SCO2

Summary

SCO2 (synthesis of cytochrome C oxidase 2, HGNC:10604) is a protein-coding gene on chromosome 22q13.33, encoding Cytochrome c oxidase assembly factor SCO2 (O43819). Copper metallochaperone essential for the synthesis and maturation of cytochrome c oxidase subunit II (MT-CO2/COX2); together with SCO1, facilitates the incorporation of copper into the Cu(A) site of MT-CO2/COX2.

Cytochrome c oxidase (COX) catalyzes the transfer of electrons from cytochrome c to molecular oxygen, which helps to maintain the proton gradient across the inner mitochondrial membrane that is necessary for aerobic ATP production. Human COX is a multimeric protein complex that requires several assembly factors; this gene encodes one of the COX assembly factors. The encoded protein is a metallochaperone that is involved in the biogenesis of cytochrome c oxidase subunit II. Mutations in this gene are associated with fatal infantile encephalocardiomyopathy and myopia 6.

Source: NCBI Gene 9997 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 113 total — 9 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 170
• Druggable target: yes
• MANE Select transcript: NM_005138

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10604
Approved symbol	SCO2
Name	synthesis of cytochrome C oxidase 2
Location	22q13.33
Locus type	gene with protein product
Status	Approved
Aliases	SCO1L
Ensembl gene	ENSG00000284194
Ensembl biotype	protein_coding
OMIM	604272
Entrez	9997

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

ENST00000252785, ENST00000395693, ENST00000535425, ENST00000543927, ENST00000638598, ENST00000862162, ENST00000862163, ENST00000862164, ENST00000862165, ENST00000862166, ENST00000862167, ENST00000862168, ENST00000862169, ENST00000928020

RefSeq mRNA: 4 — MANE Select: NM_005138 NM_001169109, NM_001169110, NM_001169111, NM_005138

CCDS: CCDS14095

Canonical transcript exons

ENST00000395693 — 2 exons

Exon	Start	End
ENSE00001522509	50525472	50525598
ENSE00003902118	50523568	50524424

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 98.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.8442 / max 59.4095, expressed in 1799 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194754	8.3682	1719
194755	2.2973	1178
194756	2.0937	1201
194757	0.0851	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	98.58	gold quality
granulocyte	CL:0000094	97.35	gold quality
mucosa of transverse colon	UBERON:0004991	96.39	gold quality
monocyte	CL:0000576	95.53	gold quality
mononuclear cell	CL:0000842	95.39	gold quality
leukocyte	CL:0000738	94.87	gold quality
gingival epithelium	UBERON:0001949	94.00	gold quality
gingiva	UBERON:0001828	92.32	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.09	gold quality
cervix squamous epithelium	UBERON:0006922	92.09	gold quality
palpebral conjunctiva	UBERON:0001812	91.46	gold quality
squamous epithelium	UBERON:0006914	90.83	gold quality
periodontal ligament	UBERON:0008266	90.78	gold quality
right lobe of liver	UBERON:0001114	90.01	gold quality
esophagus squamous epithelium	UBERON:0006920	89.95	gold quality
epithelium of bronchus	UBERON:0002031	89.88	gold quality
bronchial epithelial cell	CL:0002328	89.84	gold quality
blood	UBERON:0000178	89.68	gold quality
esophagus mucosa	UBERON:0002469	89.57	gold quality
bronchus	UBERON:0002185	89.32	gold quality
right lung	UBERON:0002167	89.13	gold quality
lower esophagus mucosa	UBERON:0035834	89.04	gold quality
epithelium of esophagus	UBERON:0001976	88.86	gold quality
transverse colon	UBERON:0001157	88.66	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.61	gold quality
apex of heart	UBERON:0002098	88.27	gold quality
endothelial cell	CL:0000115	88.21	gold quality
parietal pleura	UBERON:0002400	87.94	gold quality
upper lobe of left lung	UBERON:0008952	87.64	gold quality
omental fat pad	UBERON:0010414	87.24	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6379	no	351.97
E-MTAB-7052	no	201.13
E-MTAB-4850	no	179.46
E-ANND-3	no	1.55

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

Literature-anchored findings (GeneRIF, showing 39)

• Mutations can cause fatal cytochrome c oxidase deficiency. Affected myoblasts can be rescued in vitro by transduction of the normal SCO2 gene or by copper administration. (PMID:11751685)
• Copper supplementation restores cytochrome c oxidase activity in cultured cells from patients with SCO2 mutations. (PMID:11931660)
• One novel SCO2 mutation has been identified in a patient with hypertrophic cardiomyopathy. (PMID:12538779)
• SCO2 mutation is associated spinal muscular atrophy type I phenotype (PMID:14994243)
• SCO2 transfers copper to the CuA site at an early stage of COX assembly in mitochondria. (PMID:15229189)
• The consequences of SCO2 and SURF1 mutations suggest the existence of tissue-specific functional differences of these proteins that may serve different tissue-specific requirements for the regulation of COX biogenesis. (PMID:16083427)
• data suggest that both Cu(I) and Cu(II) binding are critical for normal Sco function. (PMID:16091356)
• findings show that p53 modulates the balance between the utilization of respiratory and glycolytic pathways; identifed Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect (PMID:16728594)
• These results suggest a mitochondrial pathway for the regulation of cellular copper content that involves signaling through SCO1 and SCO2, perhaps by their thiol redox or metal-binding state. (PMID:17189203)
• structural and metal binding features of human Cu(I)Sco2 are similar to the Sco1 homolog, although the dynamic properties and the conformational disorder are quite different when apo forms and the copper(I)-loaded forms of the two proteins are compared (PMID:17850752)
• report extends knowledge of the pathology of COX deficiency caused by mutations in the SCO2 gene (PMID:18254779)
• Spinal muscular atrophy has been associated with mtDNA depletion or with mutations in the cytochrome-c oxidase assembly gene (SCO2; OMIM 604377). (PMID:18332255)
• Mutations in the SCO2 gene are a cause of prenatal-onset hypertrophic cardiomyopathy. (PMID:18924171)
• SCO2 acts upstream of SCO1, and that it is indispensable for CO II synthesis. (PMID:19336478)
• observations confirm that mutations in the SCO2 gene are frequently associated with the neurogenic pattern of skeletal muscle involvement accompanied by mitochondrial abnormalities (PMID:19353431)
• Mutations of SCO2 gene should be considered as a possible cause of neurogenic skeletal muscle features (including SMA-like) in infants with encephalomyopathy even in the absence of heart involvement and COX deficit. (PMID:19879173)
• recombinant fusion L-Sco2 protein was successfully transduced into the mitochondria of primary fibroblasts derived from SCO2/COX deficient patient and facilitated recovery of COX activity (PMID:20193760)
• Results describe the tissue distribution of SCO1 and SCO2 in mouse and human tissues. (PMID:20864674)
• These results suggest that p53 can modulate the metabolic pathways via the proteins SCO2 and TIGAR in human breast cancer. (PMID:21820150)
• Analysis of the mtDNA revealed that COX deficiency is caused by high levels of mtDNA deletions which accumulate with age in alzheimer disease. (PMID:21925769)
• wild-type p53 gene silencing reduced the expression of synthesis of cytochrome c oxidase 2 (SCO2), an effector necessary for respiratory chain function (PMID:22120717)
• Exogenous addition of the SCO2 gene to hypoxic cancer cells and hypoxic tumors induces apoptosis. (PMID:23319048)
• Autosomal recessive mutations in SCO2 are known to be associated with COX deficiency recognized as fatal infantile cardio-encephalomyopathy (PMID:23364397)
• oroxylin A could increase protein and mRNA expression of TP53-induced glycolysis and apoptosis regulator (TIGAR) and synthesis of cytochrome c oxidase 2 (SCO2), which are the key metabolic modulators regulated by p53. (PMID:23612020)
• Mutations in SCO2 are associated with autosomal-dominant high-grade myopia. (PMID:23643385)
• alpha-particle-induced bystander effect is regulated by p53 and its downstream SCO2 in the irradiated hepatoma cells (PMID:23786650)
• COX20 cooperates with SCO1 and SCO2 to mature COX2 and promote the assembly of cytochrome c oxidase. (PMID:24403053)
• mutation in LRPAP1 is associated with high myopia. Further studies are expected to evaluate the pathogenicity of the variants in CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2. (PMID:25525168)
• Letter/Case Report: SCO2 mutations resulting in Leigh disease revealed at autopsy. (PMID:25720770)
• Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies. (PMID:25959673)
• oncoprotein HBXIP enhances glucose metabolism reprogramming through suppressing SCO2 and PDHA1 in breast cancer (PMID:26309161)
• Sco1 is a metallochaperone that selectively transfers Cu(I) ions based on loop recognition, whereas Sco2 is a copper-dependent thiol reductase of the cysteine ligands in the oxidase. (PMID:26351686)
• oxidative stress-induced glycolysis-to-OXPHOS switch is mediated by synthesis of cytochrome c oxidase 2 (SCO2). These findings demonstrate p53-mediated OXPHOS function as a compensatory alteration in Fanconi anemia (FA)hematopoietic stem cells to ensure a functional but mildly impaired energy metabolism and suggest a cautious approach to manipulating p53 signaling in FA. (PMID:26676373)
• Geranylgeranoic acid increased the SCO2 gene expression, which might enhance aerobic respiration. (PMID:26700591)
• We identified one novel possibility of an extreme myopia-causing mutation in SCO2. No other disease-causing mutation was found in 101 extremely myopic Japanese patients, suggesting that SCO2 plays a limited role in Japanese extreme myopia. (PMID:27052445)
• In gastric cancer, the expression of SCO2 and COX were not shown to be associated with the regulatory role of p53, unlike TIGAR expression. Nevertheless, a significantly high recurrence rate was found in a patient group with high COX expression (PMID:27499152)
• High expression of synthesis of cytochrome c oxidase 2 and TP53-induced glycolysis and apoptosis regulator can predict poor prognosis in human lung adenocarcinoma (PMID:29634976)
• Systemic Mitochondrial Oxidative Phosphorylation Protein Levels Correlate with Neuroimaging Measures in Chronically HIV-Infected Individuals. (PMID:31617381)
• TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation. (PMID:34369624)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	sco2	ENSDARG00000045555
mus_musculus	Sco2	ENSMUSG00000091780

Paralogs (1): SCO1 (ENSG00000133028)

Protein

Protein identifiers

Cytochrome c oxidase assembly factor SCO2 — O43819 (reviewed: O43819)

All UniProt accessions (2): A0A1W2PQK0, O43819

UniProt curated annotations — full annotation on UniProt →

Function. Copper metallochaperone essential for the synthesis and maturation of cytochrome c oxidase subunit II (MT-CO2/COX2); together with SCO1, facilitates the incorporation of copper into the Cu(A) site of MT-CO2/COX2. Could also act as a thiol-disulfide oxidoreductase to regulate the redox state of the cysteines in SCO1 during maturation of MT-CO2/COX2.

Subunit / interactions. Homodimer. Interacts with COA6. Found in a complex with TMEM177, COX20, COA6, MT-CO2/COX2, COX18 and SCO1. Interacts with TMEM177 in a COX20-dependent manner. Interacts with COX20 in a MT-CO2/COX2- and COX18-dependent manner. Interacts with COX16.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Ubiquitous.

Disease relevance. Mitochondrial complex IV deficiency, nuclear type 2 (MC4DN2) [MIM:604377] An autosomal recessive, severe mitochondrial disorder characterized by hypotonia, global developmental delay, hypertrophic cardiomyopathy, lactic acidosis, gliosis, and neuronal loss in basal ganglia, brainstem and spinal cord. Serum lactate is increased, and laboratory studies show decreased mitochondrial complex IV protein and activity levels in various tissues, including heart and skeletal muscle. Most patients die in infancy of cardiorespiratory failure. The disease is caused by variants affecting the gene represented in this entry. Myopia 6 (MYP6) [MIM:608908] A refractive error of the eye, in which parallel rays from a distant object come to focus in front of the retina, vision being better for near objects than for far. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SCO1/2 family.

RefSeq proteins (4): NP_001162580, NP_001162581, NP_001162582, NP_005129* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003782	SCO1/SenC	Family
IPR013766	Thioredoxin_domain	Domain
IPR017276	Synth_of_cyt-c-oxidase_Sco1/2	Family
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF02630

UniProt features (34 total): sequence variant 11, strand 8, helix 4, binding site 3, topological domain 2, transit peptide 1, chain 1, turn 1, transmembrane region 1, domain 1, disulfide bond 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2RLI	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43819-F1	84.14	0.64

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 (3): 133; 137; 224

Disulfide bonds (1): 133–137

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-9864848	Complex IV assembly
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-611105	Respiratory electron transport
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 424 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, MCLACHLAN_DENTAL_CARIES_UP, GOBP_RESPIRATORY_CHAIN_COMPLEX_IV_ASSEMBLY, MODULE_45, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, MODULE_66, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, RICKMAN_METASTASIS_DN, ONKEN_UVEAL_MELANOMA_UP, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, GOBP_ELECTRON_TRANSPORT_CHAIN, GOCC_MITOCHONDRIAL_ENVELOPE, MODULE_88

GO Biological Process (9): eye development (GO:0001654), in utero embryonic development (GO:0001701), muscle system process (GO:0003012), intracellular copper ion homeostasis (GO:0006878), response to activity (GO:0014823), respiratory electron transport chain (GO:0022904), mitochondrial respiratory chain complex IV assembly (GO:0033617), respiratory chain complex IV assembly (GO:0008535), copper ion homeostasis (GO:0055070)

GO Molecular Function (5): copper ion binding (GO:0005507), protein-disulfide reductase activity (GO:0015035), copper chaperone activity (GO:0016531), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), myofibril (GO:0030016), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Transcriptional Regulation by TP53	1
Respiratory electron transport	1
Metabolism	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
Aerobic respiration and respiratory electron transport	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory organ development	1
visual system development	1
chordate embryonic development	1
system process	1
intracellular monoatomic cation homeostasis	1
copper ion homeostasis	1
response to stimulus	1
electron transport chain	1
cellular respiration	1
mitochondrion	1
respiratory chain complex IV assembly	1
mitochondrial respiratory chain complex assembly	1
cytochrome complex assembly	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
transition metal ion binding	1
disulfide oxidoreductase activity	1
catalytic activity, acting on a protein	1
copper ion binding	1
metallochaperone activity	1
binding	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
contractile muscle fiber	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1800 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCO2	COX17	Q14061	965
SCO2	SURF1	Q15526	956
SCO2	COX10	Q12887	939
SCO2	COX15	Q7KZN9	925
SCO2	MT-CO2	P00403	890
SCO2	COX11	Q9Y6N1	862
SCO2	COA6	Q5JTJ3	832
SCO2	ATOX1	O00244	821
SCO2	TIGAR	Q9NQ88	801
SCO2	MT-CO1	P00395	796
SCO2	MT-CO3	P00414	781
SCO2	COX4I1	P13073	765
SCO2	COX6B1	P14854	764
SCO2	TACO1	Q9BSH4	761
SCO2	LRPPRC	P42704	684
SCO2	BCS1L	Q9Y276	684

IntAct

96 interactions, top by confidence:

A	B	Type	Score
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
SCO2	CIDEB	psi-mi:“MI:0915”(physical association)	0.560
EGFR	NDUFA4	psi-mi:“MI:0914”(association)	0.530
ARMC6	SLC27A2	psi-mi:“MI:0914”(association)	0.530
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
COX17	SCO2	psi-mi:“MI:0407”(direct interaction)	0.440
AIFM1	HAX1	psi-mi:“MI:0914”(association)	0.420
TUBA1A	TUBAL3	psi-mi:“MI:0914”(association)	0.420
TGOLN2	PGRMC1	psi-mi:“MI:0914”(association)	0.420
MET	NDUFA4	psi-mi:“MI:0914”(association)	0.420
MET	NDUFA4	psi-mi:“MI:2364”(proximity)	0.420
	SCO2	psi-mi:“MI:0915”(physical association)	0.400
Prkacb	TBC1D31	psi-mi:“MI:0914”(association)	0.350
ARMC6		psi-mi:“MI:0914”(association)	0.350
MAGEA10	XPO1	psi-mi:“MI:0914”(association)	0.350
CEP162	IPO5	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
	PGRMC1	psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
PB1	HAX1	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
PPEF1	ILVBL	psi-mi:“MI:0914”(association)	0.350
SMARCB1		psi-mi:“MI:0914”(association)	0.350
STK38L		psi-mi:“MI:0914”(association)	0.350
DND1	RPSA2	psi-mi:“MI:0914”(association)	0.350
P2RY6	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (147): SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS), SCO2 (Affinity Capture-MS)

ESM2 similar proteins: A1A4J8, A6H784, D3ZS74, D4A6D7, E9QBI7, O42899, O43819, O60341, O75880, P00258, P10109, P23833, P24483, P30048, P38072, Q05B51, Q0VCH8, Q12931, Q2KHU5, Q2NKY8, Q2TBI4, Q3ULF4, Q4VAE3, Q5EA41, Q5REY3, Q5RH02, Q5SUC9, Q69ZP3, Q6DKK2, Q6PI78, Q6ZQ88, Q7ZUC7, Q8BMS4, Q8JZQ2, Q8LAL0, Q8N490, Q8VCL2, Q920A7, Q95N00, Q96HS1

Diamond homologs: A1A4J8, A6H784, O42899, O43819, O75880, P23833, P38072, P47206, Q1RIN4, Q1RKK4, Q4UKW2, Q4UNH4, Q52720, Q5RH02, Q5SUC9, Q68WF1, Q8LAL0, Q8VCL2, Q8VYP0, Q92H76, Q92JM5, Q9ZCW7, Q9ZEB4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TP53	“up-regulates quantity by expression”	SCO2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial protein import	6	15.7×	5e-04
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	6	9.1×	2e-03
PIP3 activates AKT signaling	6	6.3×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein autophosphorylation	7	11.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	7
Uncertain significance	33
Likely benign	41
Benign	8

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1396309	NM_001953.5(TYMP):c.1062dup (p.Gly355fs)	Pathogenic
2735939	NM_005138.3(SCO2):c.116_131dup (p.Glu45fs)	Pathogenic
2780143	NM_005138.3(SCO2):c.172C>T (p.Arg58Ter)	Pathogenic
3012048	NM_001953.5(TYMP):c.1255dup (p.Val419fs)	Pathogenic
5683	NM_005138.3(SCO2):c.179_188dup (p.Ile63fs)	Pathogenic
5684	NM_005138.3(SCO2):c.398G>A (p.Cys133Tyr)	Pathogenic
658290	NM_001953.5(TYMP):c.1040dup (p.Ala348fs)	Pathogenic
831985	NC_000022.11:g.(?50525760)(50529719_?)del	Pathogenic
976870	NC_000022.11:g.43802117_50806121del	Pathogenic
1163689	NM_001953.5(TYMP):c.1301-2_1305del	Likely pathogenic
1325042	NM_005138.3(SCO2):c.224G>A (p.Trp75Ter)	Likely pathogenic
3240429	NM_005138.3(SCO2):c.563del (p.Leu188fs)	Likely pathogenic
3588119	NM_005138.3(SCO2):c.738_750dup (p.Ser251delinsGlyTer)	Likely pathogenic
3588121	NM_005138.3(SCO2):c.210_229del (p.Leu71fs)	Likely pathogenic
3588122	NM_001953.5(TYMP):c.1447T>C (p.Ter483Gln)	Likely pathogenic
554264	NM_001953.5(TYMP):c.1308dup (p.Trp437fs)	Likely pathogenic

SpliceAI

755 predictions. Top by Δscore:

Variant	Effect	Δscore
22:50526241:CTCA:C	donor_loss	1.0000
22:50526242:TCAC:T	donor_loss	1.0000
22:50526243:CACC:C	donor_loss	1.0000
22:50526245:C:CG	donor_loss	1.0000
22:50526245:CCAT:C	donor_gain	1.0000
22:50525531:C:CA	donor_gain	0.9900
22:50525917:CC:C	acceptor_gain	0.9900
22:50525917:CCCT:C	acceptor_loss	0.9900
22:50525918:CC:C	acceptor_gain	0.9900
22:50525920:T:G	acceptor_loss	0.9900
22:50526232:C:CA	donor_gain	0.9900
22:50526233:C:A	donor_gain	0.9900
22:50526240:GCTCA:G	donor_loss	0.9900
22:50526244:A:AC	donor_gain	0.9900
22:50526245:C:CC	donor_gain	0.9900
22:50526269:T:TA	donor_gain	0.9900
22:50525443:T:TA	donor_gain	0.9800
22:50525524:T:TA	donor_gain	0.9800
22:50525919:C:CC	acceptor_gain	0.9800
22:50526000:CCA:C	donor_gain	0.9800
22:50526244:AC:A	donor_gain	0.9800
22:50526245:CC:C	donor_gain	0.9800
22:50525466:CCGCA:C	donor_loss	0.9700
22:50525467:CGCA:C	donor_loss	0.9700
22:50525468:GCA:G	donor_loss	0.9700
22:50525469:CAC:C	donor_loss	0.9700
22:50525470:ACCT:A	donor_loss	0.9700
22:50525471:C:A	donor_loss	0.9700
22:50525915:GTCC:G	acceptor_gain	0.9700
22:50525916:TCC:T	acceptor_gain	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000069929 (22:50524727 C>G), RS1000474738 (22:50525566 G>A,C,T), RS1001277545 (22:50528375 A>G), RS1002867388 (22:50524744 C>T), RS1003394781 (22:50527512 A>G), RS1004185268 (22:50525204 C>T), RS1004654285 (22:50528126 C>T), RS1004918962 (22:50525810 G>A), RS1006214787 (22:50526771 T>C), RS1006356818 (22:50523136 G>A), RS1006549502 (22:50523472 A>G), RS1006645801 (22:50527810 T>C), RS1007113477 (22:50527797 AAG>A), RS1007342769 (22:50523370 C>A,G,T), RS1007416904 (22:50524210 C>G,T)

Disease associations

OMIM: gene MIM:604272 | disease phenotypes: MIM:603041, MIM:604377, MIM:608908, MIM:253300, MIM:220110, MIM:606232

GenCC curated gene-disease

Disease	Classification	Inheritance
Leigh syndrome	Definitive	Autosomal recessive
cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1	Definitive	Autosomal recessive
myopia 6	Strong	Autosomal dominant
Charcot-Marie-Tooth disease	Moderate	Autosomal recessive
autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR
mitochondrial disease	Definitive	AR
Charcot-Marie-Tooth disease	Moderate	AR

Mondo (11): mitochondrial DNA depletion syndrome 1 (MONDO:0011283), cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 (MONDO:0011451), myopia 6 (MONDO:0012154), spinal muscular atrophy (MONDO:0001516), mitochondrial complex IV deficiency, nuclear type 1 (MONDO:0700250), dilated cardiomyopathy (MONDO:0005021), mitochondrial neurogastrointestinal encephalomyopathy (MONDO:0017575), Phelan-McDermid syndrome (MONDO:0011652), Leigh syndrome (MONDO:0009723), Charcot-Marie-Tooth disease (MONDO:0015626), autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect (MONDO:0033850)

Orphanet (4): Mitochondrial neurogastrointestinal encephalomyopathy (Orphanet:298), Fatal infantile cytochrome C oxidase deficiency (Orphanet:1561), Dilated cardiomyopathy (Orphanet:217604), Phelan-McDermid syndrome (Orphanet:48652)

HPO phenotypes

170 total (30 of 170 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000124	Renal tubular dysfunction
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000308	Microretrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000577	Exotropia
HP:0000580	Pigmentary retinopathy
HP:0000597	Ophthalmoparesis
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000741	Apathy
HP:0000750	Delayed speech and language development
HP:0000952	Jaundice
HP:0001098	Abnormal fundus morphology
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001256	Mild intellectual disability

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000587_8	Mean corpuscular hemoglobin	4.000000e-08
GCST001198_66	Multiple sclerosis	2.000000e-08
GCST001765_31	Red blood cell traits	5.000000e-23
GCST004146_29	Chronic lymphocytic leukemia	3.000000e-09
GCST004608_120	Granulocyte percentage of myeloid white cells	7.000000e-09
GCST012020_515	Serum metabolite levels	4.000000e-82
GCST90002390_285	Mean corpuscular hemoglobin	3.000000e-11
GCST90002392_231	Mean corpuscular volume	4.000000e-12
GCST90002404_416	Red cell distribution width	3.000000e-33

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0009188	Red cell distribution width

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
D009134	Muscular Atrophy, Spinal	C10.228.854.468; C10.574.562.500; C10.668.467.500
C536105	Myopia 6 (supp.)
C536801	Telomeric 22q13 Monosomy Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067029 (SINGLE PROTEIN)

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11479	SCO2, TYMP	3	5.50	1	capecitabine;fluorouracil
rs112723255	SCO2, TYMP		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects binding, increases reaction, decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Copper	decreases abundance, affects abundance, affects oxidation	2
Reactive Oxygen Species	increases reaction, affects cotreatment, increases abundance, increases expression, increases phosphorylation (+1 more)	2
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
cupric chloride	increases activity, increases reaction	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
(+)-JQ1 compound	decreases expression	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	decreases expression	1
Bezafibrate	increases activity, increases reaction	1
Ethyl Methanesulfonate	decreases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Nickel	increases expression	1
Ozone	increases abundance, affects expression	1
Paraquat	increases expression	1
Selenium	increases expression	1
Smoke	decreases expression	1
Theophylline	affects cotreatment, decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases expression, increases methylation	1
Vincristine	decreases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	decreases 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
CHEMBL5652395	Binding	Binding affinity to human SCO2 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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01422200	PHASE4	COMPLETED	Flu Vaccine Study in Neuromuscular Patients 2011
NCT05232929	PHASE4	ACTIVE_NOT_RECRUITING	Long-term Follow-up Study of Risdiplam in Participants With Spinal Muscular Atrophy (SMA)
NCT05522361	PHASE4	ACTIVE_NOT_RECRUITING	Risdiplam in Patients With Spinal Muscular Atrophy Previously Treated With Nusinersen
NCT07448610	PHASE4	NOT_YET_RECRUITING	ASsessing The REAl-world Safety & Effectiveness of Spinal Muscular Atrophy Participants Treated With Intrathecal Onasemnogene Abeparvovec-brve (OAV101B) (ITVISMA®): A U.S. Pragmatic Multicenter Study (STREAM)
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT01671384	PHASE3	UNKNOWN	Valproate and Levocarnitine in Children With Spinal Muscular Atrophy
NCT02193074	PHASE3	TERMINATED	A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy
NCT02292537	PHASE3	COMPLETED	A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA)
NCT02594124	PHASE3	COMPLETED	A Study for Participants With Spinal Muscular Atrophy (SMA) Who Previously Participated in Nusinersen (ISIS 396443) Investigational Studies
NCT03505099	PHASE3	COMPLETED	Pre-Symptomatic Study of Intravenous Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2
NCT03837184	PHASE3	COMPLETED	Single-Dose Gene Replacement Therapy Using for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies
NCT04042025	PHASE3	ACTIVE_NOT_RECRUITING	Long-term Follow-up Study of Patients Receiving Onasemnogene Abeparvovec-xioi
NCT04851873	PHASE3	COMPLETED	Safety and Efficacy of Intravenous OAV101 (AVXS-101) in Pediatric Patients With Spinal Muscular Atrophy (SMA)
NCT05067790	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn About the Effect of Higher Doses of Nusinersen (BIIB058) Given as Injections to Participants With Spinal Muscular Atrophy (SMA) Who Were Previously Treated With Risdiplam (ASCEND)
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05335876	PHASE3	RECRUITING	Long-term Follow-up of Patients With Spinal Muscular Atrophy Treated With OAV101 in Clinical Trials
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05386680	PHASE3	COMPLETED	Phase IIIb, Open-label, Multi-center Study to Evaluate Safety, Tolerability and Efficacy of OAV101 Administered Intrathecally to Participants With SMA Who Discontinued Treatment With Nusinersen or Risdiplam
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT07265232	PHASE3	RECRUITING	Real World Clinical Effectiveness & Safety of Vesemnogene Lantuparvovec for Spinal Muscular Atrophy (SMA) in Low-middle Income Countries (LMIC).
NCT07444476	PHASE3	RECRUITING	A Study to Learn About Salanersen’s (BIIB115) Effects on Movement and Its Safety in Participants Aged 15 to 60 Years With Spinal Muscular Atrophy (SMA) Who Are Either New to SMA Treatment or Were Previously Treated With Risdiplam
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT05849766	PHASE3	COMPLETED	Effect of Dapagliflozin on Cardiac Structure, Function and Secondary Mitral Regurgitation in Patients with Left Ventricle Dysfunction
NCT06250257	PHASE3	RECRUITING	Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome