mitochondrial complex IV deficiency, nuclear type 4

Summary

mitochondrial complex IV deficiency, nuclear type 4 (MONDO:0033636) is a disease caused by SCO1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: SCO1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 83

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex IV deficiency, nuclear type 4
Mondo ID	MONDO:0033636
OMIM	619048
DOID	DOID:0070493
UMLS	C5436683
MedGen	1748100
GARD	0016405
Is cancer (heuristic)	no

Also known as: MC4DN4 · mitochondrial complex IV deficiency, nuclear type 4

Data availability: 83 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial respiratory chain complex deficiency › mitochondrial complex IV deficiency, nuclear-type › mitochondrial complex IV deficiency, nuclear type 4

Related subtypes (21): pancreatic insufficiency-anemia-hyperostosis syndrome, mitochondrial complex IV deficiency, nuclear type 3, mitochondrial complex IV deficiency, nuclear type 7, mitochondrial complex IV deficiency, nuclear type 8, mitochondrial complex IV deficiency, nuclear type 10, mitochondrial complex IV deficiency, nuclear type 11, mitochondrial complex IV deficiency, nuclear type 12, mitochondrial complex IV deficiency, nuclear type 14, mitochondrial complex IV deficiency, nuclear type 15, mitochondrial complex IV deficiency, nuclear type 16, mitochondrial complex IV deficiency, nuclear type 17, mitochondrial complex IV deficiency, nuclear type 18, mitochondrial complex IV deficiency, nuclear type 19, mitochondrial complex IV deficiency, nuclear type 20, mitochondrial complex IV deficiency, nuclear type 21, mitochondrial complex IV deficiency, nuclear type 1, mitochondrial complex IV deficiency, nuclear type 22, mitochondrial complex IV deficiency, nuclear type 23, COX deficiency, benign infantile mitochondrial myopathy, mitochondrial complex IV deficiency, nuclear type 24, mitochondrial complex 4 deficiency, nuclear type 25

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

83 retrieved; paginated sample, class counts are floors:

64 uncertain significance, 4 pathogenic/likely pathogenic, 4 likely pathogenic, 3 conflicting classifications of pathogenicity, 3 benign/likely benign, 3 likely benign, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
120177	NM_004589.4(SCO1):c.394G>A (p.Gly132Ser)	SCO1	Pathogenic	no assertion criteria provided
280792	NM_004589.4(SCO1):c.551del (p.Val184fs)	SCO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3581628	NM_004589.4(SCO1):c.227G>A (p.Trp76Ter)	SCO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
418798	NM_004589.4(SCO1):c.261del (p.Ser88fs)	SCO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6177	NM_004589.4(SCO1):c.364_364+1del	SCO1	Pathogenic	criteria provided, multiple submitters, no conflicts
6178	NM_004589.4(SCO1):c.521C>T (p.Pro174Leu)	SCO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3581641	NM_004589.4(SCO1):c.32_33dup (p.Met12fs)	LOC112529895	Likely pathogenic	criteria provided, single submitter
4845919	NM_004589.4(SCO1):c.89G>A (p.Trp30Ter)	LOC112529895	Likely pathogenic	criteria provided, single submitter
3581622	NM_004589.4(SCO1):c.348del (p.Glu118fs)	SCO1	Likely pathogenic	criteria provided, single submitter
3581625	NM_004589.4(SCO1):c.269_270del (p.Pro90fs)	SCO1	Likely pathogenic	criteria provided, single submitter
1331157	NM_004589.4(SCO1):c.242C>G (p.Pro81Arg)	SCO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
321791	NM_004589.4(SCO1):c.868A>G (p.Ile290Val)	SCO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
388662	NM_004589.4(SCO1):c.620G>A (p.Arg207Lys)	SCO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2045643	NM_004589.4(SCO1):c.10C>G (p.Leu4Val)	LOC112529895	Uncertain significance	criteria provided, multiple submitters, no conflicts
2075675	NM_004589.4(SCO1):c.4G>T (p.Ala2Ser)	LOC112529895	Uncertain significance	criteria provided, multiple submitters, no conflicts
215120	NM_004589.4(SCO1):c.41C>T (p.Pro14Leu)	LOC112529895	Uncertain significance	criteria provided, multiple submitters, no conflicts
215121	NM_004589.4(SCO1):c.61C>G (p.Arg21Gly)	LOC112529895	Uncertain significance	criteria provided, multiple submitters, no conflicts
2233257	NM_004589.4(SCO1):c.31G>A (p.Val11Ile)	LOC112529895	Uncertain significance	criteria provided, multiple submitters, no conflicts
3581633	NM_004589.4(SCO1):c.173C>G (p.Pro58Arg)	LOC112529895	Uncertain significance	criteria provided, single submitter
3581634	NM_004589.4(SCO1):c.170G>T (p.Arg57Leu)	LOC112529895	Uncertain significance	criteria provided, single submitter
3581636	NM_004589.4(SCO1):c.164C>G (p.Ser55Trp)	LOC112529895	Uncertain significance	criteria provided, single submitter
3581637	NM_004589.4(SCO1):c.62G>T (p.Arg21Leu)	LOC112529895	Uncertain significance	criteria provided, single submitter
3581638	NM_004589.4(SCO1):c.56T>C (p.Leu19Pro)	LOC112529895	Uncertain significance	criteria provided, single submitter
3581639	NM_004589.4(SCO1):c.40C>T (p.Pro14Ser)	LOC112529895	Uncertain significance	criteria provided, single submitter
3581640	NM_004589.4(SCO1):c.35T>C (p.Met12Thr)	LOC112529895	Uncertain significance	criteria provided, single submitter
3581643	NM_004589.4(SCO1):c.19G>T (p.Val7Leu)	LOC112529895	Uncertain significance	criteria provided, multiple submitters, no conflicts
3581644	NM_004589.4(SCO1):c.7A>G (p.Met3Val)	LOC112529895	Uncertain significance	criteria provided, multiple submitters, no conflicts
3581645	NM_004589.4(SCO1):c.1A>T (p.Met1Leu)	LOC112529895	Uncertain significance	criteria provided, single submitter
4079981	NM_004589.4(SCO1):c.145G>A (p.Ala49Thr)	LOC112529895	Uncertain significance	criteria provided, single submitter
440960	NM_004589.4(SCO1):c.5C>A (p.Ala2Glu)	LOC112529895	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SCO1	Definitive	Autosomal recessive	mitochondrial complex IV deficiency, nuclear type 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCO1	Orphanet:1561	Fatal infantile cytochrome C oxidase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCO1	HGNC:10603	ENSG00000133028	O75880	Cytochrome c oxidase assembly factor SCO1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCO1	Cytochrome c oxidase assembly factor SCO1	Copper metallochaperone essential for the maturation of cytochrome c oxidase subunit II (MT-CO2/COX2).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCO1	Other/Unknown	no		SCO1/SenC, Synth_of_cyt-c-oxidase_Sco1/2, Thioredoxin-like_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left ventricle myocardium	1
mucosa of transverse colon	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCO1	243	ubiquitous	marker	left ventricle myocardium, primordial germ cell in gonad, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCO1	2,050

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCO1	O75880	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Complex IV assembly	1	228.4×	0.015	SCO1
Respiratory electron transport	1	95.2×	0.015	SCO1
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	SCO1
Metabolism	1	11.6×	0.086	SCO1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intracellular copper ion homeostasis	1	936.2×	0.002	SCO1
mitochondrial respiratory chain complex IV assembly	1	624.1×	0.002	SCO1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCO1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SCO1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SCO1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.