GPX6

Summary

GPX6 (glutathione peroxidase 6, HGNC:4558) is a protein-coding gene on chromosome 6p22.1, encoding Glutathione peroxidase 6 (P59796).

The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of hydrogen peroxide, organic hydroperoxides and lipid hydroperoxides, and thereby protect cells against oxidative damage. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. Expression of this gene has been observed in embryos and olfactory epithelium; however, the exact function of this gene is not known. This isozyme is a selenoprotein in humans, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3’ UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. The orthologs of this gene in mouse and rat (and some other species) contain a cysteine (Cys) residue in place of the Sec residue, and their corresponding mRNAs lack SECIS element.

Source: NCBI Gene 257202 — RefSeq curated summary.

At a glance

• GWAS associations: 25
• Clinical variants (ClinVar): 30 total
• MANE Select transcript: NM_182701

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4558
Approved symbol	GPX6
Name	glutathione peroxidase 6
Location	6p22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000198704
Ensembl biotype	protein_coding
OMIM	607913
Entrez	257202

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000361902, ENST00000474923, ENST00000483058

RefSeq mRNA: 1 — MANE Select: NM_182701 NM_182701

CCDS: CCDS43432

Canonical transcript exons

ENST00000361902 — 5 exons

Exon	Start	End
ENSE00001434684	28503296	28504498
ENSE00001436844	28506312	28506429
ENSE00001473230	28515657	28515793
ENSE00001963153	28505703	28505802
ENSE00003590503	28510751	28510904

Expression profiles

Bgee: expression breadth broad, 12 present calls, max score 85.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.8313 / max 121.1757, expressed in 1350 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2878	13.8313	1350

Top tissues by expression

113 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	85.72	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.77	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	50.30	gold quality
sural nerve	UBERON:0015488	49.41	gold quality
right testis	UBERON:0004534	38.30	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
apex of heart	UBERON:0002098	35.76	gold quality
hindlimb stylopod muscle	UBERON:0004252	35.66	gold quality
granulocyte	CL:0000094	35.50	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
testis	UBERON:0000473	35.48	silver quality
skeletal muscle tissue	UBERON:0001134	34.56	gold quality
left testis	UBERON:0004533	34.54	silver quality
leukocyte	CL:0000738	32.80	silver quality
monocyte	CL:0000576	32.75	silver quality
muscle tissue	UBERON:0002385	31.93	gold quality
bone marrow	UBERON:0002371	31.74	gold quality
primary visual cortex	UBERON:0002436	30.37	gold quality
liver	UBERON:0002107	29.88	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
prefrontal cortex	UBERON:0000451	29.85	gold quality
cortex of kidney	UBERON:0001225	28.82	gold quality
tonsil	UBERON:0002372	28.73	gold quality
uterine cervix	UBERON:0000002	28.28	gold quality
duodenum	UBERON:0002114	28.14	gold quality
kidney	UBERON:0002113	28.10	gold quality
islet of Langerhans	UBERON:0000006	27.94	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

58 targeting GPX6, 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-8485	100.00	77.57	4731
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514

Literature-anchored findings (GeneRIF, showing 1)

• Association between genetic variants in oxidative stress-related genes and osteoporotic bone fracture. The Hortega follow-up study. (PMID:34688818)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpx4a	ENSDARG00000068478
mus_musculus	Gpx6	ENSMUSG00000004341
rattus_norvegicus	Gpx6	ENSRNOG00000060749
caenorhabditis_elegans		WBGENE00007516
caenorhabditis_elegans		WBGENE00007517
caenorhabditis_elegans		WBGENE00011045
caenorhabditis_elegans	gpx-8	WBGENE00018850
caenorhabditis_elegans		WBGENE00022377

Paralogs (7): GPX7 (ENSG00000116157), GPX8 (ENSG00000164294), GPX4 (ENSG00000167468), GPX2 (ENSG00000176153), GPX3 (ENSG00000211445), GPX5 (ENSG00000224586), GPX1 (ENSG00000233276)

Protein

Protein identifiers

Glutathione peroxidase 6 — P59796 (reviewed: P59796)

All UniProt accessions (2): P59796, A0A182DWH6

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Secreted.

Tissue specificity. Expressed in olfactory epithelium and embryos.

Similarity. Belongs to the glutathione peroxidase family.

RefSeq proteins (1): NP_874360* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000889	Glutathione_peroxidase	Family
IPR029759	GPX_AS	Active_site
IPR029760	GPX_CS	Conserved_site
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF00255

Enzyme classification (BRENDA):

• EC 1.11.1.9 — glutathione peroxidase (BRENDA: 58 organisms, 96 substrates, 65 inhibitors, 63 Km, 23 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
H2O2	0.0023–19.08	19
GSH	0.033–11.1	18
CUMENE HYDROPEROXIDE	0.006–7.8	6
TERT-BUTYL HYDROPEROXIDE	0.059–7.9	6
GLUTATHIONE	0.022–1.73	4
CUMENE PEROXIDE	0.09–0.42	2
L-ALPHA-PHOSPHATIDYLCHOLINE HYDROPEROXIDE	0.026–9.7	2
LINOLENIC ACID HYDROPEROXIDE	0.007–3.8	2
CHOLESTEROL 5ALPHA-HYDROPEROXIDE	0.004	1
CHOLESTEROL 7ALPHA-HYDROPEROXIDE	0.011	1
CHOLESTEROL 7BETA-HYDROPEROXIDE	0.003	1
TERT-BUTYLHYDROPEROXIDE	0.024	1

Catalyzed reactions (Rhea), 1 shown:

• 2 glutathione + H2O2 = glutathione disulfide + 2 H2O (RHEA:16833)

UniProt features (14 total): sequence variant 10, signal peptide 1, chain 1, active site 1, non-standard amino acid 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for P59796 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Catalytic / active sites (1): 73

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3299685	Detoxification of Reactive Oxygen Species

MSigDB gene sets: 50 (showing top): GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM5, GOBP_DETOXIFICATION, GOMF_ANTIOXIDANT_ACTIVITY, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PEROXIDE_AS_ACCEPTOR, GOBP_RESPONSE_TO_TOXIC_SUBSTANCE, GOMF_GLUTATHIONE_PEROXIDASE_ACTIVITY, KEGG_GLUTATHIONE_METABOLISM, YOSHIMURA_MAPK8_TARGETS_UP, REACTOME_DETOXIFICATION_OF_REACTIVE_OXYGEN_SPECIES, ESC_J1_UP_EARLY.V1_UP, REACTOME_CELLULAR_RESPONSES_TO_STIMULI, GOBP_CELLULAR_RESPONSE_TO_CHEMICAL_STRESS, MIR8485, MIR4306

GO Biological Process (2): response to oxidative stress (GO:0006979), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (3): glutathione peroxidase activity (GO:0004602), peroxidase activity (GO:0004601), oxidoreductase activity (GO:0016491)

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to chemical stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stress	1
cellular detoxification	1
peroxidase activity	1
antioxidant activity	1
oxidoreductase activity, acting on peroxide as acceptor	1
catalytic activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3286 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPX6	GSR	P00390	967
GPX6	TXN	P10599	896
GPX6	XDH	P47989	884
GPX6	SOD2	P04179	851
GPX6	F5H3C5	F5H3C5	850
GPX6	GLRX	P35754	841
GPX6	HMOX1	P09601	838
GPX6	TXNRD1	Q16881	833
GPX6	SOD1	P00441	816
GPX6	H6PD	O95479	804
GPX6	G6PD	P11413	804
GPX6	GPT	P24298	802
GPX6	NFE2L2	Q16236	795
GPX6	TXNRD3	Q86VQ6	776
GPX6	MSRB1	Q9NZV6	771

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A1Q3EPF5, A0A2Z5VKM8, A0AAW1I778, A1KV41, B3EWI1, E3W9M2, G9JJU2, O16580, O18994, O75715, O77404, P06610, P07191, P07192, P0A0T4, P0A0T5, P0C2T0, P0CU34, P10901, P28714, P28843, P30710, P34760, P35666, P36014, P36973, P48822, P52033, P59796, P67877, P67878, P80602, Q04120, Q59WD3, Q5HKZ3, Q5N863, Q69TH4, Q69TI0, Q69TI2, Q6Y0Z3

Diamond homologs: A1KV41, G9JJU2, O02621, O04922, O18994, O22448, O22850, O23814, O23968, O23970, O24031, O24296, O32770, O46607, O48646, O49069, O59858, O62327, O70325, O75715, P00435, P04041, P06610, P07203, P0A0T4, P0A0T5, P0C2T0, P11352, P11909, P18283, P21765, P22352, P23764, P28714, P30708, P30710, P35666, P36014, P36968, P36969

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	28
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

511 predictions. Top by Δscore:

Variant	Effect	Δscore
6:28506310:A:AC	donor_gain	1.0000
6:28506311:C:CC	donor_gain	1.0000
6:28504512:A:C	acceptor_gain	0.9900
6:28504730:T:TA	donor_gain	0.9900
6:28504733:T:TA	donor_gain	0.9900
6:28504739:C:A	donor_gain	0.9900
6:28506313:TGAG:T	donor_gain	0.9900
6:28510762:G:C	donor_gain	0.9900
6:28510900:TCCAC:T	acceptor_gain	0.9900
6:28510901:CCACC:C	acceptor_gain	0.9900
6:28510903:ACCT:A	acceptor_loss	0.9900
6:28510904:CCTGG:C	acceptor_loss	0.9900
6:28510905:CTGG:C	acceptor_loss	0.9900
6:28510906:T:G	acceptor_loss	0.9900
6:28510913:T:C	acceptor_gain	0.9900
6:28510913:T:TC	acceptor_gain	0.9900
6:28504738:T:A	donor_gain	0.9800
6:28504748:T:A	donor_gain	0.9800
6:28506303:AGCAC:A	donor_loss	0.9800
6:28506304:GCAC:G	donor_loss	0.9800
6:28506305:CACTC:C	donor_loss	0.9800
6:28506306:ACTCA:A	donor_loss	0.9800
6:28506307:C:A	donor_loss	0.9800
6:28506308:TCA:T	donor_loss	0.9800
6:28506309:C:CT	donor_loss	0.9800
6:28506310:ACT:A	donor_loss	0.9800
6:28506311:C:CA	donor_loss	0.9800
6:28506425:CAGTT:C	acceptor_gain	0.9800
6:28506430:C:CC	acceptor_gain	0.9800
6:28510901:CCAC:C	acceptor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000073950 (6:28512026 G>A,C), RS1000085202 (6:28514457 C>G,T), RS1000297654 (6:28514200 A>G), RS1000594187 (6:28506052 T>C), RS1000870997 (6:28517681 G>T), RS1000902954 (6:28515375 CA>C), RS1000923380 (6:28517318 G>C,T), RS1001454997 (6:28513168 G>A), RS1001833703 (6:28503580 T>C), RS1001834318 (6:28513450 C>G,T), RS1001842070 (6:28512054 C>T), RS1001909788 (6:28503232 T>A,G), RS1002002624 (6:28505865 C>T), RS1002181228 (6:28503776 G>A,C), RS1002315613 (6:28512536 A>C)

Disease associations

OMIM: gene MIM:607913 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST002748_15	Epithelial ovarian cancer	6.000000e-06
GCST002748_20	Epithelial ovarian cancer	3.000000e-08
GCST003518_56	Daytime sleep phenotypes	2.000000e-07
GCST004521_112	Autism spectrum disorder or schizophrenia	3.000000e-26
GCST004521_166	Autism spectrum disorder or schizophrenia	4.000000e-24
GCST004521_212	Autism spectrum disorder or schizophrenia	5.000000e-14
GCST004521_43	Autism spectrum disorder or schizophrenia	2.000000e-27
GCST004521_7	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_73	Autism spectrum disorder or schizophrenia	8.000000e-11
GCST004521_77	Autism spectrum disorder or schizophrenia	1.000000e-19
GCST004750_42	Squamous cell lung carcinoma	2.000000e-10
GCST006575_10	Takayasu arteritis	5.000000e-06
GCST008921_4	Asthma and major depressive disorder	2.000000e-11
GCST010002_50	Refractive error	4.000000e-34
GCST010142_16	Fish- and plant-related diet	2.000000e-10
GCST010142_19	Fish- and plant-related diet	4.000000e-10
GCST010142_34	Fish- and plant-related diet	7.000000e-09
GCST010142_35	Fish- and plant-related diet	8.000000e-09
GCST010142_42	Fish- and plant-related diet	1.000000e-08
GCST010142_7	Fish- and plant-related diet	3.000000e-12
GCST010702_75	Subcortical volume (MOSTest)	3.000000e-11
GCST010703_272	Brain morphology (MOSTest)	7.000000e-16
GCST012226_450	Waist circumference adjusted for body mass index	2.000000e-08
GCST90020028_837	Hip circumference adjusted for BMI	3.000000e-08
GCST90020028_839	Hip circumference adjusted for BMI	2.000000e-12

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
lasiocarpine	decreases expression	1
bisphenol A	affects methylation, affects cotreatment, increases methylation	1
CGP 52608	affects binding, increases reaction	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Quercetin	increases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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