mitochondrial complex IV deficiency, nuclear type 3

Summary

mitochondrial complex IV deficiency, nuclear type 3 (MONDO:0033635) is a disease caused by COX10 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: COX10 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 94

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex IV deficiency, nuclear type 3
Mondo ID	MONDO:0033635
OMIM	619046
DOID	DOID:0070492
UMLS	C5436682
MedGen	1764816
GARD	0016404
Is cancer (heuristic)	no

Also known as: MC4DN3 · mitochondrial complex IV deficiency, nuclear type 3

Data availability: 94 ClinVar variants · 2 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 3

Related subtypes (21): pancreatic insufficiency-anemia-hyperostosis syndrome, mitochondrial complex IV deficiency, nuclear type 4, 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

94 retrieved; paginated sample, class counts are floors:

70 uncertain significance, 7 likely pathogenic, 6 conflicting classifications of pathogenicity, 4 likely benign, 4 pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
7522	NM_001303.4(COX10):c.612C>A (p.Asn204Lys)	COX10	Pathogenic	no assertion criteria provided
7523	NM_001303.4(COX10):c.587C>A (p.Thr196Lys)	COX10	Pathogenic	no assertion criteria provided
7525	NM_001303.4(COX10):c.1007A>T (p.Asp336Val)	COX10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7526	NM_001303.4(COX10):c.1007A>G (p.Asp336Gly)	COX10	Pathogenic	no assertion criteria provided
7527	NM_001303.4(COX10):c.2T>C (p.Met1Thr)	COX10	Pathogenic	no assertion criteria provided
1162812	NM_001303.4(COX10):c.688C>T (p.Gln230Ter)	COX10	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2582413	NM_001303.4(COX10):c.620del (p.Asn207fs)	COX10	Likely pathogenic	criteria provided, single submitter
3581652	NM_001303.4(COX10):c.177+1G>A	COX10	Likely pathogenic	criteria provided, single submitter
3581660	NM_001303.4(COX10):c.412A>T (p.Lys138Ter)	COX10	Likely pathogenic	criteria provided, single submitter
3581668	NM_001303.4(COX10):c.928+1G>A	COX10	Likely pathogenic	criteria provided, single submitter
3581669	NM_001303.4(COX10):c.929-2A>C	COX10	Likely pathogenic	criteria provided, single submitter
7524	NM_001303.4(COX10):c.674C>T (p.Pro225Leu)	COX10	Likely pathogenic	criteria provided, multiple submitters, no conflicts
136996	NM_001303.4(COX10):c.738G>A (p.Pro246=)	COX10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
137002	NM_001303.4(COX10):c.1096G>T (p.Val366Leu)	COX10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1677043	NM_001303.4(COX10):c.413_414del (p.Lys138fs)	COX10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2137929	NM_001303.4(COX10):c.1015C>T (p.Arg339Trp)	COX10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
235251	NM_001303.4(COX10):c.1193G>A (p.Arg398His)	COX10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
449007	NM_001303.4(COX10):c.311C>T (p.Pro104Leu)	COX10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1013385	NM_001303.4(COX10):c.724TGT[1] (p.Cys243del)	COX10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030366	NM_001303.4(COX10):c.1064G>A (p.Arg355His)	COX10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030367	NM_001303.4(COX10):c.394G>T (p.Asp132Tyr)	COX10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031965	NM_001303.4(COX10):c.1186G>A (p.Gly396Ser)	COX10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031966	NM_001303.4(COX10):c.1192C>T (p.Arg398Cys)	COX10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1162813	NM_001303.4(COX10):c.1070C>T (p.Ala357Val)	COX10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1301292	NM_001303.4(COX10):c.1066G>A (p.Val356Met)	COX10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333055	NM_001303.4(COX10):c.1096G>A (p.Val366Met)	COX10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1370660	NM_001303.4(COX10):c.520G>A (p.Ala174Thr)	COX10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1500533	NM_001303.4(COX10):c.625T>C (p.Phe209Leu)	COX10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1693693	NM_001303.4(COX10):c.34C>T (p.Leu12Phe)	COX10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1713495	NM_001303.4(COX10):c.1315G>A (p.Gly439Arg)	COX10	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
COX10	Definitive	Autosomal recessive	mitochondrial complex IV deficiency, nuclear type 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COX10	Orphanet:254905	Isolated 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
COX10	HGNC:2260	ENSG00000006695	Q12887	Protoheme IX farnesyltransferase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COX10	Protoheme IX farnesyltransferase, mitochondrial	Converts protoheme IX and farnesyl diphosphate to heme O.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COX10	Enzyme (other)	yes	2.5.1.141	UbiA_prenyltransferase, Protohaem_IX_farnesylTrfase, Protohaem_IX_farnesylTrfase_mt

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
diaphragm	1
left ventricle myocardium	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COX10	245	ubiquitous	marker	tibialis anterior, diaphragm, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COX10	1,984

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COX10	Q12887	77.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Heme biosynthesis	1	761.3×	0.001	COX10

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
copper ion homeostasis	1	4213.0×	0.001	COX10
leukocyte differentiation	1	3370.4×	0.001	COX10
respiratory chain complex IV assembly	1	2407.4×	0.001	COX10
heme A biosynthetic process	1	1532.0×	0.001	COX10
mitochondrial fission	1	1053.2×	0.002	COX10
heme biosynthetic process	1	601.9×	0.002	COX10
aerobic respiration	1	247.8×	0.005	COX10
multicellular organism growth	1	137.0×	0.008	COX10
lipid metabolic process	1	91.6×	0.011	COX10

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
COX10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
COX10	2.5.1.141	heme o synthase

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	1	COX10
E	Difficult family or no structure, no drug	0

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)
COX10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.