mitochondrial complex I deficiency, nuclear type 10

Summary

mitochondrial complex I deficiency, nuclear type 10 (MONDO:0032616) is a disease caused by NDUFAF2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: NDUFAF2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 10
Mondo ID	MONDO:0032616
OMIM	618233
DOID	DOID:0112075
UMLS	C4748768
MedGen	1648426
GARD	0016320
Is cancer (heuristic)	no

Also known as: MC1DN10

Data availability: 22 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 I deficiency › mitochondrial complex I deficiency, nuclear type › mitochondrial complex I deficiency, nuclear type 10

Related subtypes (36): mitochondrial complex I deficiency, nuclear type 12, mitochondrial complex I deficiency, nuclear type 30, Leber hereditary optic neuropathy, autosomal recessive, mitochondrial complex I deficiency, nuclear type 36, mitochondrial complex I deficiency, nuclear type 37, mitochondrial complex I deficiency, nuclear type 2, mitochondrial complex I deficiency, nuclear type 3, mitochondrial complex I deficiency, nuclear type 4, mitochondrial complex I deficiency, nuclear type 5, mitochondrial complex I deficiency, nuclear type 6, mitochondrial complex I deficiency, nuclear type 7, mitochondrial complex I deficiency, nuclear type 8, mitochondrial complex I deficiency, nuclear type 9, mitochondrial complex I deficiency, nuclear type 11, mitochondrial complex I deficiency, nuclear type 13, mitochondrial complex I deficiency, nuclear type 14, mitochondrial complex I deficiency, nuclear type 15, mitochondrial complex I deficiency, nuclear type 16, mitochondrial complex I deficiency, nuclear type 17, mitochondrial complex I deficiency, nuclear type 18, mitochondrial complex I deficiency, nuclear type 19, mitochondrial complex I deficiency, nuclear type 21, mitochondrial complex I deficiency, nuclear type 22, mitochondrial complex I deficiency, nuclear type 23, mitochondrial complex I deficiency, nuclear type 24, mitochondrial complex I deficiency, nuclear type 25, mitochondrial complex I deficiency, nuclear type 26, mitochondrial complex I deficiency, nuclear type 27, mitochondrial complex I deficiency, nuclear type 28, mitochondrial complex I deficiency, nuclear type 29, mitochondrial complex I deficiency, nuclear type 31, mitochondrial complex I deficiency, nuclear type 32, mitochondrial complex I deficiency, nuclear type 33, mitochondrial complex I deficiency, nuclear type 34, mitochondrial complex I deficiency, nuclear type 1, mitochondrial complex I deficiency, nuclear type 39

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

22 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
419231	NM_174889.5(NDUFAF2):c.114C>G (p.Tyr38Ter)	ERCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1323336	NM_174889.5(NDUFAF2):c.184del (p.Tyr62fs)	NDUFAF2	Pathogenic	criteria provided, multiple submitters, no conflicts
1594	NM_174889.5(NDUFAF2):c.139C>T (p.Arg47Ter)	NDUFAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1595	NM_174889.5(NDUFAF2):c.103del (p.Ile35fs)	NDUFAF2	Pathogenic	no assertion criteria provided
2885898	NM_174889.5(NDUFAF2):c.119dup (p.Asn40fs)	NDUFAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496555	NM_174889.5(NDUFAF2):c.221G>A (p.Trp74Ter)	NDUFAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496596	NM_174889.5(NDUFAF2):c.1A>T (p.Met1Leu)	NDUFAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496598	NM_174889.5(NDUFAF2):c.9G>A (p.Trp3Ter)	NDUFAF2	Pathogenic	criteria provided, single submitter
558212	NM_174889.5(NDUFAF2):c.13C>T (p.Gln5Ter)	ERCC8	Likely pathogenic	criteria provided, single submitter
3592732	NM_174889.5(NDUFAF2):c.167del (p.Asn56fs)	NDUFAF2	Likely pathogenic	criteria provided, single submitter
3592733	NM_174889.5(NDUFAF2):c.265_268del (p.Leu89fs)	NDUFAF2	Likely pathogenic	criteria provided, single submitter
3592734	NM_174889.5(NDUFAF2):c.289G>T (p.Glu97Ter)	NDUFAF2	Likely pathogenic	criteria provided, single submitter
3592735	NM_174889.5(NDUFAF2):c.304del (p.Ser102fs)	NDUFAF2	Likely pathogenic	criteria provided, single submitter
3592737	NM_174889.5(NDUFAF2):c.330dup (p.Leu111fs)	NDUFAF2	Likely pathogenic	criteria provided, single submitter
2890272	NM_174889.5(NDUFAF2):c.36G>A (p.Trp12Ter)	NDUFAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2434085	NM_174889.5(NDUFAF2):c.263T>C (p.Ile88Thr)	NDUFAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2637644	NM_174889.5(NDUFAF2):c.282_283del (p.His94fs)	NDUFAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2689551	NM_174889.5(NDUFAF2):c.50G>A (p.Arg17Lys)	NDUFAF2	Uncertain significance	criteria provided, single submitter
3393376	NM_174889.5(NDUFAF2):c.76G>C (p.Asp26His)	NDUFAF2	Uncertain significance	criteria provided, single submitter
129691	NM_174889.5(NDUFAF2):c.60G>A (p.Lys20=)	NDUFAF2	Benign	criteria provided, multiple submitters, no conflicts
138457	NM_174889.5(NDUFAF2):c.462T>C (p.Phe154=)	NDUFAF2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
671559	NM_174889.5(NDUFAF2):c.217+42A>G	NDUFAF2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 5 · 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
NDUFAF2	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 10	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDUFAF2	Orphanet:2609	Isolated complex I deficiency
ERCC8	Orphanet:178338	UV-sensitive syndrome
ERCC8	Orphanet:90321	Cockayne syndrome type 1
ERCC8	Orphanet:90322	Cockayne syndrome type 2
ERCC8	Orphanet:90324	Cockayne syndrome type 3

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
NDUFAF2	HGNC:28086	ENSG00000164182	Q8N183	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 2	gencc,clinvar
ERCC8	HGNC:3439	ENSG00000049167	Q13216	DNA excision repair protein ERCC-8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDUFAF2	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 2	Acts as a molecular chaperone for mitochondrial complex I assembly.
ERCC8	DNA excision repair protein ERCC-8	Substrate-recognition component of the CSA complex, a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, involved in transcription-coupled nucleotide excision repair (TC-NER), a process during which RNA polymerase II-blocking lesio…

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NDUFAF2	Other/Unknown	no		NDUFA12, ComplexI_NDUFA12
ERCC8	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
gastrocnemius	1
lower esophagus muscularis layer	1
adrenal tissue	1
primordial germ cell in gonad	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDUFAF2	139	ubiquitous	marker	calcaneal tendon, lower esophagus muscularis layer, gastrocnemius
ERCC8	218	ubiquitous	yes	adrenal tissue, ventricular zone, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFAF2	1,633
ERCC8	1,550

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC8	Q13216	16

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NDUFAF2	Q8N183	78.98

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
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	132.8×	0.022	ERCC8
Formation of TC-NER Pre-Incision Complex	1	105.7×	0.022	ERCC8
Gap-filling DNA repair synthesis and ligation in TC-NER	1	89.2×	0.022	ERCC8
Dual incision in TC-NER	1	86.5×	0.022	ERCC8
Complex I biogenesis	1	82.8×	0.022	NDUFAF2
Respiratory electron transport	1	47.6×	0.029	NDUFAF2
Aerobic respiration and respiratory electron transport	1	44.3×	0.029	NDUFAF2
Neddylation	1	23.7×	0.047	ERCC8
Metabolism	1	5.8×	0.165	NDUFAF2

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
regulation of transcription-coupled nucleotide-excision repair	1	8426.0×	0.002	ERCC8
negative regulation of insulin secretion involved in cellular response to glucose stimulus	1	842.6×	0.006	NDUFAF2
double-strand break repair via classical nonhomologous end joining	1	842.6×	0.006	ERCC8
single strand break repair	1	702.2×	0.006	ERCC8
transcription-coupled nucleotide-excision repair	1	601.9×	0.006	ERCC8
response to X-ray	1	443.5×	0.006	ERCC8
response to auditory stimulus	1	366.4×	0.007	ERCC8
mitochondrial respiratory chain complex I assembly	1	205.5×	0.009	NDUFAF2
response to UV	1	183.2×	0.009	ERCC8
positive regulation of DNA repair	1	179.3×	0.009	ERCC8
protein autoubiquitination	1	117.0×	0.013	ERCC8
response to oxidative stress	1	65.3×	0.022	ERCC8
protein polyubiquitination	1	57.7×	0.023	ERCC8
cilium assembly	1	36.8×	0.033	NDUFAF2
DNA damage response	1	26.8×	0.040	ERCC8
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.040	ERCC8
protein ubiquitination	1	20.7×	0.048	ERCC8

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NDUFAF2	0	0
ERCC8	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
NDUFAF2	5	Binding:5

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	NDUFAF2, ERCC8

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)
NDUFAF2	5	—
ERCC8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.