mitochondrial complex IV deficiency, nuclear type 21

Summary

mitochondrial complex IV deficiency, nuclear type 21 (MONDO:0033656) is a disease caused by COXFA4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: COXFA4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex IV deficiency, nuclear type 21
Mondo ID	MONDO:0033656
OMIM	619065
DOID	DOID:0070506
UMLS	C5436727
MedGen	1732562
GARD	0016418
Is cancer (heuristic)	no

Also known as: MC4DN21 · mitochondrial complex IV deficiency, nuclear type 21

Data availability: 3 ClinVar variants · 1 GenCC gene-disease record.

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 21

Related subtypes (21): pancreatic insufficiency-anemia-hyperostosis syndrome, mitochondrial complex IV deficiency, nuclear type 3, 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 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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2444066	NM_002489.4(COXFA4):c.42+1del	COXFA4	Pathogenic	criteria provided, single submitter
977513	NM_002489.4(COXFA4):c.42+1G>C	COXFA4	Pathogenic	no assertion criteria provided
3255019	NM_002489.4(COXFA4):c.131+1G>A	COXFA4	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
COXFA4	Strong	Autosomal recessive	mitochondrial complex IV deficiency, nuclear type 1	3

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
COXFA4	HGNC:7687	ENSG00000189043	O00483	Cytochrome c oxidase subunit FA4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COXFA4	Cytochrome c oxidase subunit FA4	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.

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)
COXFA4	Other/Unknown	no		B12D

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
cerebellar vermis	1
heart right ventricle	1
myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COXFA4	288	ubiquitous	marker	heart right ventricle, myocardium, cerebellar vermis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COXFA4	2,279

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COXFA4	O00483	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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×	0.024	COXFA4
Cytoprotection by HMOX1	1	184.2×	0.024	COXFA4
Cellular response to chemical stress	1	142.8×	0.024	COXFA4
TP53 Regulates Metabolic Genes	1	129.8×	0.024	COXFA4
Respiratory electron transport	1	95.2×	0.024	COXFA4
Aerobic respiration and respiratory electron transport	1	88.5×	0.024	COXFA4
Transcriptional Regulation by TP53	1	62.1×	0.030	COXFA4
Cellular responses to stress	1	36.8×	0.044	COXFA4
Cellular responses to stimuli	1	31.5×	0.046	COXFA4
RNA Polymerase II Transcription	1	22.5×	0.058	COXFA4
Gene expression (Transcription)	1	17.8×	0.066	COXFA4
Generic Transcription Pathway	1	15.1×	0.072	COXFA4
Metabolism	1	11.6×	0.086	COXFA4

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
mitochondrial electron transport, cytochrome c to oxygen	1	766.0×	0.003	COXFA4
cellular respiration	1	432.1×	0.003	COXFA4
mitochondrial electron transport, NADH to ubiquinone	1	358.6×	0.003	COXFA4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COXFA4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
COXFA4	7	Binding:7

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	COXFA4

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)
COXFA4	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.