonary Aspergillosis (ABPA)
NCT00843817	PHASE4	COMPLETED	RhDNase and Biodistribution of PMN Serine Proteases in Cystic Fibrosis Sputum
NCT00890370	PHASE4	COMPLETED	Should Any One Airway Clearance Technique be Recommended for People With Cystic Fibrosis?
NCT00996424	PHASE4	TERMINATED	The Effect of Inhaled N-Acetylcysteine Compared to Normal Saline on Sputum Rheology and Lung Function
NCT01044719	PHASE4	UNKNOWN	Duration of Antibiotics in Infective Exacerbations of Cystic Fibrosis
NCT01100606	PHASE4	COMPLETED	A Study to Evaluate the Mode of Administration and Safety of EUR-1008 (APT-1008) in Infants 1 to 12 Months of Age
NCT01131507	PHASE4	COMPLETED	PR-018: An Open-Label, Safety Extension of Study PR-011
NCT01207245	PHASE4	COMPLETED	Circadian Rhythm In Tobramycin Elimination In Cystic Fibrosis
NCT01323101	PHASE4	COMPLETED	Doxycycline Effects on Inflammation in Cystic Fibrosis
NCT01327703	PHASE4	COMPLETED	Control of Steatorrhea in Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency
NCT01377792	PHASE4	COMPLETED	Study of Long-term Treatment With Hypertonic Saline in Patients With Cystic Fibrosis
NCT01400750	PHASE4	COMPLETED	Comparison of 2 Treatment Regimens for Eradication of P Aeruginosa Infection in Children With Cystic Fibrosis
NCT01429259	PHASE4	COMPLETED	Population Pharmacokinetics of Prolonged Infusion Meropenem in Cystic Fibrosis (CF) Children
NCT01608555	PHASE4	COMPLETED	Tobramycin 300 mg Once-a-day (o.d.) Aerosol in Adults With Cystic Fibrosis
NCT01667094	PHASE4	UNKNOWN	A Study Comparing Continuous Infusion Antibiotics to Standard Treatment for Lung Infections in Cystic Fibrosis
NCT01694069	PHASE4	TERMINATED	Continuous Infusion Piperacillin-tazobactam for the Treatment of Cystic Fibrosis
NCT01702415	PHASE4	WITHDRAWN	Zoledronic Acid in Cystic Fibrosis
NCT01712334	PHASE4	COMPLETED	A Study of the Comparable Efficacy and Safety of Pulmozyme (Dornase Alfa) Delivered by the eRapid Nebulizer System in Patients With Cystic Fibrosis
NCT01737983	PHASE4	COMPLETED	Effect of Lactobacillus Reuteri in Cystic Fibrosis
NCT01844778	PHASE4	COMPLETED	Ease of Use and Microbial Contamination of Tobramycin Inhalation Powder (TIP) Versus Nebulised Tobramycin Inhalation Solution (TIS) and Nebulised Colistimethate (COLI)
NCT01880346	PHASE4	COMPLETED	Comparison of Absorption of Vitamin D in Cystic Fibrosis
NCT01882400	PHASE4	COMPLETED	Assessment of Response to Treatment of Osteoporosis With Oral Bisphosphonates in Patients With Muscular Dystrophy
NCT01937325	PHASE4	UNKNOWN	CPET in CF Patients With One G551D Mutation Taking VX770
NCT02015663	PHASE4	TERMINATED	Tobramycin Inhalation Powder (TIP) Administered Once Daily Continuously Versus TIP Administered BID in 28 Day on / 28 Day Off Cycles
NCT02048592	PHASE4	UNKNOWN	Impact of Immunonutrition on the Patients With Cystic Fibrosis