SOD3

Summary

SOD3 (superoxide dismutase 3, HGNC:11181) is a protein-coding gene on chromosome 4p15.2, encoding Extracellular superoxide dismutase [Cu-Zn] (P08294). Protect the extracellular space from toxic effect of reactive oxygen intermediates by converting superoxide radicals into hydrogen peroxide and oxygen.

This gene encodes a member of the superoxide dismutase (SOD) protein family. SODs are antioxidant enzymes that catalyze the conversion of superoxide radicals into hydrogen peroxide and oxygen, which may protect the brain, lungs, and other tissues from oxidative stress. Proteolytic processing of the encoded protein results in the formation of two distinct homotetramers that differ in their ability to interact with the extracellular matrix (ECM). Homotetramers consisting of the intact protein, or type C subunit, exhibit high affinity for heparin and are anchored to the ECM. Homotetramers consisting of a proteolytically cleaved form of the protein, or type A subunit, exhibit low affinity for heparin and do not interact with the ECM. A mutation in this gene may be associated with increased heart disease risk.

Source: NCBI Gene 6649 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 66 total
• Druggable target: yes
• MANE Select transcript: NM_003102

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11181
Approved symbol	SOD3
Name	superoxide dismutase 3
Location	4p15.2
Locus type	gene with protein product
Status	Approved
Aliases	EC-SOD
Ensembl gene	ENSG00000109610
Ensembl biotype	protein_coding
OMIM	185490
Entrez	6649

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 retained_intron

ENST00000382120, ENST00000593742, ENST00000598411, ENST00000880265, ENST00000952028, ENST00000952029, ENST00000952030, ENST00000952031

RefSeq mRNA: 1 — MANE Select: NM_003102 NM_003102

CCDS: CCDS3430

Canonical transcript exons

ENST00000382120 — 2 exons

Exon	Start	End
ENSE00001490975	24799506	24800842
ENSE00001490977	24795573	24795651

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 99.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.1218 / max 1098.1488, expressed in 997 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47112	27.3830	944
47111	4.8701	812
47113	3.8687	747

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
descending thoracic aorta	UBERON:0002345	99.63	gold quality
right uterine tube	UBERON:0001302	99.60	gold quality
thoracic aorta	UBERON:0001515	99.51	gold quality
ascending aorta	UBERON:0001496	99.50	gold quality
aorta	UBERON:0000947	99.32	gold quality
right coronary artery	UBERON:0001625	99.32	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.27	gold quality
popliteal artery	UBERON:0002250	99.26	gold quality
tibial artery	UBERON:0007610	99.26	gold quality
lower esophagus	UBERON:0013473	99.24	gold quality
left coronary artery	UBERON:0001626	99.21	gold quality
coronary artery	UBERON:0001621	99.09	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.09	gold quality
mucosa of stomach	UBERON:0001199	98.96	gold quality
endocervix	UBERON:0000458	98.27	gold quality
right lung	UBERON:0002167	98.18	gold quality
left lobe of thyroid gland	UBERON:0001120	98.16	gold quality
tibial nerve	UBERON:0001323	98.10	gold quality
right lobe of thyroid gland	UBERON:0001119	97.92	gold quality
right atrium auricular region	UBERON:0006631	97.75	gold quality
left uterine tube	UBERON:0001303	97.64	gold quality
metanephros cortex	UBERON:0010533	97.55	gold quality
body of uterus	UBERON:0009853	97.52	gold quality
ectocervix	UBERON:0012249	97.45	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.32	gold quality
thyroid gland	UBERON:0002046	97.21	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.15	gold quality
omental fat pad	UBERON:0010414	97.14	gold quality
peritoneum	UBERON:0002358	97.06	gold quality
upper lobe of left lung	UBERON:0008952	96.89	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-HCAD-11	yes	2238.89
E-HCAD-36	yes	1189.97
E-MTAB-5061	yes	209.66
E-MTAB-6701	yes	118.36
E-HCAD-1	yes	84.32
E-MTAB-10287	yes	71.05
E-MTAB-8410	yes	65.01
E-GEOD-135922	yes	61.22
E-GEOD-81547	yes	22.02
E-MTAB-10553	yes	18.83
E-MTAB-9543	yes	16.19
E-CURD-46	yes	15.20
E-GEOD-134144	yes	8.80
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, ELF1, SOX10, SP1, SP3

miRNA regulators (miRDB)

38 targeting SOD3, 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-4533	100.00	69.48	2758
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-4680-3P	98.64	68.60	2093
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-4518	98.12	66.82	1030
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-6769A-5P	97.99	64.16	851
HSA-MIR-1266-5P	97.71	66.92	1052
HSA-MIR-219B-3P	97.31	66.96	672
HSA-MIR-656-5P	96.82	67.67	372

Literature-anchored findings (GeneRIF, showing 40)

• Furin proteolytically processes the heparin-binding region of extracellular superoxide dismutase (PMID:11861638)
• prevents endothelial cell-mediated oxidative modification of LDL (PMID:12052468)
• EC-SOD has a role as an antioxidant gene product in human fibroblasts (PMID:12475988)
• In NIDDM serum EC-SOD concentration levels may be a marker of vascular injury, possibly reflecting hyperglycemia-induced oxidative injury to the vascular endothelium. (PMID:12663605)
• Higher frequencies of SOD2 allele Val and genotype Val/Val and of SOD3 allele Arg and genotype Arg/Arg were established for group DPN+. On this evidence, SOD2 and SOD3 were associated with DPN in DM type 1. (PMID:12815947)
• There is lower activity in diabetic compared with normal subjects. (PMID:12830380)
• EC-SOD may play an important protective role against increased oxidative stress during acute ischemic coronary events. (PMID:14592844)
• Chromosome mapping of SOD3 to chromosome band 4p15.3–>p15.1. (PMID:14619883)
• intracellular proteolytic processing of extracellular superoxide dismutase is a two-step event (PMID:15044467)
• Review. Blood vessels express 3 isoforms of superoxide dismutase SOD, 1 of which is an extracellular form of CuZn-SOD. This review will focus mainly on the role of individual SODs in relation to endothelium under normal conditions and in disease states. (PMID:15166009)
• EcSOD-fibulin-5 interaction is needed for ecSOD binding to vascular tissues, regulating their O2*- levels. This is a new mechanism for controlling vascular redox state in the extracellular space in cardiovascular diseases with high oxidative stress. (PMID:15528465)
• Atox1 functions not only as a copper chaperone for SOD3 but also as a positive regulator for SOD3 transcription and may have an important role in modulating oxidative stress in the cardiovascular system. (PMID:15761197)
• EC-SOD gene mutations were screened in a sample of southern Italian population. (PMID:15899505)
• A common gene variant in the heparin-binding domain of ecSOD, which is a risk factor for ischemic heart disease, may be a risk factor for vascular maladaptation and endothelial dysfunction in heart failure. (PMID:16014615)
• Transgenic hEC-SOD ameliorated the 95% O2-impaired bromodeoxyuridine uptake in alveolar and bronchiolar epithelium at P3, but not at P5 and P7, when overall epithelial proliferation rates were lower in air-exposed wild-type mice. (PMID:16100289)
• Extracellular superoxide dismutase R213G heterozygosity protects against development of COPD in the Danish general population. (PMID:16399992)
• EC-SOD with high affinity for heparin-Sepharose formed not only a tetramer but also an octamer composed of both aEC-SOD and iEC-SOD folding variants (PMID:16469315)
• The roles these SOD isoforms, especially SOD3, play in both normal nasal mucosa and NP require further clarification. (PMID:16540901)
• EC-SOD expression in aged transgenic mice impaired contextual learning, but the impairment was decreased in the aged transgenic mice. (PMID:16611809)
• Is endocytosed into endothelial cells through clathrin-mediated pathway, but does not translocate to the nucleus. Impairment of endocytosis may contribute to high plasma levels of EC-SOD(R213G) in R213G carriers. (PMID:16809550)
• consistent with several other antioxidant enzymes, ECSOD is very low in fibrotic areas of idiopathic pulmonary fibrosis/usual interstitial pneumonia, which may further increase the oxidant burden in this disease (PMID:16842247)
• the decrease of antioxidant defense strategies play a primary role by compromising NO availability in normally aged individuals, particularly through a progressive decrease of EC-SOD activity (PMID:16899934)
• Reduction in extracellular superoxide dismutase activity is associated with hypertension (PMID:17023265)
• we present the crystal structure of fully cysteine-depleted human SOD (SOD(CallA)), representing a reduced, marginally stable intermediate on the folding pathway in vivo that has also been implicated as neurotoxic precursor state. (PMID:17070542)
• No significant association with prostate cancer was observed for polymorphic variants in SOD3. (PMID:17646272)
• Cultured keratoconus stromal cells respond with a reduced SOD3 synthesis to interleukin-1alpha, which is not the case in corresponding normal or bullous keratopathy cells. (PMID:17679946)
• Common human gene variant of ECSOD fails to protect against endothelial dysfunction produced by an inflammatory stimulus. (PMID:17717013)
• Variation in enzymatic potency of 3 dimers of EC-SOD can regulate antioxidant level in the extracellular space and represents a novel way of modulating enzymatic activity. (PMID:17937792)
• inhibition of oxidative hyaluronan fragmentation probably represents one mechanism by which EC-SOD inhibits inflammation in response to lung injury. (PMID:18165226)
• Sp1 and Sp3 plays role in regulating the expression of human EC-SOD in the lung. (PMID:18314536)
• generation of the EC-SOD folding variants is an intracellular event that depends on a free cysteine residue not involved in disulfide bonding. (PMID:18385137)
• chronic hypoxia decreased lung EC-SOD activity and protein expression in wild-type mice, but EC-SOD activity remained five to seven times higher in EC-SOD TG mice under hypoxic conditions (PMID:18599502)
• common variants in the SOD2, SOD3, and CAT genes may influence brain tumor risk. (PMID:18682580)
• two novel polymorphisms in a conserved region of the SOD3 gene are associated with lung function or chronic obstructive pulmonary disease (PMID:18703790)
• Based on the results of our haplotype-based case-control study, the T-A haplotype may be a genetic marker for essential hypertension, and thus the EC-SOD gene might be a susceptibility gene for it (PMID:18971527)
• Carriers of the Ala40Thr single nucleotide polymorphism showed an increased risk for severe fetal growth restriction-complicated pre-eclampsia. (PMID:19108943)
• The C-C-C haplotypes could be genetic markers for cerebral infarction, and the EC-SOD gene may be a susceptibility gene for CI in women. (PMID:19200140)
• The Arg213Gly snp in SOD3 has a protective effect on the FEV in never-smokers. The G(-4466)T(rs8192288) SOD3 snp is associated with the level of vital capacity in the general population. (PMID:19213780)
• crystal structure of human SOD3 at 1.7 A resolution; binding sites (PMID:19289127)
• Human SOD3 genetic variants are associated with lower lung function in children (PMID:19318538)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sod3a	ENSDARG00000070168
danio_rerio	sod3b	ENSDARG00000079183
mus_musculus	Sod3	ENSMUSG00000072941
rattus_norvegicus	Sod3	ENSRNOG00000003869

Paralogs (2): SOD1 (ENSG00000142168), CCS (ENSG00000173992)

Protein

Protein identifiers

Extracellular superoxide dismutase [Cu-Zn] — P08294 (reviewed: P08294)

All UniProt accessions (3): P08294, A0A140VJU8, M0R1V4

UniProt curated annotations — full annotation on UniProt →

Function. Protect the extracellular space from toxic effect of reactive oxygen intermediates by converting superoxide radicals into hydrogen peroxide and oxygen.

Subunit / interactions. Homotetramer. Directly interacts with ATP7A; this interaction is copper-dependent and is required for SOD3 activity.

Subcellular location. Secreted. Extracellular space. Golgi apparatus. trans-Golgi network.

Tissue specificity. Expressed in blood vessels, heart, lung, kidney and placenta. Major SOD isoenzyme in extracellular fluids such as plasma, lymph and synovial fluid.

Cofactor. Binds 1 copper ion per subunit. Binds 1 zinc ion per subunit.

Polymorphism. The variant Gly-231 which is found in about 2.2% of individual displays a 10-fold increased plasma EC-SOD content due to reduced heparin-binding affinity and thus the impairment of its binding ability to endothelial cell surface.

Similarity. Belongs to the Cu-Zn superoxide dismutase family.

RefSeq proteins (1): NP_003093* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001424	SOD_Cu_Zn_dom	Domain
IPR018152	SOD_Cu/Zn_BS	Binding_site
IPR024134	SOD_Cu/Zn_/chaperone	Family
IPR036423	SOD-like_Cu/Zn_dom_sf	Homologous_superfamily

Pfam: PF00080

Enzyme classification (BRENDA):

• EC 1.15.1.1 — superoxide dismutase (BRENDA: 258 organisms, 98 substrates, 359 inhibitors, 19 Km, 7 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NITRO BLUE TETRAZOLIUM	0.025–15	2
RIBOFLAVIN	0.0016–2.3	2
SUPEROXIDE	0.0115–0.046	2
O2-	0.355	1
O2.-	—	0

Catalyzed reactions (Rhea), 1 shown:

• 2 superoxide + 2 H(+) = H2O2 + O2 (RHEA:20696)

UniProt features (34 total): strand 10, binding site 8, site 3, glycosylation site 3, sequence variant 3, helix 3, disulfide bond 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2JLP	X-RAY DIFFRACTION	1.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08294-F1	88.56	0.75

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 (3): 41 (not glycated); 92 (not glycated); 238 (not glycated)

Ligand- & substrate-binding residues (8): 114; 116; 131; 131; 139; 142; 145; 181

Disulfide bonds (2): 63–208, 125–207

Glycosylation sites (3): 107, 229, 230

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-3299685	Detoxification of Reactive Oxygen Species
R-HSA-9818027	NFE2L2 regulating anti-oxidant/detoxification enzymes
R-HSA-2262752	Cellular responses to stress
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711123	Cellular response to chemical stress
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-9759194	Nuclear events mediated by NFE2L2

MSigDB gene sets: 184 (showing top): CHIBA_RESPONSE_TO_TSA_UP, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_DN, GOBP_SUPEROXIDE_METABOLIC_PROCESS, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, TGACCTY_ERR1_Q2, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, MODULE_66, MARTINEZ_RB1_TARGETS_UP, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, PAPASPYRIDONOS_UNSTABLE_ATEROSCLEROTIC_PLAQUE_DN, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE

GO Biological Process (4): response to hypoxia (GO:0001666), removal of superoxide radicals (GO:0019430), superoxide metabolic process (GO:0006801), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (8): superoxide dismutase activity (GO:0004784), copper ion binding (GO:0005507), heparin binding (GO:0008201), molecular adaptor activity (GO:0060090), protein binding (GO:0005515), antioxidant activity (GO:0016209), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), Golgi lumen (GO:0005796), extracellular exosome (GO:0070062), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Cellular response to chemical stress	2
Nuclear events mediated by NFE2L2	1
Cellular responses to stimuli	1
Cellular responses to stress	1
KEAP1-NFE2L2 pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular oxidant detoxification	2
molecular_function	2
binding	2
response to stress	1
response to decreased oxygen levels	1
superoxide metabolic process	1
cellular response to superoxide	1
reactive oxygen species metabolic process	1
cellular detoxification	1
antioxidant activity	1
oxidoreductase activity, acting on superoxide radicals as acceptor	1
removal of superoxide radicals	1
transition metal ion binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
catalytic activity	1
cation binding	1
cellular anatomical structure	1
Golgi apparatus	1
intracellular organelle lumen	1
extracellular vesicle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2932 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOD3	GPX3	P22352	653
SOD3	GPX7	Q96SL4	650
SOD3	GPX8	Q8TED1	649
SOD3	ATOX1	O00244	646
SOD3	SOD2	P04179	640
SOD3	GPX2	P18283	636
SOD3	F5H3C5	F5H3C5	629
SOD3	GPX5	O75715	627
SOD3	GPX6	P59796	626
SOD3	FAM13A	O94988	597
SOD3	TXN	P10599	596
SOD3	GSR	P00390	589
SOD3	NOX4	Q9NPH5	568
SOD3	CYBB	P04839	566
SOD3	HMOX1	P09601	550
SOD3	GSTM1	P09488	550

IntAct

31 interactions, top by confidence:

A	B	Type	Score
SOD3	SGTA	psi-mi:“MI:0915”(physical association)	0.560
SGTA	SOD3	psi-mi:“MI:0915”(physical association)	0.560
SOD3		psi-mi:“MI:0915”(physical association)	0.560
SOD3	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
SOD3	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
SOD3	KCNIP3	psi-mi:“MI:0915”(physical association)	0.560
SOD3	SGTB	psi-mi:“MI:0915”(physical association)	0.560
SOD3	KCNIP1	psi-mi:“MI:0915”(physical association)	0.560
SOD3	ASPH	psi-mi:“MI:0915”(physical association)	0.560
	SOD3	psi-mi:“MI:0915”(physical association)	0.560
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
ECSIT	NDUFA2	psi-mi:“MI:0914”(association)	0.350
SOD3	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
SOD3	UBQLN1	psi-mi:“MI:0915”(physical association)	0.000
SOD3	KCNIP3	psi-mi:“MI:0915”(physical association)	0.000
SOD3	KCNIP1	psi-mi:“MI:0915”(physical association)	0.000
SOD3	SGTB	psi-mi:“MI:0915”(physical association)	0.000
ASPH	SOD3	psi-mi:“MI:0915”(physical association)	0.000
KCNIP3	SOD3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): SOD3 (Two-hybrid), SOD3 (Affinity Capture-MS), KCNIP3 (Two-hybrid), UBQLN1 (Two-hybrid), CASC4 (Two-hybrid), KCNIP1 (Two-hybrid), UBQLN2 (Two-hybrid), SGTB (Two-hybrid), ASPH (Two-hybrid), SOD3 (Affinity Capture-MS), SOD3 (Affinity Capture-Western)

ESM2 similar proteins: B1AUH1, B3LV44, B3P7F8, B4G2I8, B4HFB7, B4JTF5, B4K4M0, B4LZT9, B4NJP3, B4PN49, B4R1D8, D3YWQ0, F1MAB7, F8W3R9, G3V9H8, O09164, O43278, O97827, P07949, P08294, P09758, P10731, P14925, P19021, P30432, P35546, P41975, P56674, P97467, Q02936, Q08420, Q0P4P2, Q29AA9, Q5XIL0, Q5ZEQ8, Q7QIQ6, Q80TS3, Q86B61, Q8IUK5, Q8K1S3

Diamond homologs: A2QMY6, A2XGP6, B6QEB3, C0HK70, H6BDU4, J9VLJ9, O04996, O04997, O09164, O22373, O42724, O46412, O49044, O49073, O59924, O65174, O65175, O65198, O65199, O65768, O73872, O78310, O94178, P00441, P00442, P00443, P00445, P03946, P04178, P07505, P07509, P07632, P08228, P08294, P09212, P09670, P09678, P10791, P10792, P11418

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
SOD3	“down-regulates quantity”	superoxide	“chemical modification”
SOD3	“up-regulates quantity”	dioxygen	“chemical modification”
SOD3	“up-regulates quantity”	“hydrogen peroxide”	“chemical modification”
superoxide	“up-regulates activity”	SOD3	“precursor of”
ATP7A	“up-regulates activity”	SOD3
copper(1+)	“up-regulates activity”	SOD3	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	5
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

484 predictions. Top by Δscore:

Variant	Effect	Δscore
4:24795648:AAAG:A	donor_loss	0.9900
4:24795649:AAG:A	donor_loss	0.9900
4:24795650:AGG:A	donor_loss	0.9900
4:24795653:T:G	donor_loss	0.9900
4:24795655:GGTGC:G	donor_gain	0.9900
4:24796352:GCT:G	donor_gain	0.9900
4:24796365:G:GT	donor_gain	0.9800
4:24799490:C:CA	acceptor_gain	0.9800
4:24799491:G:A	acceptor_gain	0.9800
4:24795656:GTGC:G	donor_gain	0.9700
4:24795657:TGCT:T	donor_gain	0.9700
4:24795622:A:T	donor_gain	0.9600
4:24795659:C:G	donor_gain	0.9600
4:24796344:TGTCA:T	donor_gain	0.9600
4:24796391:G:GT	donor_gain	0.9600
4:24799055:G:GT	donor_gain	0.9500
4:24799503:CAG:C	acceptor_loss	0.9400
4:24799504:AGGTG:A	acceptor_loss	0.9400
4:24795650:AGGTG:A	donor_gain	0.9300
4:24799039:G:GT	donor_gain	0.9300
4:24799089:C:T	donor_gain	0.9300
4:24799394:G:GT	donor_gain	0.9300
4:24799484:C:G	acceptor_gain	0.9300
4:24799488:C:CA	acceptor_gain	0.9300
4:24795652:G:GG	donor_gain	0.9200
4:24799483:A:AG	acceptor_gain	0.9200
4:24795648:A:T	donor_gain	0.9100
4:24795664:T:G	donor_gain	0.9100
4:24797745:T:A	acceptor_gain	0.9100
4:24795658:GCTA:G	donor_gain	0.9000

AlphaMissense

1544 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:24799772:T:C	F84S	0.993
4:24800117:G:T	G199V	0.990
4:24800075:A:T	D185V	0.985
4:24800060:T:A	V180D	0.984
4:24800074:G:C	D185H	0.983
4:24800175:G:C	W218C	0.983
4:24800175:G:T	W218C	0.983
4:24799766:T:A	V82D	0.982
4:24800117:G:A	G199E	0.982
4:24799826:T:C	F102S	0.981
4:24799859:T:C	I113T	0.981
4:24800039:T:A	I173N	0.981
4:24800075:A:C	D185A	0.981
4:24800076:C:A	D185E	0.981
4:24800076:C:G	D185E	0.981
4:24800116:G:T	G199W	0.981
4:24799859:T:A	I113N	0.980
4:24799936:C:G	H139D	0.980
4:24799826:T:G	F102C	0.979
4:24800144:G:A	C208Y	0.978
4:24799867:C:G	H116D	0.977
4:24799709:G:A	C63Y	0.976
4:24799772:T:G	F84C	0.976
4:24799965:C:A	N148K	0.976
4:24799965:C:G	N148K	0.976
4:24800145:C:G	C208W	0.976
4:24799760:G:T	G80V	0.973
4:24799938:C:A	H139Q	0.973
4:24799938:C:G	H139Q	0.973
4:24800104:A:C	S195R	0.973

dbSNP variants (sampled 300 via entrez): RS1001239092 (4:24799068 C>A,T), RS1001999409 (4:24800483 T>C), RS1002154904 (4:24795394 A>C), RS1002493412 (4:24794265 C>A,T), RS1002516516 (4:24794814 G>A), RS1002670249 (4:24797731 C>G), RS1003677058 (4:24799245 G>A,C), RS1003817666 (4:24799926 G>A), RS1003991587 (4:24793742 A>C), RS1004308869 (4:24793802 A>T), RS1004400623 (4:24794145 G>A,C), RS1004658251 (4:24799262 G>C), RS1005193695 (4:24796392 G>T), RS1005492673 (4:24798410 C>T), RS1006299977 (4:24798151 A>G)

Disease associations

OMIM: gene MIM:185490 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001850_21	Major depressive disorder	7.000000e-06
GCST006585_1632	Blood protein levels	1.000000e-64
GCST006585_2167	Blood protein levels	1.000000e-55

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2069159 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1799895	SOD3		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, increases expression, decreases expression, decreases reaction	5
Estradiol	decreases expression, decreases reaction, affects cotreatment	3
bisphenol A	decreases expression, decreases methylation	2
Air Pollutants	increases abundance, increases expression, affects cotreatment	2
Cisplatin	increases expression, affects response to substance	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Particulate Matter	increases abundance, increases expression, increases response to substance	2
aristolochic acid I	increases expression	1
4-(E)-((p-tolylimino)-methylbenzene-1,2-diol)	increases expression	1
decabromobiphenyl ether	increases expression	1
arsenite	increases methylation	1
sodium arsenite	increases expression	1
cinnamyl alcohol	increases expression	1
ochratoxin A	increases expression	1
acipimox	increases expression	1
nickel sulfate	increases expression	1
puerarin	decreases expression	1
isoeugenol	increases expression	1
epigallocatechin gallate	decreases expression	1
brequinar	increases expression	1
Bandrowski’s base	increases expression	1
tamibarotene	decreases expression	1
hexyl cinnamic aldehyde	increases expression	1
paricalcitol	increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
GW 4064	decreases reaction, increases phosphorylation, affects binding, increases reaction, increases expression	1
GW 501516	decreases expression, decreases reaction	1
pomiferin	decreases expression	1
osajin	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2073218	Binding	Inhibition of human erythrocyte Cu-Zn SOD by NBT reduction assay	In vitro and in vivo trypanosomicidal activity of pyrazole-containing macrocyclic and macrobicyclic polyamines: their action on acute and chronic phases of Chagas disease. — J Med Chem

Clinical trials (associated diseases)

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