SOD2

Summary

SOD2 (superoxide dismutase 2, HGNC:11180) is a protein-coding gene on chromosome 6q25.3, encoding Superoxide dismutase [Mn], mitochondrial (P04179). Destroys superoxide anion radicals which are normally produced within the cells and which are toxic to biological systems. It is a selective cancer dependency (DepMap: 76.5% of cell lines).

This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 1.

Source: NCBI Gene 6648 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiomyopathy (Limited, GenCC) — +2 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 81 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 76.5% of screened cell lines
• MANE Select transcript: NM_000636

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11180
Approved symbol	SOD2
Name	superoxide dismutase 2
Location	6q25.3
Locus type	gene with protein product
Status	Approved
Aliases	GC1, IPOB, MnSOD, GClnc1, lncRNA-GC1
Ensembl gene	ENSG00000291237
Ensembl biotype	protein_coding
OMIM	147460
Entrez	6648

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 13 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000337404, ENST00000367054, ENST00000367055, ENST00000401980, ENST00000444946, ENST00000452684, ENST00000535459, ENST00000535561, ENST00000537657, ENST00000538183, ENST00000540491, ENST00000541573, ENST00000545162, ENST00000546087, ENST00000546260, ENST00000881541, ENST00000942970

RefSeq mRNA: 9 — MANE Select: NM_000636 NM_000636, NM_001024465, NM_001024466, NM_001322814, NM_001322815, NM_001322816, NM_001322817, NM_001322819, NM_001322820

CCDS: CCDS34564, CCDS5265, CCDS83141, CCDS83142, CCDS83143

Canonical transcript exons

ENST00000538183 — 5 exons

Exon	Start	End
ENSE00002235995	159693145	159693241
ENSE00003550043	159669069	159682638
ENSE00003677462	159692661	159692863
ENSE00003900962	159684854	159685033
ENSE00003901796	159688126	159688242

Expression profiles

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1136.6268 / max 36524.2596, expressed in 1827 samples.

FANTOM5 promoters (41 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76516	1050.5371	1822
76517	42.1766	1784
76513	7.4887	885
76532	7.2327	1785
76519	5.9185	1536
76474	3.4546	649
76531	3.2371	1244
76485	1.7625	444
76518	1.6122	476
76512	1.4033	431

Top tissues by expression

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, ATF1, BTG2, CEBPB, CEBPG, COQ7, CREB1, DDB2, DNMT1, EGR1, ELF4, EPAS1, FARP2, FOS, FOXC1, FOXL2, FOXM1, FOXO1, FOXO3, FOXO4, HIF1A, IRF6, JUN, KAT5, NFE2L2, NFKB1, NFKB, NFKBIA, NFKBIB, NKX2-1, PAX1, PPARA, PPARD, PPARG, PPARGC1A, REL, RELA, RELB, SIRT1

miRNA regulators (miRDB)

100 targeting SOD2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6739-5P	99.80	67.87	2806

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 76.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Review: Contribution of proteomics to the molecular analysis of renal cell carcinoma with an emphasis on manganese superoxide dismutase. (PMID:11721640)
• Cu,Zn-SOD and Mn-SOD are differently regulated by estrogen and progesterone in human endometrial stromal cells (PMID:11756571)
• Polymorphism in MnSOD is associated with age among hispanics with colorectal carcinoma (PMID:11836586)
• Increased expression of manganese superoxide dismutase is associated with that of nitrotyrosine in myopathies with rimmed vacuoles. (PMID:11837748)
• AP-2 down-regulates transcription of the human SOD2 gene via its interaction with Sp1 within the promoter region. (PMID:11853549)
• Transcription regulation of human manganese superoxide dismutase gene. (PMID:11912921)
• Catalytic pathway of manganese superoxide dismutase by direct observation of superoxide. (PMID:11912930)
• NF-kappaB-dependent MnSOD expression protects adenocarcinoma cells from TNF-alpha-induced apoptosis (PMID:12032830)
• Manganese superoxide dismutase transgenic mice: characteristics and implications (PMID:12078513)
• Nuclear factor-kappa B is required for tumor necrosis factor-alpha-induced manganese superoxide dismutase expression in human endometrial stromal cells. (PMID:12161520)
• PKB-regulated Forkhead transcription factor FOXO3a (also known as FKHR-L1) protects quiescent cells from oxidative stress by directly increasing their quantities of manganese superoxide dismutase (MnSOD) messenger RNA and protein (PMID:12239572)
• Val-Ala polymorphism in Mn-SOD influences neither susceptibility to alcohol-induced liver fibrosis nor alcohol-induced oxidative stress. (PMID:12447859)
• Manganese superoxide dismutase expression within tumor cells is closely related to mode of invasion in human gastric carcinoma (PMID:12469139)
• a new thiol-sensitive mutant form of the human mitochondrial enzyme (PMID:12517793)
• Gene transfer of this enzyme extends islet graft function in a mouse model of autoimmune diabetes. (PMID:12540612)
• This isoform, when expressed in PC-12 cells affects t-butylhydroperoxide-induced apoptosis differentially from its isoenzyme. (PMID:12551919)
• In prostate cancer cells, one of the downstream mediators of the senescence-associated tumor suppression effect of mac25/IGFBP-rP1 is SOD-2. (PMID:12592389)
• Replacement of His-30 with Val in human MnSOD results in a mutant with much decreased catalytic activity and highly susceptible to product inhibition compared to wild-type. (PMID:12627943)
• protein whose expression is deregulated in the epidermis of the elderly (PMID:12644569)
• It is indicated that polymorphic mutations of Mn-SOD exist in human normal cells and that the deletions might be obtained in the course of malignant transformation of OSC although decrease in Mn-SOD activity is not involved in the transformation. (PMID:12683635)
• data suggest communication between the proximal promoter region and the TNF-responsive element which involves chromatin remodeling and histone acetylation during the induction process of Mn-SOD in response to TNF. (PMID:12684509)
• MnSOD may be a tumor suppressor gene in human pancreatic cancer (PMID:12700280)
• 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)
• Overexpression of the human MnSOD transgene in 32D cl 3 cells results in stabilization of the mitochondria and reduction in radiation-, TNF-alpha-, or IL-3 withdrawal-induced damage. (PMID:12829021)
• no significant differences in the genotype, allele, and phenotype frequencies of MnSOD gene polymorphisms between patients with ankylosing spondylitis and controls (PMID:12880680)
• Elevated expression of MnSOD in neuronal ceroid lipofuscinosis. (PMID:12946273)
• the influence of a functional polymorphism of the dopamine D3 receptor, and its interaction with a Mn superoxide dismutase (MnSOD) polymorphism, in contributing to tardive dyskinesia in a chronic inpatient population with schizophrenia (PMID:12960753)
• No association of the Ala-9Val MnSOD polymorphism to the development of breast cancer (PMID:12963120)
• Results suggest that the failure of manganese-superoxide dismutase mRNA induction by oxidative stress in peripheral lymphocytes may be involved in the development of gastric cancer. (PMID:14503839)
• Regulation of MnSOD by IL-1 in retinoic acid-differentiated neuroblastoma cells was mediated by the nuclear factor kappaB. (PMID:14515147)
• Cu/Zn-SOD in cytosol and Mn-SOD in mitochondria each are capable of protecting HepG2 cells expressing CYP2E1 against cytotoxicity induced by pro-oxidants. (PMID:14578853)
• The role of manganese superoxide dismutase (Mn SOD) genes polymorphisms in the pathogenesis of systemic lupus erythematosus (SLE). (PMID:14611903)
• His30 and Tyr166 in wild-type Mn-SOD have roles in prolonging the lifetime of the inhibited complex (PMID:14638684)
• CYP1A1 4887A may be a risk factor for the development of reactive arthritis, especially in the presence of Mn SOD 1183T/T (PMID:14687717)
• an active site mutant of human manganese-superoxide dismutase has anti-proliferative functions and demonstrates the signaling role of MnSOD (PMID:14688256)
• Increase in hydroxyl radical concentration in the extracellular space of muscles from wild-type mice after the contraction protocol most likely results from degradation of hydrogen peroxide generated by MnSOD activity. (PMID:15075214)
• human SOD2 gene is induced by nucleophosmin and NF-kappaB (PMID:15087454)
• functional polymorphisms in MTP and MnSOD may be involved in determining susceptibility of non-alcoholic steatohepatitis (PMID:15094225)
• Review. Blood vessels express 3 isoforms of superoxide dismutase, 1 of which is manganese SOD in mitochondria. This review will focus mainly on the role of individual SODs in relation to endothelium under normal conditions and in disease states. (PMID:15166009)
• Neoplastic cells in breast carcinomas retain their capability to produce MNSOD, thus are protected from possible cellular damage by reactive oxygen species. MNSOD content varies according to the degree of differentiation of breast carcinoma. (PMID:15168344)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sod2	ENSDARG00000042644
mus_musculus	Sod2	ENSMUSG00000006818
rattus_norvegicus	Sod2	ENSRNOG00000086727
drosophila_melanogaster	Sod2	FBGN0010213
caenorhabditis_elegans	sod-2	WBGENE00004931
caenorhabditis_elegans		WBGENE00004932

Protein

Protein identifiers

Superoxide dismutase [Mn], mitochondrial — P04179 (reviewed: P04179)

All UniProt accessions (8): P04179, A0A384NL29, F5GXZ9, F5GYZ5, F5H3C5, F5H4R2, G5E9P6, G8JLJ2

UniProt curated annotations — full annotation on UniProt →

Function. Destroys superoxide anion radicals which are normally produced within the cells and which are toxic to biological systems.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. Nitrated under oxidative stress. Nitration coupled with oxidation inhibits the catalytic activity. Acetylation at Lys-122 decreases enzymatic activity. Deacetylated by SIRT3 upon exposure to ionizing radiations or after long fasting. Polyubiquitinated; leading to proteasomal degradation. Deubiquitinated by USP36 which increases protein stability.

Disease relevance. Microvascular complications of diabetes 6 (MVCD6) [MIM:612634] Pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. Disease susceptibility is associated with variants affecting the gene represented in this entry.

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

Induction. Expression is regulated by KRIT1.

Similarity. Belongs to the iron/manganese superoxide dismutase family.

Isoforms (4)

UniProt ID	Names	Canonical?
P04179-1	1	yes
P04179-2	2
P04179-3	3
P04179-4	4

RefSeq proteins (9): NP_000627, NP_001019636, NP_001019637, NP_001309743, NP_001309744, NP_001309745, NP_001309746, NP_001309748, NP_001309749 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001189	Mn/Fe_SOD	Family
IPR019831	Mn/Fe_SOD_N	Domain
IPR019832	Mn/Fe_SOD_C	Domain
IPR019833	Mn/Fe_SOD_BS	Binding_site
IPR036314	SOD_C_sf	Homologous_superfamily
IPR036324	Mn/Fe_SOD_N_sf	Homologous_superfamily
IPR050265	Fe/Mn_Superoxide_Dismutase	Family

Pfam: PF00081, PF02777

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 (53 total): helix 12, modified residue 11, sequence conflict 8, sequence variant 6, binding site 4, splice variant 3, strand 3, mutagenesis site 2, turn 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

48 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9NSJ	X-RAY DIFFRACTION	1.33
9BWQ	X-RAY DIFFRACTION	1.4
1PL4	X-RAY DIFFRACTION	1.47
2P4K	X-RAY DIFFRACTION	1.48
9BWR	X-RAY DIFFRACTION	1.5
1XIL	X-RAY DIFFRACTION	1.53
9NR0	X-RAY DIFFRACTION	1.55
8VJ4	X-RAY DIFFRACTION	1.68
1PM9	X-RAY DIFFRACTION	1.7
8VJ8	X-RAY DIFFRACTION	1.7
8VJ5	X-RAY DIFFRACTION	1.76
5T30	X-RAY DIFFRACTION	1.77
1N0N	X-RAY DIFFRACTION	1.82
5VF9	X-RAY DIFFRACTION	1.82
1LUV	X-RAY DIFFRACTION	1.85
1XDC	X-RAY DIFFRACTION	1.85
1ZTE	X-RAY DIFFRACTION	1.85
1AP6	X-RAY DIFFRACTION	1.9
1ZSP	X-RAY DIFFRACTION	1.9
1SZX	X-RAY DIFFRACTION	1.95
1ZUQ	X-RAY DIFFRACTION	2
7KKU	X-RAY DIFFRACTION	2.02
1JA8	X-RAY DIFFRACTION	2.12
1EM1	X-RAY DIFFRACTION	2.13
7KLB	X-RAY DIFFRACTION	2.16
1AP5	X-RAY DIFFRACTION	2.2
1N0J	X-RAY DIFFRACTION	2.2
2QKA	X-RAY DIFFRACTION	2.2
3C3T	X-RAY DIFFRACTION	2.2
7KKS	NEUTRON DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04179-F1	93.55	0.89

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): 50; 98; 183; 187

Post-translational modifications (11): 75, 114, 122, 122, 130, 130, 202, 58, 68, 68, 75

Mutagenesis-validated functional residues (2):

Position	Phenotype
58	reduced enzyme activity.
58	loss of nitration. enhanced dityrosine formation on peroxynitrite treatment.

Function

Pathways and Gene Ontology

Reactome pathways

24 pathways

ID	Pathway
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-3299685	Detoxification of Reactive Oxygen Species
R-HSA-8862803	Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models
R-HSA-8950505	Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-9841251	Mitochondrial unfolded protein response (UPRmt)
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-1643685	Disease
R-HSA-168256	Immune System
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-447115	Interleukin-12 family signaling
R-HSA-449147	Signaling by Interleukins
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8863678	Neurodegenerative Diseases
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9020591	Interleukin-12 signaling
R-HSA-9614085	FOXO-mediated transcription
R-HSA-9645723	Diseases of programmed cell death
R-HSA-9711123	Cellular response to chemical stress
R-HSA-9734009	Defective Intrinsic Pathway for Apoptosis

MSigDB gene sets: 631 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, BROWNE_HCMV_INFECTION_4HR_UP, GOBP_RESPONSE_TO_ETHANOL, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_ZINC_ION, GOBP_BEHAVIOR, MCLACHLAN_DENTAL_CARIES_UP, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, XU_HGF_TARGETS_REPRESSED_BY_AKT1_UP, GOBP_CIRCULATORY_SYSTEM_PROCESS

GO Biological Process (66): response to superoxide (GO:0000303), response to hypoxia (GO:0001666), release of cytochrome c from mitochondria (GO:0001836), liver development (GO:0001889), detection of oxygen (GO:0003032), acetylcholine-mediated vasodilation involved in regulation of systemic arterial blood pressure (GO:0003069), regulation of transcription by RNA polymerase II (GO:0006357), glutathione metabolic process (GO:0006749), superoxide metabolic process (GO:0006801), heart development (GO:0007507), locomotory behavior (GO:0007626), regulation of blood pressure (GO:0008217), negative regulation of cell population proliferation (GO:0008285), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), intrinsic apoptotic signaling pathway in response to oxidative stress (GO:0008631), response to xenobiotic stimulus (GO:0009410), post-embryonic development (GO:0009791), response to manganese ion (GO:0010042), response to zinc ion (GO:0010043), response to selenium ion (GO:0010269), response to gamma radiation (GO:0010332), positive regulation of hydrogen peroxide biosynthetic process (GO:0010729), response to activity (GO:0014823), removal of superoxide radicals (GO:0019430), respiratory electron transport chain (GO:0022904), hemopoiesis (GO:0030097), positive regulation of cell migration (GO:0030335), intracellular oxygen homeostasis (GO:0032364), response to lipopolysaccharide (GO:0032496), response to L-ascorbic acid (GO:0033591), response to silicon dioxide (GO:0034021), cellular response to oxidative stress (GO:0034599), response to isolation stress (GO:0035900), response to immobilization stress (GO:0035902), response to hydrogen peroxide (GO:0042542), superoxide anion generation (GO:0042554), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of nitric oxide biosynthetic process (GO:0045429), negative regulation of fat cell differentiation (GO:0045599), response to cadmium ion (GO:0046686)

GO Molecular Function (9): DNA binding (GO:0003677), superoxide dismutase activity (GO:0004784), oxygen binding (GO:0019825), enzyme binding (GO:0019899), manganese ion binding (GO:0030145), identical protein binding (GO:0042802), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), mitochondrial nucleoid (GO:0042645), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Mitochondrial biogenesis	1
Cellular response to chemical stress	1
Neurodegenerative Diseases	1
Interleukin-12 signaling	1
FOXO-mediated transcription	1
Cellular responses to stress	1
Immune System	1
Organelle biogenesis and maintenance	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Signaling by Interleukins	1
Cytokine Signaling in Immune system	1
Gene expression (Transcription)	1
Defective Intrinsic Pathway for Apoptosis	1
Interleukin-12 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intrinsic apoptotic signaling pathway	2
response to chemical	2
response to metal ion	2
protein binding	2
mitochondrion	2
response to oxygen radical	1
response to stress	1
response to decreased oxygen levels	1
apoptotic mitochondrial changes	1
apoptotic signaling pathway	1
gland development	1
hepaticobiliary system development	1
detection of chemical stimulus	1
response to oxygen levels	1
regulation of systemic arterial blood pressure by acetylcholine	1
negative regulation of systemic arterial blood pressure	1
vasodilation	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
modified amino acid metabolic process	1
sulfur compound metabolic process	1
reactive oxygen species metabolic process	1
animal organ development	1
circulatory system development	1
behavior	1
blood circulation	1
regulation of biological quality	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
DNA damage response	1
multicellular organism development	1
multicellular organismal process	1
nucleic acid binding	1
antioxidant activity	1
oxidoreductase activity, acting on superoxide radicals as acceptor	1
removal of superoxide radicals	1
small molecule binding	1
transition metal ion binding	1
binding	1

Protein interactions and networks

STRING

6387 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOD2	WDR5	P61964	988
SOD2	KAT2A	Q92830	987
SOD2	ACO2	Q99798	876
SOD2	ACO1	P21399	868
SOD2	FOXO3	O43524	867
SOD2	GPX7	Q96SL4	858
SOD2	GPX8	Q8TED1	858
SOD2	GPX3	P22352	854
SOD2	GPX2	P18283	854
SOD2	GPX6	P59796	851
SOD2	GPX5	O75715	851
SOD2	SIRT3	Q9NTG7	823
SOD2	SOD1	P00441	821
SOD2	GSR	P00390	800
SOD2	TFAM	Q00059	796

IntAct

77 interactions, top by confidence:

A	B	Type	Score
CNOT3	CNOT1	psi-mi:“MI:0914”(association)	0.740
SOD2	SOD2	psi-mi:“MI:0915”(physical association)	0.570
SOD2	TAE1	psi-mi:“MI:0915”(physical association)	0.560
TAE1	SOD2	psi-mi:“MI:0915”(physical association)	0.560
SOD2	CEP70	psi-mi:“MI:0915”(physical association)	0.560
SOD2	UBR2	psi-mi:“MI:0915”(physical association)	0.400
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
NLRP12	SOD2	psi-mi:“MI:0915”(physical association)	0.370
CYP4F12	SOD2	psi-mi:“MI:0915”(physical association)	0.370
STK4	SOD2	psi-mi:“MI:0915”(physical association)	0.370
NIT1	PMPCB	psi-mi:“MI:0914”(association)	0.350
PPM1K	PMPCB	psi-mi:“MI:0914”(association)	0.350
SPRYD4	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
TRIM24	DDTL	psi-mi:“MI:0914”(association)	0.350
H2AX	ANXA6	psi-mi:“MI:0914”(association)	0.350
MAP3K7	ACOT7	psi-mi:“MI:0914”(association)	0.350
NOXO1	SOD1	psi-mi:“MI:0914”(association)	0.350
VCP	FAM171A2	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350
TGFBRAP1	CCDC85C	psi-mi:“MI:0914”(association)	0.350
BRAF	SOD2	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	SOD2	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	SOD2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (116): UBR2 (Affinity Capture-MS), ABAT (Co-fractionation), ACO2 (Co-fractionation), ALDH1B1 (Co-fractionation), ALDH2 (Co-fractionation), ALDH4A1 (Co-fractionation), CAT (Co-fractionation), ENO3 (Co-fractionation), FH (Co-fractionation), GPX4 (Co-fractionation), HSPE1 (Co-fractionation), MDH1 (Co-fractionation), PEBP1 (Co-fractionation), PEPD (Co-fractionation), PRDX5 (Co-fractionation)

ESM2 similar proteins: A0R652, O51917, O86165, O93724, P04179, P09738, P0A4J1, P0A4J2, P0C0I0, P0C0I1, P0DF72, P0DF73, P11796, P13367, P19665, P28767, P41976, P41982, P42821, P46728, P47201, P50912, P50913, P53643, P53644, P53645, P53646, P53647, P53648, P53649, P53650, P53651, P53655, P80293, P9WGE6, P9WGE7, Q42684, Q59519, Q5XBF8, Q7TVI9

Diamond homologs: A0R652, J9VWW9, O13401, O35023, O49066, O51917, O75007, O81235, O84296, O86165, O93724, O96347, P00447, P00449, P04179, P07895, P09233, P09671, P09737, P09738, P0A4J6, P0A4J7, P0C0F8, P0C0F9, P0C0I1, P11796, P13367, P18868, P23744, P27084, P28760, P28763, P28764, P31161, P35017, P41976, P41977, P41978, P41979, P41980

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
NfKb-p65/p50	“up-regulates quantity by expression”	SOD2	“transcriptional regulation”
FARP2	“up-regulates quantity by expression”	SOD2	“transcriptional regulation”
PPARGC1A	“up-regulates quantity by expression”	SOD2	“transcriptional regulation”
SIRT1	“up-regulates quantity by expression”	SOD2	“transcriptional regulation”
BTG2	“up-regulates quantity by expression”	SOD2	“transcriptional regulation”
NFE2L2	“up-regulates quantity by expression”	SOD2	“transcriptional regulation”
SOD2	“down-regulates quantity”	superoxide	“chemical modification”
SOD2	“up-regulates quantity”	dioxygen	“chemical modification”
SOD2	“up-regulates quantity”	“hydrogen peroxide”	“chemical modification”
superoxide	“up-regulates activity”	SOD2	“precursor of”
PPARGC1A	up-regulates	SOD2
DIP2A	“up-regulates activity”	SOD2	binding
SIRT3	“up-regulates activity”	SOD2	deacetylation
SP1	“up-regulates quantity by expression”	SOD2	“transcriptional regulation”
USP36	“up-regulates quantity by stabilization”	SOD2	deubiquitination
copper(1+)	“up-regulates activity”	SOD2	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2583 predictions. Top by Δscore:

Variant	Effect	Δscore
6:159682472:A:AC	donor_gain	1.0000
6:159682473:C:CC	donor_gain	1.0000
6:159682473:CT:C	donor_gain	1.0000
6:159682473:CTCAG:C	donor_gain	1.0000
6:159682477:G:C	donor_gain	1.0000
6:159682495:A:AC	donor_gain	1.0000
6:159682496:C:CC	donor_gain	1.0000
6:159692659:AC:A	donor_gain	1.0000
6:159692660:CC:C	donor_gain	1.0000
6:159692675:T:TA	donor_gain	1.0000
6:159692685:T:TA	donor_gain	1.0000
6:159736292:GAAG:G	donor_gain	1.0000
6:159736297:T:A	donor_loss	1.0000
6:159738985:TATAG:T	acceptor_loss	1.0000
6:159738987:TAGGT:T	acceptor_loss	1.0000
6:159738988:A:AG	acceptor_gain	1.0000
6:159738988:AGGT:A	acceptor_loss	1.0000
6:159738989:G:GG	acceptor_gain	1.0000
6:159739030:A:G	donor_gain	1.0000
6:159739041:CTAAG:C	donor_loss	1.0000
6:159739042:TAAGG:T	donor_loss	1.0000
6:159739043:AAGGT:A	donor_loss	1.0000
6:159739044:AG:A	donor_loss	1.0000
6:159739045:GG:G	donor_loss	1.0000
6:159739046:GT:G	donor_loss	1.0000
6:159739047:T:A	donor_loss	1.0000
6:159742082:TATTA:T	acceptor_loss	1.0000
6:159742083:ATTAG:A	acceptor_loss	1.0000
6:159742084:TTAGA:T	acceptor_loss	1.0000
6:159742085:TA:T	acceptor_loss	1.0000

AlphaMissense

1460 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:159682605:T:A	E186V	0.999
6:159688199:G:C	F90L	0.999
6:159688199:G:T	F90L	0.999
6:159688201:A:G	F90L	0.999
6:159682601:G:C	H187Q	0.998
6:159682601:G:T	H187Q	0.998
6:159682607:C:A	W185C	0.998
6:159682607:C:G	W185C	0.998
6:159682609:A:G	W185R	0.998
6:159682609:A:T	W185R	0.998
6:159682614:T:A	D183V	0.998
6:159684938:A:G	W147R	0.998
6:159684938:A:T	W147R	0.998
6:159688165:A:G	W102R	0.998
6:159688165:A:T	W102R	0.998
6:159688177:G:C	H98D	0.998
6:159682571:C:A	R197S	0.997
6:159682571:C:G	R197S	0.997
6:159682604:C:A	E186D	0.997
6:159682604:C:G	E186D	0.997
6:159682613:A:C	D183E	0.997
6:159682613:A:T	D183E	0.997
6:159682614:T:G	D183A	0.997
6:159682615:C:A	D183Y	0.997
6:159682615:C:G	D183H	0.997
6:159684932:A:G	W149R	0.997
6:159684932:A:T	W149R	0.997
6:159684936:C:A	W147C	0.997
6:159684936:C:G	W147C	0.997
6:159684940:C:T	G146D	0.997

dbSNP variants (sampled 300 via entrez): RS1000024361 (6:159731391 C>A), RS1000045877 (6:159756818 G>A,T), RS1000046560 (6:159714348 C>T), RS1000113082 (6:159673550 G>A), RS1000138692 (6:159741814 C>A,G,T), RS1000166955 (6:159672875 A>G), RS1000196404 (6:159750763 C>G,T), RS1000204859 (6:159712354 C>G,T), RS1000205665 (6:159691271 T>C), RS1000216280 (6:159762331 T>A,C), RS1000217088 (6:159720742 C>T), RS1000312919 (6:159762505 T>A,C), RS1000337235 (6:159713930 C>A,T), RS1000389129 (6:159733393 G>A), RS1000389447 (6:159738944 T>C)

Disease associations

OMIM: gene MIM:147460 | disease phenotypes: MIM:612634

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiomyopathy	Limited	Autosomal recessive
dilated cardiomyopathy	Limited	Autosomal recessive
microvascular complications of diabetes, susceptibility to, 6	Limited	Autosomal dominant

Mondo (3): microvascular complications of diabetes, susceptibility to, 6 (MONDO:0012970), cardiomyopathy (MONDO:0004994), dilated cardiomyopathy (MONDO:0005021)

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001578_9	Age-related macular degeneration (geographic atrophy)	3.000000e-07
GCST003127_12	Lipoprotein (a) levels	5.000000e-11
GCST006218_56	Erosive tooth wear (severe vs non-severe)	3.000000e-08
GCST007096_217	Pulse pressure	1.000000e-16
GCST008367_2	Plasma anti-thyroglobulin and anti-thyroid peroxidase levels (bivariate analysis)	4.000000e-06
GCST010687_3	Polycystic ovary syndrome	3.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0006925	lipoprotein A measurement
EFO:0005763	pulse pressure measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4105776 (SINGLE PROTEIN), CHEMBL4106171 (PROTEIN FAMILY)

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

PharmGKB clinical annotations

7 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2758339	Toxicity	3	heroin	Heroin Dependence
rs4880	Toxicity	3	valproic acid	Epilepsy
rs4880	Toxicity	3	paclitaxel	Breast Neoplasms
rs4880	Toxicity	3	asparaginase	Acute lymphoblastic leukemia
rs4880	Efficacy	3	cyclophosphamide	Breast Neoplasms
rs4880	Other	3	methotrexate
rs5746136	Toxicity	3	heroin	Heroin Dependence

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4880	SOD2	3	3.00	5	cyclophosphamide;valproic acid;paclitaxel;asparaginase;methotrexate
rs7754103	SOD2		0.00	0
rs2758339	SOD2	3	3.00	1	heroin
rs5746136	SOD2	3	0.50	1	heroin

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetylcysteine	decreases reaction, increases abundance, increases reaction, affects reaction, increases expression (+8 more)	19
Hydrogen Peroxide	decreases reaction, increases abundance, affects reaction, affects abundance, affects response to substance (+9 more)	19
Resveratrol	decreases reaction, increases expression, decreases expression, affects binding, increases acetylation (+5 more)	18
Reactive Oxygen Species	decreases expression, increases activity, decreases abundance, increases reaction, affects reaction (+10 more)	18
Paraquat	decreases reaction, increases cleavage, increases chemical synthesis, increases secretion, decreases response to substance (+5 more)	16
Tetradecanoylphorbol Acetate	decreases reaction, increases activity, affects reaction, increases reaction, affects cotreatment (+5 more)	16
Doxorubicin	affects reaction, decreases activity, increases cleavage, decreases expression, increases expression (+5 more)	15
Glucose	decreases reaction, decreases activity, increases secretion, increases chemical synthesis, increases O-linked glycosylation (+9 more)	11
Particulate Matter	increases abundance, increases methylation, decreases activity, decreases reaction, affects cotreatment (+5 more)	11
Oxygen	increases activity, increases expression, decreases response to substance, affects reaction, affects cotreatment (+4 more)	10
Tobacco Smoke Pollution	increases reaction, affects expression, decreases expression, increases expression	10
Cadmium Chloride	increases activity, decreases reaction, decreases activity, decreases expression, increases abundance (+1 more)	10
tert-Butylhydroperoxide	decreases expression, increases reaction, increases acetylation, affects response to substance, decreases reaction (+3 more)	10
bisphenol A	increases methylation, increases abundance, affects response to substance, decreases reaction, increases expression (+2 more)	8
sodium arsenite	affects cotreatment, increases abundance, increases expression, affects reaction, decreases expression (+1 more)	8
Estradiol	affects cotreatment, increases activity, increases expression, decreases expression, increases abundance (+1 more)	8
Lipopolysaccharides	affects cotreatment, increases expression, increases reaction, decreases reaction, increases activity (+1 more)	8
Asbestos, Crocidolite	increases expression, affects expression	8
Acetaminophen	affects reaction, affects expression, affects cotreatment, increases expression, decreases expression	6
Air Pollutants	increases response to substance, affects cotreatment, increases abundance, affects methylation, increases methylation (+3 more)	6
Arsenic	affects expression, decreases expression, increases expression, affects cotreatment, increases abundance (+1 more)	6
Cadmium	increases expression, increases response to substance, decreases reaction, increases phosphorylation, decreases activity (+2 more)	6
Plant Extracts	decreases reaction, increases expression, affects cotreatment, decreases activity, increases reaction (+1 more)	6
Silicon Dioxide	increases expression	6
Superoxides	decreases abundance, increases metabolic processing, decreases response to substance, increases abundance, increases expression (+5 more)	6
N-(2-mercaptoethyl)-1,3-diaminopropane	decreases reaction, increases expression, increases activity	5
pterostilbene	affects reaction, increases expression, affects cotreatment, affects binding, decreases reaction (+2 more)	5
Ascorbic Acid	increases expression, decreases reaction, decreases expression, increases abundance, increases response to substance	5
Rotenone	affects cotreatment, decreases reaction, increases expression, increases activity, decreases activity (+2 more)	5
Valproic Acid	decreases expression, affects expression	5

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4021417	Binding	Inhibition of mitochondrial SOD2 in human DLD1 cells at 100 uM using xanthine as substrate pretreated for 24 hrs followed by substrate addition after 5 mins by NBT dye based spectrophotometric method	Synthesis, structural characterization and biological activity of novel Knoevenagel condensates on DLD-1 human colon carcinoma. — Bioorg Med Chem Lett

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3HW	Abcam HEK293T SOD2 KO	Transformed cell line	Female
CVCL_B6AU	HepaRG SOD2 KO	Cancer cell line	Female
CVCL_C0CZ	HEK293T SOD2 KO	Transformed cell line	Female
CVCL_C0D0	HEL 92.1.7 SOD2 KO clone 5	Cancer cell line	Male
CVCL_C0D1	HEL 92.1.7 SOD2 KO clone 13	Cancer cell line	Male
CVCL_KU05	HeLa SilenciX SOD2	Cancer cell line	Female
CVCL_TP98	HAP1 SOD2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00170183	PHASE3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	PHASE3	COMPLETED	A Study of Short-Term Outcomes and Economic Impact For Patients With Worsening Congestive Heart Failure When Natrecor (Nesiritide) is Added to Standard-Care Therapy, Compared to Administration of Placebo With Standard-Care Therapy
NCT00321295	PHASE3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	PHASE3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	PHASE3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	PHASE3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	PHASE3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	PHASE3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	PHASE3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	PHASE3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	PHASE3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	PHASE3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	PHASE3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	PHASE3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	PHASE3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT00185250	PHASE2	COMPLETED	Betaferon/ Betaseron (Interferon Beta-1b) in Patients With Chronic Viral Cardiomyopathy
NCT00490347	PHASE2	COMPLETED	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Feasibility Trial
NCT00694161	PHASE2	COMPLETED	The Effects Of Fx-1006A On Transthyretin Stabilization And Clinical Outcome Measures In Patients With V122I Or Wild-Type TTR Amyloid Cardiomyopathy