mitochondrial complex IV deficiency, nuclear type 17

Summary

mitochondrial complex IV deficiency, nuclear type 17 (MONDO:0033652) is a disease caused by COA8 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: COA8 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 29

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex IV deficiency, nuclear type 17
Mondo ID	MONDO:0033652
OMIM	619061
DOID	DOID:0070502
UMLS	C5436718
MedGen	1730423
GARD	0016414
Is cancer (heuristic)	no

Also known as: MC4DN17 · mitochondrial complex IV deficiency, nuclear type 17

Data availability: 29 ClinVar variants · 3 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 17

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 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

29 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 5 likely pathogenic, 5 pathogenic, 4 conflicting classifications of pathogenicity, 4 likely benign, 3 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2429110	NC_000014.9:g.102573453_103575949del	AMN	Pathogenic	criteria provided, single submitter
156421	NM_001370595.2(COA8):c.196C>T (p.Arg66Ter)	COA8	Pathogenic	criteria provided, multiple submitters, no conflicts
156422	NM_001370595.2(COA8):c.124-1G>A	COA8	Pathogenic	no assertion criteria provided
156424	NM_001370595.2(COA8):c.328GAA[1] (p.Glu111del)	COA8	Pathogenic	no assertion criteria provided
2581720	NM_001370595.2(COA8):c.170_173dup (p.Pro59fs)	COA8	Pathogenic	criteria provided, single submitter
1333711	NM_001370595.2(COA8):c.388C>G (p.Gln130Glu)	COA8	Likely pathogenic	criteria provided, single submitter
2428493	NM_001370595.2(COA8):c.321+2T>A	COA8	Likely pathogenic	no assertion criteria provided
2502314	NM_001370595.2(COA8):c.328G>T (p.Glu110Ter)	COA8	Likely pathogenic	criteria provided, single submitter
2690568	NM_001370595.2(COA8):c.352A>T (p.Lys118Ter)	COA8	Likely pathogenic	criteria provided, single submitter
3255585	NM_001370595.2(COA8):c.102_121dup (p.Gly41fs)	COA8	Likely pathogenic	criteria provided, single submitter
1030024	NM_001370595.2(COA8):c.-10dup	COA8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156423	NM_001370595.2(COA8):c.314T>C (p.Phe105Ser)	COA8	Conflicting classifications of pathogenicity	no assertion criteria provided
1681856	NM_001370595.2(COA8):c.85G>A (p.Glu29Lys)	COA8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
514386	NM_001370595.2(COA8):c.123+6C>T	COA8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1061664	NM_001370595.2(COA8):c.40C>T (p.Pro14Ser)	COA8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1681858	NM_001370595.2(COA8):c.97G>A (p.Glu33Lys)	COA8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1681862	NM_001370595.2(COA8):c.172C>A (p.Pro58Thr)	COA8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1681863	NM_001370595.2(COA8):c.197G>A (p.Arg66Gln)	COA8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1681870	NM_001370595.2(COA8):c.433G>A (p.Glu145Lys)	COA8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1809698	NM_001370595.2(COA8):c.106G>T (p.Asp36Tyr)	COA8	Uncertain significance	criteria provided, single submitter
559337	NM_001370595.2(COA8):c.101G>T (p.Arg34Leu)	COA8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1681860	NM_001370595.2(COA8):c.123+10G>C	COA8	Likely benign	criteria provided, multiple submitters, no conflicts
1681861	NM_001370595.2(COA8):c.129A>C (p.Ser43=)	COA8	Likely benign	criteria provided, multiple submitters, no conflicts
379942	NM_001370595.2(COA8):c.40C>G (p.Pro14Ala)	COA8	Benign	criteria provided, multiple submitters, no conflicts
380180	NM_001370595.2(COA8):c.351A>G (p.Leu117=)	COA8	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
384236	NM_001370595.2(COA8):c.476+19C>T	COA8	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
389633	NM_001370595.2(COA8):c.123+12C>T	COA8	Likely benign	criteria provided, multiple submitters, no conflicts
515737	NM_001370595.2(COA8):c.123+10G>A	COA8	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
715529	NM_001370595.2(COA8):c.81T>C (p.Ala27=)	COA8	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 6 · 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
COA8	Definitive	Autosomal recessive	mitochondrial complex IV deficiency, nuclear type 17	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COA8	Orphanet:436271	Non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy
AMN	Orphanet:35858	Imerslund-Gräsbeck syndrome
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COA8	HGNC:20492	ENSG00000256053	Q96IL0	Cytochrome c oxidase assembly factor 8	gencc,clinvar
AMN	HGNC:14604	ENSG00000166126	Q9BXJ7	Protein amnionless	clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COA8	Cytochrome c oxidase assembly factor 8	Required for cytochrome c complex (COX) IV assembly and function Protects COX assembly from oxidation-induced degradation, COX being the terminal component of the mitochondrial respiratory chain.
AMN	Protein amnionless	Membrane-bound component of the endocytic receptor formed by AMN and CUBN.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Transporter	1	25.9×	0.076
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COA8	Other/Unknown	no		COA8
AMN	Other/Unknown	no		AMN
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	1
left testis	1
right testis	1
duodenum	1
jejunal mucosa	1
mucosa of transverse colon	1
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COA8	248	ubiquitous	marker	left testis, right testis, hindlimb stylopod muscle
AMN	223	broad	marker	mucosa of transverse colon, jejunal mucosa, duodenum
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCD1	1,181
AMN	414
COA8	227

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCD1	P33897	14
AMN	Q9BXJ7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COA8	Q96IL0	81.19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCD1 causes ALD	1	2855.0×	0.005	ABCD1
Defective AMN causes MGA1	1	1903.3×	0.005	AMN
Defective CUBN causes MGA1	1	1903.3×	0.005	AMN
HDL clearance	1	1142.0×	0.006	AMN
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	951.7×	0.006	ABCD1
Linoleic acid (LA) metabolism	1	571.0×	0.006	ABCD1
Uptake of dietary cobalamins into enterocytes	1	571.0×	0.006	AMN
Transport of small molecules	2	25.1×	0.006	AMN, ABCD1
Beta-oxidation of very long chain fatty acids	1	439.2×	0.006	ABCD1
Defects in cobalamin (B12) metabolism	1	407.9×	0.006	AMN
alpha-linolenic acid (ALA) metabolism	1	356.9×	0.006	ABCD1
Peroxisomal lipid metabolism	1	335.9×	0.006	ABCD1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	317.2×	0.006	AMN
ABC transporters in lipid homeostasis	1	300.5×	0.006	ABCD1
Defects in vitamin and cofactor metabolism	1	300.5×	0.006	AMN
Class I peroxisomal membrane protein import	1	259.6×	0.007	ABCD1
Plasma lipoprotein clearance	1	237.9×	0.007	AMN
ABC transporter disorders	1	219.6×	0.007	ABCD1
Disease	2	13.1×	0.009	AMN, ABCD1
Metabolism	2	11.6×	0.011	AMN, ABCD1
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.012	AMN
Protein localization	1	95.2×	0.014	ABCD1
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.014	AMN
Disorders of transmembrane transporters	1	69.6×	0.017	ABCD1
Fatty acid metabolism	1	65.6×	0.018	ABCD1
ABC-family protein mediated transport	1	60.7×	0.018	ABCD1
Metabolism of vitamins and cofactors	1	58.3×	0.018	AMN
Diseases of metabolism	1	40.2×	0.026	AMN
Metabolism of lipids	1	15.8×	0.062	ABCD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peroxisomal membrane transport	1	2808.7×	0.004	ABCD1
very long-chain fatty-acyl-CoA catabolic process	1	2808.7×	0.004	ABCD1
renal protein absorption	1	1872.4×	0.004	AMN
positive regulation of unsaturated fatty acid biosynthetic process	1	1872.4×	0.004	ABCD1
sterol homeostasis	1	1404.3×	0.004	ABCD1
long-chain fatty acid import into peroxisome	1	1123.5×	0.004	ABCD1
regulation of fatty acid beta-oxidation	1	936.2×	0.004	ABCD1
long-chain fatty acid catabolic process	1	936.2×	0.004	ABCD1
myelin maintenance	1	936.2×	0.004	ABCD1
regulation of mitochondrial depolarization	1	936.2×	0.004	ABCD1
fatty acid elongation	1	802.5×	0.004	ABCD1
very long-chain fatty acid catabolic process	1	802.5×	0.004	ABCD1
cobalamin transport	1	624.1×	0.004	AMN
cobalamin metabolic process	1	510.7×	0.004	AMN
positive regulation of fatty acid beta-oxidation	1	510.7×	0.004	ABCD1
fatty acid derivative biosynthetic process	1	510.7×	0.004	ABCD1
regulation of cellular response to oxidative stress	1	432.1×	0.005	ABCD1
regulation of oxidative phosphorylation	1	401.2×	0.005	ABCD1
neuron projection maintenance	1	374.5×	0.005	ABCD1
response to reactive oxygen species	1	351.1×	0.005	COA8
negative regulation of reactive oxygen species biosynthetic process	1	330.4×	0.005	ABCD1
fatty acid homeostasis	1	312.1×	0.005	ABCD1
alpha-linolenic acid metabolic process	1	295.6×	0.005	ABCD1
peroxisome organization	1	267.5×	0.006	ABCD1
very long-chain fatty acid metabolic process	1	255.3×	0.006	ABCD1
linoleic acid metabolic process	1	234.1×	0.006	ABCD1
unsaturated fatty acid biosynthetic process	1	216.1×	0.006	ABCD1
mitochondrial respiratory chain complex IV assembly	1	208.1×	0.006	COA8
Golgi to plasma membrane protein transport	1	175.5×	0.007	AMN
long-chain fatty acid biosynthetic process	1	147.8×	0.008	ABCD1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
COA8	0	0
AMN	0	0
ABCD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	ABCD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COA8, AMN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COA8	0	—
AMN	0	—
ABCD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.