GSS

Summary

GSS (glutathione synthetase, HGNC:4624) is a protein-coding gene on chromosome 20q11.22, encoding Glutathione synthetase (P48637). Catalyzes the production of glutathione from gamma-glutamylcysteine and glycine in an ATP-dependent manner.

Glutathione is important for a variety of biological functions, including protection of cells from oxidative damage by free radicals, detoxification of xenobiotics, and membrane transport. The protein encoded by this gene functions as a homodimer to catalyze the second step of glutathione biosynthesis, which is the ATP-dependent conversion of gamma-L-glutamyl-L-cysteine to glutathione. Defects in this gene are a cause of glutathione synthetase deficiency.

Source: NCBI Gene 2937 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inherited glutathione synthetase deficiency (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 486 total — 21 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_000178

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4624
Approved symbol	GSS
Name	glutathione synthetase
Location	20q11.22
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100983
Ensembl biotype	protein_coding
OMIM	601002
Entrez	2937

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 22 protein_coding, 8 retained_intron, 6 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000451957, ENST00000642493, ENST00000642498, ENST00000642538, ENST00000643188, ENST00000643203, ENST00000643271, ENST00000643443, ENST00000643502, ENST00000643628, ENST00000643690, ENST00000643908, ENST00000644197, ENST00000644538, ENST00000644608, ENST00000644694, ENST00000644793, ENST00000645102, ENST00000645328, ENST00000645408, ENST00000645723, ENST00000646405, ENST00000646497, ENST00000646502, ENST00000646512, ENST00000646735, ENST00000646766, ENST00000651619, ENST00000854975, ENST00000854976, ENST00000854977, ENST00000854978, ENST00000854979, ENST00000854980, ENST00000854981, ENST00000854982, ENST00000912769, ENST00000961050, ENST00000961051

RefSeq mRNA: 3 — MANE Select: NM_000178 NM_000178, NM_001322494, NM_001322495

CCDS: CCDS13245

Canonical transcript exons

ENST00000651619 — 13 exons

Exon	Start	End
ENSE00000661494	34929401	34929590
ENSE00000661495	34931336	34931417
ENSE00000661496	34931939	34932133
ENSE00000661497	34935576	34935642
ENSE00000661498	34936763	34936840
ENSE00000661499	34936943	34937023
ENSE00000661500	34941713	34941829
ENSE00000661501	34942488	34942627
ENSE00000661502	34942931	34943006
ENSE00000860151	34951724	34951860
ENSE00003505856	34945953	34946098
ENSE00003841766	34928432	34928951
ENSE00003843894	34955727	34955806

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.8498 / max 249.8566, expressed in 1820 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187012	33.8498	1820

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
frontal pole	UBERON:0002795	98.10	gold quality
middle frontal gyrus	UBERON:0002702	97.93	gold quality
endometrium epithelium	UBERON:0004811	97.37	gold quality
paraflocculus	UBERON:0005351	97.35	gold quality
cervix squamous epithelium	UBERON:0006922	96.88	gold quality
mucosa of transverse colon	UBERON:0004991	96.60	gold quality
rectum	UBERON:0001052	95.50	gold quality
right adrenal gland	UBERON:0001233	95.19	gold quality
right adrenal gland cortex	UBERON:0035827	95.18	gold quality
sperm	CL:0000019	95.08	gold quality
corpus epididymis	UBERON:0004359	95.04	gold quality
left adrenal gland	UBERON:0001234	94.64	gold quality
male germ cell	CL:0000015	94.58	gold quality
left adrenal gland cortex	UBERON:0035825	94.54	gold quality
adrenal cortex	UBERON:0001235	94.49	gold quality
metanephros cortex	UBERON:0010533	94.12	gold quality
transverse colon	UBERON:0001157	94.04	gold quality
endothelial cell	CL:0000115	94.00	gold quality
adrenal gland	UBERON:0002369	93.93	gold quality
Brodmann (1909) area 10	UBERON:0013541	93.93	gold quality
nasal cavity epithelium	UBERON:0005384	93.77	gold quality
adult mammalian kidney	UBERON:0000082	93.70	gold quality
esophagus mucosa	UBERON:0002469	93.58	gold quality
trachea	UBERON:0003126	93.58	gold quality
gingival epithelium	UBERON:0001949	93.50	gold quality
nephron tubule	UBERON:0001231	93.33	gold quality
lower esophagus mucosa	UBERON:0035834	93.19	gold quality
tongue squamous epithelium	UBERON:0006919	93.17	gold quality
hair follicle	UBERON:0002073	93.16	gold quality
pancreatic ductal cell	CL:0002079	93.13	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.22

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, NFE2, NFE2L2, NRF1

miRNA regulators (miRDB)

36 targeting GSS, 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-3617-3P	99.98	67.86	918
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-4266	98.53	67.29	1035
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-561-5P	98.25	68.13	1365
HSA-MIR-541-5P	98.24	67.77	1181
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-6847-5P	97.93	66.74	1808

Literature-anchored findings (GeneRIF, showing 22)

• Glutathione synthetase deficiency: is gamma-glutamylcysteine accumulation a way to cope with oxidative stress in cells with insufficient levels of glutathione? (PMID:12638941)
• analysis of conserved residues of human glutathione synthetase (PMID:14990577)
• The cloning and characterization of a 2.2 kb 5’-flanking region of the human glutathione synthetase gene is reported. (PMID:15890065)
• glutathione synthetase autosomal mutations result in glutathione synthetase deficiency, which may cause progressive retinal dystrophy with hyperpigmentations and maculopathy [case report] (PMID:17206463)
• Glutathione synthase expression may indicate better survival in early stage adenocarcinoma of the lung, and manipulation of glutathione synthase may be a potential basis for treatment of some non-small cell lung cancers. (PMID:17234469)
• Severe glutathione synthetase deficiency is associated with progressive retinal dystrophy of the rod-cone type, affecting the central retina with advanced macular edema in adulthood. (PMID:19111905)
• A novel alternative splicing variant (ASV) of the GSS gene was identified in 10 human normal tissues and five human cancer cell lines. (PMID:19672693)
• the cause of cellular ATP depletion in nephrotic cystinosis may be the futile cycle, formed between two ATP-dependant gamma-glutamyl cycle enzymes, gamma-glutamyl cysteine synthetase and 5-oxoprolinase (PMID:20413906)
• Single-nucleotide polymorphism in glutathione synthetase is associated with small-cell lung cancer. (PMID:20439344)
• This research indicates that Gly369 and Gly370 have essential roles in hGS, while Gly371 has a lesser involvement. (PMID:20800579)
• We have shown that susceptibility to health effects of air pollution on lung function growth is associated with genetic variation in the GSS gene (PMID:20802163)
• SNPs not associted with schizophrenia in Japanese individuals (PMID:21105962)
• These results imply that residues V44 and V45 are integral to the stability of human glutathione synthetase. (PMID:21683691)
• The findings indicate that Asp458 is essential for hGS catalysis and that it impacts the allostery of hGS. (PMID:21771585)
• Its depletion causes protein oxidization in ATL cells. (PMID:24323765)
• Studied the role of protein-protein interactions in the structural stability, activity and allostery of enzymes using the obligate homodimer human glutathione synthetase as an ideal model. (PMID:25070563)
• Four SNPs (rs7265992, rs6060124, rs7260770, and rs4911455) in GSS were significantly associated with bladder cancer recurrence after transurethral resection and BCG treatment. (PMID:25851338)
• In this study, clinical, biochemical, and genetic aspects of five Chinese 5-oxoprolinuria patients with OPLAH or GSS gene mutations were investigated. (PMID:25851806)
• GCLC and GSS were expressed at higher levels in colon cancer tissue, as compared with normal mucosa. (PMID:26059756)
• Mutation in Glutathione Synthase gene is associated with chronic metabolic acidosis in glutathione synthetase deficiency. (PMID:26669244)
• Data suggest that the potential of clusterin and glutathione synthetase (GSH-S) as platelet biomarkers for early detection of colorectal cancer (CRC) could improve existing screening modalities in clinical application. (PMID:28849249)
• Salivary IL-6, MMP-8 and GSS mRNA levels in combination with urine test analysis could be useful diagnostic tool for the very distributed disorder of pyelonephritis in childhood. (PMID:31881666)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gss	ENSDARG00000037706
mus_musculus	Gss	ENSMUSG00000027610
rattus_norvegicus	Gss	ENSRNOG00000018964
drosophila_melanogaster	Gss1	FBGN0030882
drosophila_melanogaster	Gss2	FBGN0052495
caenorhabditis_elegans		WBGENE00010941

Protein

Protein identifiers

Glutathione synthetase — P48637 (reviewed: P48637)

Alternative names: Glutathione synthase

All UniProt accessions (14): P48637, A0A0S2Z4J7, A0A2R8Y2F2, A0A2R8Y2X9, A0A2R8Y430, A0A2R8Y446, A0A2R8Y4V9, A0A2R8Y5T7, A0A2R8Y6Q7, A0A2R8Y6Y6, A0A2R8Y790, A0A2R8Y7I7, A0A2R8YF34, V9HWJ1

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the production of glutathione from gamma-glutamylcysteine and glycine in an ATP-dependent manner. Glutathione (gamma-glutamylcysteinylglycine, GSH) is the most abundant intracellular thiol in living aerobic cells and is required for numerous processes including the protection of cells against oxidative damage, amino acid transport, the detoxification of foreign compounds, the maintenance of protein sulfhydryl groups in a reduced state and acts as a cofactor for a number of enzymes. Participates in ophthalmate biosynthesis in hepatocytes.

Subunit / interactions. Homodimer.

Disease relevance. Glutathione synthetase deficiency (GSSD) [MIM:266130] An autosomal recessive disorder characterized by massive urinary excretion of 5-oxoproline, metabolic acidosis, hemolytic anemia, and central nervous system damage. The disease is caused by variants affecting the gene represented in this entry. Anemia, congenital, non-spherocytic hemolytic, 6 (CNSHA6) [MIM:231900] A mild form of glutathione synthetase deficiency, resulting in hemolytic anemia. Affected individuals do not have neurologic abnormalities. CNSHA6 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Mg(2+) ion per subunit.

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

Miscellaneous. Detected in colon, kidney, lung, liver, placenta, peripheral blood and uterus, but not in heart, skeletal muscle and spleen.

Similarity. Belongs to the eukaryotic GSH synthase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P48637-1	1	yes
P48637-2	2

RefSeq proteins (3): NP_000169, NP_001309423, NP_001309424 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004887	GSH_synth_subst-bd	Domain
IPR005615	Glutathione_synthase	Family
IPR014042	Glutathione_synthase_a-hlx	Homologous_superfamily
IPR014049	Glutathione_synthase_N_euk	Homologous_superfamily
IPR014709	Glutathione_synthase_C_euk	Homologous_superfamily
IPR016185	PreATP-grasp_dom_sf	Homologous_superfamily
IPR037013	GSH-S_sub-bd_sf	Homologous_superfamily

Pfam: PF03199, PF03917

Enzyme classification (BRENDA):

• EC 6.3.2.3 — glutathione synthase (BRENDA: 48 organisms, 164 substrates, 81 inhibitors, 217 Km, 115 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.012–13.4	64
GLY	0.09–29.8	46
GAMMA-GLU-L-CYS	0.03–81	25
GLYCINE	0.07–51	20
GAMMA-L-GLUTAMYL-L-CYSTEINE	0.099–1.93	12
GAMMA-GLU-CYS	0.2–3.33	9
GAMMA-L-GLU-AMINOBUTANOATE	0.1–1.6	9
GAMMA-L-GLU-L-CYS	0.34–8.3	5
BETA-ALA	0.32–170	4
GAMMA-GLU-2-AMINOBUTYRATE	0.22–0.5	3
GAMMA-(ALPHA-AMINOMETHYL)GLU-2-AMINOBUTYRATE	80	1
GAMMA-GLU-L-2-AMINOBUTYRATE	0.091	1
GAMMA-GLU-S-METHYLCYSTEINE	0.28	1
GAMMA-GLUTAMYL-ALPHA-AMINOBUTYRATE	0.063	1
GAMMA-L-GLU-L-ALPHA-AMINOBUTYRATE	0.042	1

Catalyzed reactions (Rhea), 2 shown:

• gamma-L-glutamyl-L-cysteine + glycine + ATP = glutathione + ADP + phosphate + H(+) (RHEA:13557)
• gamma-L-glutamyl-(2S)-2-aminobutanoate + glycine + ATP = ophthalmate + ADP + phosphate + H(+) (RHEA:72075)

UniProt features (89 total): helix 23, strand 23, binding site 18, sequence variant 18, modified residue 2, turn 2, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8FBZ	X-RAY DIFFRACTION	1.59
2HGS	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48637-F1	95.25	0.91

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 (18): 305; 364–373; 368; 375; 398–401; 425; 450; 452; 458; 461–462; 125; 144 …

Post-translational modifications (2): 2, 415

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-174403	Glutathione synthesis and recycling
R-HSA-5579006	Defective GSS causes GSS deficiency

MSigDB gene sets: 219 (showing top): REACTOME_BIOLOGICAL_OXIDATIONS, LFA1_Q6, NIKOLSKY_BREAST_CANCER_20Q11_AMPLICON, MORF_BRCA1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_RESPONSE_TO_METAL_ION, GOBP_PEPTIDE_METABOLIC_PROCESS, ONKEN_UVEAL_MELANOMA_UP, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, CHEOK_RESPONSE_TO_MERCAPTOPURINE_DN, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_NONRIBOSOMAL_PEPTIDE_BIOSYNTHETIC_PROCESS, GOBP_AMIDE_BIOSYNTHETIC_PROCESS, GOTZMANN_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_DN

GO Biological Process (5): amino acid metabolic process (GO:0006520), response to oxidative stress (GO:0006979), nervous system development (GO:0007399), response to cadmium ion (GO:0046686), glutathione biosynthetic process (GO:0006750)

GO Molecular Function (10): magnesium ion binding (GO:0000287), glutathione synthase activity (GO:0004363), ATP binding (GO:0005524), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), glutathione binding (GO:0043295), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874), metal ion binding (GO:0046872)

GO Cellular Component (2): cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Glutathione conjugation	1
Metabolic disorders of biological oxidation enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
primary metabolic process	1
response to stress	1
system development	1
response to metal ion	1
glutathione metabolic process	1
nonribosomal peptide biosynthetic process	1
modified amino acid biosynthetic process	1
sulfur compound biosynthetic process	1
metal ion binding	1
glutathione biosynthetic process	1
acid-amino acid ligase activity	1
non-ribosomal peptide synthetase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
anion binding	1
modified amino acid binding	1
oligopeptide binding	1
sulfur compound binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cation binding	1
cytoplasm	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

908 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GSS	GCLC	P48506	762
GSS	GCLM	P48507	761
GSS	GSR	P00390	608
GSS	CTH	P32929	569
GSS	OPLAH	O14841	522
GSS	GGT6	Q6P531	499
GSS	HPGDS	O60760	474
GSS	TXN	P10599	461
GSS	GGT1	P19440	458
GSS	PAPSS1	O43252	457
GSS	GPX2	P18283	455
GSS	GPX3	P22352	454
GSS	GLRX	P35754	449
GSS	GGT7	Q9UJ14	447
GSS	P0DN79	P0DN79	447

IntAct

26 interactions, top by confidence:

A	B	Type	Score
GSS	GSS	psi-mi:“MI:0915”(physical association)	0.830
GSS	TERF1	psi-mi:“MI:0915”(physical association)	0.510
GSS	IRF3	psi-mi:“MI:0915”(physical association)	0.400
GAPDH	GSS	psi-mi:“MI:0915”(physical association)	0.400
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
E2F1	CLIC1	psi-mi:“MI:0914”(association)	0.350
IGF1R	GLRX3	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
INSR	UBXN8	psi-mi:“MI:0914”(association)	0.350
INSR	RIMOC1	psi-mi:“MI:0914”(association)	0.350
GPKOW	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
RBM15	ILVBL	psi-mi:“MI:2364”(proximity)	0.270
SUPV3L1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
TRA2A	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
GSS	TERF1	psi-mi:“MI:0915”(physical association)	0.000
GSS	GSS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (62): GSS (Two-hybrid), GBE1 (Co-fractionation), GSS (Co-fractionation), GSS (Two-hybrid), GSS (Two-hybrid), GSS (Negative Genetic), GSS (Positive Genetic), GSS (Negative Genetic), GSS (Affinity Capture-MS), GSS (Reconstituted Complex), GSS (Affinity Capture-MS), PSPH (Co-fractionation), GSS (Affinity Capture-MS), GSS (Affinity Capture-MS), GSS (Affinity Capture-MS)

ESM2 similar proteins: A2XNR6, A2ZCP0, A5GFY8, B6TZD1, B9HCR2, D7TCD0, F1RKQ4, O08651, O43837, O60017, O60027, O77784, P21872, P22102, P22989, P29102, P37223, P48637, P49079, P49588, P50475, Q08BL7, Q0CFY3, Q0ITU1, Q0J7N5, Q0VFN1, Q28479, Q3LXA3, Q42942, Q4KLZ6, Q58DK4, Q59A32, Q5EAD2, Q5R7M2, Q5RBT4, Q5RC02, Q64737, Q68FX0, Q75LJ3, Q8BGQ7

Diamond homologs: O22494, O23732, P35668, P35669, P46413, P46416, P48637, P51855, Q08220, Q54E83, Q5EAC2, Q8HXX5

SIGNOR signaling

1 interactions.

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

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	21
Uncertain significance	146
Likely benign	227
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1076084	NM_000178.4(GSS):c.922C>T (p.Gln308Ter)	Pathogenic
2702032	NM_000178.4(GSS):c.1045del (p.Gln349fs)	Pathogenic
2714497	NM_000178.4(GSS):c.1103_1104del (p.Glu368fs)	Pathogenic
2716943	NM_000178.4(GSS):c.325C>T (p.Gln109Ter)	Pathogenic
2725232	NM_000178.4(GSS):c.882C>A (p.Cys294Ter)	Pathogenic
2736963	NM_000178.4(GSS):c.374G>A (p.Arg125His)	Pathogenic
2756529	NM_000178.4(GSS):c.527del (p.Ala176fs)	Pathogenic
2792061	NM_000178.4(GSS):c.587G>A (p.Trp196Ter)	Pathogenic
2793305	NM_000178.4(GSS):c.658C>T (p.Gln220Ter)	Pathogenic
2858234	NM_000178.4(GSS):c.547_550del (p.Asn183fs)	Pathogenic
2877418	NM_000178.4(GSS):c.49G>T (p.Glu17Ter)	Pathogenic
2903932	NM_000178.4(GSS):c.588G>A (p.Trp196Ter)	Pathogenic
2976093	NM_000178.4(GSS):c.105del (p.Ser36fs)	Pathogenic
3014333	NM_000178.4(GSS):c.1020dup (p.Leu341fs)	Pathogenic
3248261	NC_000020.10:g.(?33516631)(33517413_?)del	Pathogenic
3637395	NM_000178.4(GSS):c.37C>T (p.Gln13Ter)	Pathogenic
3699755	NM_000178.4(GSS):c.14G>A (p.Trp5Ter)	Pathogenic
4711195	NM_000178.4(GSS):c.146del (p.Pro49fs)	Pathogenic
495702	NM_000178.4(GSS):c.-9+5G>A	Pathogenic
8525	NM_000178.4(GSS):c.491G>A (p.Arg164Gln)	Pathogenic
953992	NM_000178.4(GSS):c.368_382del (p.Leu123_Tyr128delinsHis)	Pathogenic
1163162	NM_000178.4(GSS):c.533del (p.Lys178fs)	Likely pathogenic
1677096	NM_000178.3(GSS):c.1113_1132del20	Likely pathogenic
2429135	NM_000178.4(GSS):c.1192dup (p.Met398fs)	Likely pathogenic
2636316	NM_000178.4(GSS):c.706dup (p.Arg236fs)	Likely pathogenic
2736964	NM_000178.4(GSS):c.130-1G>C	Likely pathogenic
2750049	NM_000178.4(GSS):c.609-2A>C	Likely pathogenic
2819254	NM_000178.4(GSS):c.275+1G>A	Likely pathogenic
2832268	NM_000178.4(GSS):c.351+1G>C	Likely pathogenic
3251315	NM_000178.4(GSS):c.809A>G (p.Tyr270Cys)	Likely pathogenic

SpliceAI

2321 predictions. Top by Δscore:

Variant	Effect	Δscore
20:34931935:GT:G	donor_loss	1.0000
20:34931936:TACCA:T	donor_loss	1.0000
20:34931937:A:AC	donor_gain	1.0000
20:34931938:C:CC	donor_gain	1.0000
20:34931938:CCA:C	donor_gain	1.0000
20:34932036:AGCT:A	donor_gain	1.0000
20:34932129:CAATT:C	acceptor_gain	1.0000
20:34932130:AATT:A	acceptor_gain	1.0000
20:34932131:ATT:A	acceptor_gain	1.0000
20:34932132:TT:T	acceptor_gain	1.0000
20:34932132:TTC:T	acceptor_loss	1.0000
20:34932133:TC:T	acceptor_loss	1.0000
20:34932134:C:A	acceptor_loss	1.0000
20:34932134:C:CC	acceptor_gain	1.0000
20:34932137:C:CT	acceptor_gain	1.0000
20:34936761:A:AC	donor_gain	1.0000
20:34936762:C:CC	donor_gain	1.0000
20:34936762:CA:C	donor_gain	1.0000
20:34936939:TTA:T	donor_loss	1.0000
20:34936940:TA:T	donor_loss	1.0000
20:34936941:ACCT:A	donor_loss	1.0000
20:34936942:C:A	donor_loss	1.0000
20:34937024:C:CC	acceptor_gain	1.0000
20:34941711:A:AC	donor_gain	1.0000
20:34941712:C:CC	donor_gain	1.0000
20:34941825:CATGT:C	acceptor_gain	1.0000
20:34942925:GGTTA:G	donor_loss	1.0000
20:34942926:GTTAC:G	donor_loss	1.0000
20:34942927:TTAC:T	donor_loss	1.0000
20:34942928:TACCT:T	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000042628 (20:34951989 C>G,T), RS1000048150 (20:34944501 C>G,T), RS1000073857 (20:34957544 C>T), RS1000088350 (20:34951516 T>C), RS1000225533 (20:34933777 A>C), RS1000291768 (20:34944820 G>A), RS1000313495 (20:34944430 T>A), RS1000362717 (20:34957270 G>C), RS1000453675 (20:34929204 C>A), RS1000545235 (20:34956455 C>T), RS1000640367 (20:34956709 G>A), RS1000654968 (20:34930145 A>G), RS1000685243 (20:34944025 G>A,C,T), RS1000863073 (20:34943116 A>G), RS1000890314 (20:34937039 A>C,G)

Disease associations

OMIM: gene MIM:601002 | disease phenotypes: MIM:266130, MIM:231900, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
inherited glutathione synthetase deficiency	Definitive	Autosomal recessive
glutathione synthetase deficiency with 5-oxoprolinuria	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
inherited glutathione synthetase deficiency	Definitive	AR

Mondo (4): glutathione synthetase deficiency with 5-oxoprolinuria (MONDO:0009947), inherited glutathione synthetase deficiency (MONDO:0017909), glutathione synthetase deficiency without 5-oxoprolinuria (MONDO:0009284), schizophrenia (MONDO:0005090)

Orphanet (4): Glutathione synthetase deficiency with 5-oxoprolinuria (Orphanet:289846), Glutathione synthetase deficiency (Orphanet:32), Glutathione synthetase deficiency without 5-oxoprolinuria (Orphanet:289849), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0100753	Schizophrenia

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536835	Glutathione synthetase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066521 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects cotreatment, increases methylation	4
sodium arsenite	decreases expression, increases expression	4
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
deoxynivalenol	decreases expression, decreases reaction, increases reaction, increases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression, decreases reaction, increases reaction	2
Cisplatin	increases expression, affects cotreatment	2
Hydrogen Peroxide	affects cotreatment, increases expression	2
Ursodeoxycholic Acid	increases reaction, decreases expression, decreases reaction, increases expression, affects expression	2
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
bismuth tripotassium dicitrate	increases expression	1
quinone	affects reaction, increases expression	1
methylmercuric chloride	increases expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	decreases expression	1
sodium bisulfide	decreases expression, decreases reaction	1
hydroquinone	increases expression, affects reaction	1
cadmium sulfide	increases expression	1
epigallocatechin gallate	decreases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases expression, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression, increases secretion	1
bisphenol B	increases expression	1
abrine	increases expression	1
chromium histidinate	increases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651509	Binding	Binding affinity to human GSS incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 2 finite cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2YB	Abcam HEK293T GSS KO	Transformed cell line	Female
CVCL_EF94	GM03877	Finite cell line	Male
CVCL_EF95	GM03878	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety