mitochondrial complex IV deficiency, nuclear type 12

Summary

mitochondrial complex IV deficiency, nuclear type 12 (MONDO:0033646) is a disease caused by PET100 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PET100 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex IV deficiency, nuclear type 12
Mondo ID	MONDO:0033646
OMIM	619055
DOID	DOID:0070498
UMLS	C5436695
MedGen	1745691
GARD	0016410
Is cancer (heuristic)	no

Also known as: MC4DN12 · mitochondrial complex IV deficiency, nuclear type 12

Data availability: 21 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 12

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 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

21 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 3 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 likely benign, 2 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
125441	NM_001171155.2(PET100):c.3G>C (p.Met1Ile)	STXBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
128250	NM_001171155.2(PET100):c.142C>T (p.Gln48Ter)	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686017	NM_001171155.2(PET100):c.1A>G (p.Met1Val)	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2788135	NM_001171155.2(PET100):c.28-2A>G	PET100	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2889283	NM_001171155.2(PET100):c.114+1G>A	PET100	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584209	NM_001171155.2(PET100):c.3G>A (p.Met1Ile)	PET100	Likely pathogenic	criteria provided, single submitter
1695740	NM_001171155.2(PET100):c.200G>A (p.Arg67His)	PET100	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1895460	NM_001171155.2(PET100):c.115-3C>G	PET100	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1919084	NM_001171155.2(PET100):c.114+7A>G	PET100	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3584210	NM_001171155.2(PET100):c.20T>C (p.Ile7Thr)	LOC130063380	Uncertain significance	criteria provided, single submitter
3584211	NM_001171155.2(PET100):c.27+4A>G	LOC130063380	Uncertain significance	criteria provided, single submitter
1368798	NM_001171155.2(PET100):c.184GAG[1] (p.Glu63del)	PET100	Uncertain significance	criteria provided, multiple submitters, no conflicts
3584212	NM_001171155.2(PET100):c.28A>G (p.Met10Val)	PET100	Uncertain significance	criteria provided, single submitter
3584213	NM_001171155.2(PET100):c.49C>T (p.Pro17Ser)	PET100	Uncertain significance	criteria provided, single submitter
3584215	NM_001171155.2(PET100):c.140T>G (p.Leu47Arg)	PET100	Uncertain significance	criteria provided, single submitter
3584216	NM_001171155.2(PET100):c.154G>C (p.Glu52Gln)	PET100	Uncertain significance	criteria provided, single submitter
3584217	NM_001171155.2(PET100):c.205G>A (p.Ala69Thr)	PET100	Uncertain significance	criteria provided, single submitter
3584218	NM_001171155.2(PET100):c.205G>T (p.Ala69Ser)	PET100	Uncertain significance	criteria provided, multiple submitters, no conflicts
1436166	NM_001171155.2(PET100):c.138+3A>T	STXBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1218913	NM_001171155.2(PET100):c.74A>G (p.Asn25Ser)	PET100	Likely benign	criteria provided, multiple submitters, no conflicts
517815	NM_001171155.2(PET100):c.139-11_139-9del	PET100	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
PET100	Strong	Autosomal recessive	mitochondrial complex IV deficiency, nuclear type 12	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STXBP2	Orphanet:540	Familial hemophagocytic lymphohistiocytosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PET100	HGNC:40038	ENSG00000229833	P0DJ07	Protein PET100 homolog, mitochondrial	gencc,clinvar
STXBP2	HGNC:11445	ENSG00000076944	Q15833	Syntaxin-binding protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PET100	Protein PET100 homolog, mitochondrial	Plays an essential role in mitochondrial complex IV maturation and assembly.
STXBP2	Syntaxin-binding protein 2	Involved in intracellular vesicle trafficking and vesicle fusion with membranes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PET100	Other/Unknown	no		Pet100
STXBP2	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	2
bone marrow cell	1
colonic epithelium	1
granulocyte	1
leukocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PET100	134	ubiquitous	marker	bone marrow cell, colonic epithelium, monocyte
STXBP2	227	ubiquitous	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STXBP2	1,556
PET100	732

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STXBP2	Q15833	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PET100	P0DJ07	87.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 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
Other interleukin signaling	1	237.9×	0.037	STXBP2
Complex IV assembly	1	114.2×	0.037	PET100
Response to elevated platelet cytosolic Ca2+	1	81.6×	0.037	STXBP2
Platelet activation, signaling and aggregation	1	52.9×	0.041	STXBP2
Platelet degranulation	1	43.9×	0.041	STXBP2
Signaling by Interleukins	1	32.1×	0.046	STXBP2
Cytokine Signaling in Immune system	1	20.4×	0.062	STXBP2
Hemostasis	1	18.0×	0.062	STXBP2
Immune System	1	6.5×	0.148	STXBP2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
leukocyte mediated cytotoxicity	1	8426.0×	9e-04	STXBP2
presynaptic dense core vesicle exocytosis	1	2106.5×	0.002	STXBP2
neutrophil degranulation	1	1685.2×	0.002	STXBP2
regulation of mast cell degranulation	1	936.2×	0.002	STXBP2
obsolete vesicle docking involved in exocytosis	1	337.0×	0.004	STXBP2
mitochondrial respiratory chain complex IV assembly	1	312.1×	0.004	PET100
cellular response to type II interferon	1	104.0×	0.011	STXBP2
intracellular protein transport	1	32.4×	0.031	STXBP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
PET100	0	0
STXBP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	PET100, STXBP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PET100	0	—
STXBP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.