GSTT2

Summary

GSTT2 (glutathione S-transferase theta 2 (gene/pseudogene), HGNC:4642) is a protein-coding gene on chromosome 22q11.23, encoding Glutathione S-transferase theta-2 (P0CG29). Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.

The protein encoded by this gene, glutathione S-transferase (GST) theta 2 (GSTT2), is a member of a superfamily of proteins that catalyze the conjugation of reduced glutathione to a variety of electrophilic and hydrophobic compounds. Human GSTs can be divided into five main classes: alpha, mu, pi, theta, and zeta. The theta class includes GSTT1, GSTT2, and GSTT2B. GSTT2 and GSTT2B are nearly identical to each other, and share 55% amino acid identity with GSTT1. All three genes may play a role in human carcinogenesis. The GSTT2 gene is a pseudogene in some populations.

Source: NCBI Gene 2953 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 18 total — 1 pathogenic, 1 likely-pathogenic
• Druggable target: yes

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4642
Approved symbol	GSTT2
Name	glutathione S-transferase theta 2 (gene/pseudogene)
Location	22q11.23
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000099984
Ensembl biotype	protein_coding
OMIM	600437
Entrez	2953

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding_LoF

ENST00000402588, ENST00000634759

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

ENST00000402588 — 5 exons

Exon	Start	End
ENSE00001709804	23982628	23982778
ENSE00001730025	23980948	23981035
ENSE00001938639	23980058	23980309
ENSE00001946516	23983397	23983710
ENSE00003787167	23982871	23983002

Expression profiles

Bgee: expression breadth ubiquitous, 124 present calls, max score 79.49.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9431 / max 37.6472, expressed in 529 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191349	0.9431	529

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.49	gold quality
stromal cell of endometrium	CL:0002255	74.96	gold quality
lower esophagus mucosa	UBERON:0035834	74.92	gold quality
superior frontal gyrus	UBERON:0002661	68.68	gold quality
prefrontal cortex	UBERON:0000451	66.42	gold quality
fundus of stomach	UBERON:0001160	65.60	gold quality
right adrenal gland cortex	UBERON:0035827	65.54	gold quality
apex of heart	UBERON:0002098	65.11	gold quality
primary visual cortex	UBERON:0002436	64.65	gold quality
colonic epithelium	UBERON:0000397	62.92	silver quality
left adrenal gland	UBERON:0001234	62.73	gold quality
frontal cortex	UBERON:0001870	62.73	gold quality
ascending aorta	UBERON:0001496	62.70	gold quality
right adrenal gland	UBERON:0001233	62.30	gold quality
thoracic aorta	UBERON:0001515	62.28	gold quality
right atrium auricular region	UBERON:0006631	62.28	gold quality
left adrenal gland cortex	UBERON:0035825	61.84	gold quality
left coronary artery	UBERON:0001626	61.78	gold quality
tibial artery	UBERON:0007610	61.60	gold quality
popliteal artery	UBERON:0002250	61.35	gold quality
prostate gland	UBERON:0002367	61.06	gold quality
cortex of kidney	UBERON:0001225	60.67	gold quality
adrenal gland	UBERON:0002369	60.66	gold quality
left ovary	UBERON:0002119	60.17	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	59.91	gold quality
right lobe of thyroid gland	UBERON:0001119	59.65	gold quality
lower esophagus	UBERON:0013473	59.02	gold quality
skin of leg	UBERON:0001511	58.99	gold quality
lower esophagus muscularis layer	UBERON:0035833	58.78	gold quality
zone of skin	UBERON:0000014	58.67	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

Literature-anchored findings (GeneRIF, showing 8)

• dinitrosyl-diglutathionyl-iron complex, a natural carrier of nitric oxide, binds with extraordinary affinity to GSTA1-1, which is explained by molecular modeling and related to molecular evolution (PMID:12871945)
• single nucleotide polymorphisms and haplotypes of the GSTT2 promoter region are associated with colorectal cancer risk in the Korean population (PMID:17250773)
• PAH-DNA adduct formation could be modulated by common genetic variants in GSTT2 in African American, Dominican and Caucasian mothers and newborns. (PMID:18268125)
• GSTM1 (1p13.3) and GSTT2 (22q11.23) showed a statistically significant association of non-null genotypes at both loci with an additive effect for increased vulnerability to schizophrenia (PMID:19528963)
• analysis of glutathione S-transferase copy number variation alters lung gene expression (PMID:21349909)
• Polyphenol metabolites did not affect cell number but significantly upregulated GSTT2 expression and decreased COX-2. (PMID:21598179)
• Increased levels of GSTT2 in esophageal tissues of African American individuals might protect them from GERD-induced damage and contribute to the low incidence of esophageal adenocarcinoma in this population. (PMID:30578782)
• Proanthocyanidins mitigate bile acid-induced changes in GSTT2 levels in a panel of racially diverse patient-derived primary esophageal cell cultures. (PMID:34758158)

Cross-species orthologs

42 orthologs

Organism	Symbol	Gene ID
danio_rerio	gstr	ENSDARG00000042620
danio_rerio	gstt2	ENSDARG00000095464
mus_musculus	Gstt2	ENSMUSG00000033318
rattus_norvegicus	Gstt2	ENSRNOG00000052415
drosophila_melanogaster	GstD1	FBGN0001149
drosophila_melanogaster	GstD2	FBGN0010038
drosophila_melanogaster	GstD3	FBGN0010039
drosophila_melanogaster	GstD4	FBGN0010040
drosophila_melanogaster	GstD5	FBGN0010041
drosophila_melanogaster	GstD6	FBGN0010042
drosophila_melanogaster	GstD7	FBGN0010043
drosophila_melanogaster	GstD8	FBGN0010044
drosophila_melanogaster	GstE12	FBGN0027590
drosophila_melanogaster	Clic	FBGN0030529
drosophila_melanogaster	GstT3	FBGN0031117
drosophila_melanogaster	GstE13	FBGN0033381
drosophila_melanogaster	GstE1	FBGN0034335
drosophila_melanogaster	GstE11	FBGN0034354
drosophila_melanogaster	GstO3	FBGN0035904
drosophila_melanogaster	GstO2	FBGN0035906
drosophila_melanogaster	GstO1	FBGN0035907
drosophila_melanogaster	GstD9	FBGN0038020
drosophila_melanogaster	GstD10	FBGN0042206
drosophila_melanogaster	GstT1	FBGN0050000
drosophila_melanogaster	GstT2	FBGN0050005
drosophila_melanogaster	GstE9	FBGN0063491
drosophila_melanogaster	GstE8	FBGN0063492
drosophila_melanogaster	GstE7	FBGN0063493
drosophila_melanogaster	GstE6	FBGN0063494
drosophila_melanogaster	GstE5	FBGN0063495
drosophila_melanogaster	GstE4	FBGN0063496
drosophila_melanogaster	GstE3	FBGN0063497
drosophila_melanogaster	GstE2	FBGN0063498
drosophila_melanogaster	GstE10	FBGN0063499
drosophila_melanogaster	se	FBGN0086348
caenorhabditis_elegans	exc-4	WBGENE00001365
caenorhabditis_elegans		WBGENE00001371
caenorhabditis_elegans	gst-43	WBGENE00001791
caenorhabditis_elegans		WBGENE00001792
caenorhabditis_elegans		WBGENE00015337
caenorhabditis_elegans		WBGENE00021817
caenorhabditis_elegans		WBGENE00043097

Paralogs (14): GSTO2 (ENSG00000065621), GSTZ1 (ENSG00000100577), GDAP1 (ENSG00000104381), CLIC5 (ENSG00000112782), GDAP1L1 (ENSG00000124194), GSTT2B (ENSG00000133433), GSTO1 (ENSG00000148834), CLIC2 (ENSG00000155962), CLIC6 (ENSG00000159212), CLIC4 (ENSG00000169504), CLIC3 (ENSG00000169583), CLIC1 (ENSG00000213719), EEF1G (ENSG00000254772), GSTT4 (ENSG00000276950)

Protein

Protein identifiers

Glutathione S-transferase theta-2 — P0CG29 (reviewed: P0CG29)

Alternative names: GST class-theta-2

All UniProt accessions (0):

UniProt curated annotations — full annotation on UniProt →

Function. Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Has a sulfatase activity.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Cytosol. Nucleus.

Tissue specificity. Expressed at low levels in liver. In lung, expressed at low levels in ciliated bronchiolar cells, alveolar macrophages and alveolar type II cells.

Similarity. Belongs to the GST superfamily. Theta family.

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

ID	Name	Type
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
IPR040075	GST_N_Theta	Domain
IPR040077	GST_C_Theta	Domain
IPR040079	Glutathione_S-Trfase	Family
IPR051369	GST_Theta	Family

Pfam: PF00043, PF02798

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (34 total): helix 14, strand 6, turn 5, binding site 4, domain 2, initiator methionine 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4MPF	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0CG29-F1	97.70	0.99

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 (4): 40–41; 53–54; 66–67; 104–107

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-156590	Glutathione conjugation

MSigDB gene sets: 154 (showing top): REACTOME_BIOLOGICAL_OXIDATIONS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, CHANDRAN_METASTASIS_DN, GOMF_GLUTATHIONE_TRANSFERASE_ACTIVITY, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_AMIDE_METABOLIC_PROCESS, BROWNE_HCMV_INFECTION_14HR_DN, CAIRO_HEPATOBLASTOMA_DN, MORI_PRE_BI_LYMPHOCYTE_UP, WELCH_GATA1_TARGETS, REACTOME_GLUTATHIONE_CONJUGATION, GOBP_GLUTATHIONE_METABOLIC_PROCESS, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_0, CUI_TCF21_TARGETS_2_UP

GO Biological Process (1): glutathione metabolic process (GO:0006749)

GO Molecular Function (1): glutathione transferase activity (GO:0004364)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), 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	2
modified amino acid metabolic process	1
sulfur compound metabolic process	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

5 interactions, top by confidence:

A	B	Type	Score
GSTT2	MOCS2	psi-mi:“MI:0915”(physical association)	0.400
CFTR	GSTT2	psi-mi:“MI:0915”(physical association)	0.370
THEM4	KIAA0391	psi-mi:“MI:0914”(association)	0.350
THEM4	PRORP	psi-mi:“MI:0914”(association)	0.350

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: A0A1U8QXK4, A0A6J4B5J2, A2Q127, C8VQ63, P0CG29, P0CG30, P12261, P26641, P26642, P29547, P29694, P36008, P40921, P42936, Q00717, Q29387, Q3SZV3, Q4R7H5, Q4WB03, Q5Z627, Q68FR6, Q6PE25, Q6YW46, Q90YC0, Q9D8N0, Q9FUM1, Q9VG98, Q9ZRI7, S0EHD0, W7MMJ0, A0A1W2PR19, O76483, O77473, P20135, P30711, P30713, P46430, P57108, Q01579, Q03425

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	10
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2684933	GRCh37/hg19 22q11.23(chr22:23690388-25066472)x3	Pathogenic
3064991	NM_000854.1(GSTT2):c.200+1G>A	Likely pathogenic

SpliceAI

995 predictions. Top by Δscore:

Variant	Effect	Δscore
22:23980304:TCA:T	donor_gain	1.0000
22:23980305:CAAAG:C	donor_loss	1.0000
22:23980307:AAG:A	donor_loss	1.0000
22:23980308:AGGT:A	donor_loss	1.0000
22:23980309:GGTG:G	donor_loss	1.0000
22:23980310:GT:G	donor_loss	1.0000
22:23980311:T:G	donor_loss	1.0000
22:23980944:TCAG:T	acceptor_loss	1.0000
22:23980946:A:AC	acceptor_loss	1.0000
22:23980946:A:AG	acceptor_gain	1.0000
22:23980946:AG:A	acceptor_gain	1.0000
22:23980947:G:GA	acceptor_gain	1.0000
22:23980947:GG:G	acceptor_gain	1.0000
22:23980947:GGGC:G	acceptor_gain	1.0000
22:23980947:GGGCA:G	acceptor_gain	1.0000
22:23981010:G:GT	donor_gain	1.0000
22:23981011:A:T	donor_gain	1.0000
22:23982456:G:GT	donor_gain	1.0000
22:23982624:CCAGC:C	acceptor_loss	1.0000
22:23982626:A:AG	acceptor_gain	1.0000
22:23982626:AGCT:A	acceptor_loss	1.0000
22:23982626:AGCTC:A	acceptor_gain	1.0000
22:23982627:G:GT	acceptor_gain	1.0000
22:23982627:GC:G	acceptor_gain	1.0000
22:23982627:GCT:G	acceptor_gain	1.0000
22:23982627:GCTC:G	acceptor_gain	1.0000
22:23982627:GCTCG:G	acceptor_gain	1.0000
22:23982774:TCCAG:T	donor_loss	1.0000
22:23982777:AG:A	donor_loss	1.0000
22:23982778:GG:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000959418 (22:23982069 C>G), RS1004081892 (22:23984174 A>G), RS1004855495 (22:23980808 G>T), RS1007882230 (22:23982230 T>G), RS1012870914 (22:23980857 G>A,C), RS1019225265 (22:23982248 G>C), RS1023798660 (22:23980871 G>A,C), RS1027286812 (22:23982288 C>T), RS1039535364 (22:23980699 A>T), RS1041168496 (22:23984074 C>T), RS1045665383 (22:23981985 A>C), RS1052550288 (22:23983434 C>T), RS1056474739 (22:23981233 T>C,G), RS1056738118 (22:23980821 T>A), RS1126752 (22:23982630 C>T)

Disease associations

OMIM: gene MIM:600437 | disease phenotypes: MIM:604004

GenCC curated gene-disease

Mondo (1): megalencephalic leukoencephalopathy with subcortical cysts 1 (MONDO:0024555)

Orphanet (1): Megalencephalic leukoencephalopathy with subcortical cysts (Orphanet:2478)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003483_1	S-phenylmercapturic acid levels in smokers	3.000000e-134
GCST003483_2	S-phenylmercapturic acid levels in smokers	2.000000e-46
GCST010244_364	Triglyceride levels	4.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007651	urinary S-phenylmercapturic acid measurement
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2142 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
apple polyphenol extract	increases expression	2
Butyrates	decreases expression, increases expression	2
Valproic Acid	affects cotreatment, increases expression, increases methylation	2
Aflatoxin B1	increases expression, increases methylation	2
bis(tri-n-butyltin)oxide	increases expression	1
1-menaphthyl sulfate	affects metabolic processing	1
2-hydroxychavicol	increases expression	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Bosentan	decreases expression	1
Artesunate	affects response to substance	1
Acetaminophen	increases expression	1
Acetylglucosamine	increases expression	1
Benzo(a)pyrene	increases expression	1
Estradiol	decreases expression	1
Etoposide	affects response to substance	1
Hydralazine	affects cotreatment, increases expression	1
Niclosamide	decreases expression	1
Paraoxon	increases expression	1
Parathion	increases expression	1
Plant Extracts	increases expression	1
Sarin	decreases expression	1
Mifepristone	decreases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	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
CHEMBL1743236	ADMET	Substrates for human cytosolic glutathione transferase GSTT2	Casarett and Doull’s Toxicology The Basic Science of Poisons, 7th edition

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project