mitochondrial complex I deficiency, nuclear type 18

Summary

mitochondrial complex I deficiency, nuclear type 18 (MONDO:0032623) is a disease caused by NDUFAF3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: NDUFAF3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 18
Mondo ID	MONDO:0032623
OMIM	618240
DOID	DOID:0112070
UMLS	C4748790
MedGen	1648321
GARD	0016325
Is cancer (heuristic)	no

Also known as: MC1DN18

Data availability: 15 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 18

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 10, 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 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

15 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 5 pathogenic, 3 conflicting classifications of pathogenicity, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2674637	NM_199069.2(NDUFAF3):c.77+1G>A	LOC129936729	Pathogenic	no assertion criteria provided
424	NM_199069.2(NDUFAF3):c.2T>C (p.Met1Thr)	LOC129936729	Pathogenic	criteria provided, single submitter
422	NM_199069.2(NDUFAF3):c.229G>C (p.Gly77Arg)	LOC129936731	Pathogenic	no assertion criteria provided
2674636	NM_199069.2(NDUFAF3):c.302G>A (p.Ser101Asn)	NDUFAF3	Pathogenic	no assertion criteria provided
423	NM_199069.2(NDUFAF3):c.365G>C (p.Arg122Pro)	NDUFAF3	Pathogenic	no assertion criteria provided
2585571	NM_199069.2(NDUFAF3):c.127C>T (p.Gln43Ter)	LOC129936730	Likely pathogenic	criteria provided, single submitter
638292	NM_199069.2(NDUFAF3):c.494C>T (p.Ala165Val)	NDUFAF3	Likely pathogenic	criteria provided, single submitter
1207415	NM_199069.2(NDUFAF3):c.74C>T (p.Pro25Leu)	LOC129936729	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372432	NM_199069.2(NDUFAF3):c.489_490del (p.Gly164fs)	NDUFAF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
377248	NM_199069.2(NDUFAF3):c.188dup (p.Tyr63Ter)	NDUFAF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030419	NM_199069.2(NDUFAF3):c.112G>A (p.Asp38Asn)	LOC129936730	Uncertain significance	criteria provided, multiple submitters, no conflicts
2159215	NM_199069.2(NDUFAF3):c.336A>T (p.Ile112=)	NDUFAF3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434086	NM_199069.2(NDUFAF3):c.517G>A (p.Gly173Arg)	NDUFAF3	Uncertain significance	criteria provided, single submitter
4056643	NM_199069.2(NDUFAF3):c.143C>G (p.Ser48Cys)	NDUFAF3	Uncertain significance	criteria provided, single submitter
632420	NM_199069.2(NDUFAF3):c.550C>T (p.Gln184Ter)	NDUFAF3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
NDUFAF3	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 18	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDUFAF3	Orphanet:2609	Isolated complex I 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
NDUFAF3	HGNC:29918	ENSG00000178057	Q9BU61	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDUFAF3	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3	Essential factor for the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I).

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)
NDUFAF3	Other/Unknown	no		NDUFAF3/AAMDC, NDUF3, MTH938-like_sf

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
apex of heart	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDUFAF3	280	ubiquitous	marker	left testis, right testis, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFAF3	1,332

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NDUFAF3	Q9BU61	79.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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 I biogenesis	1	165.5×	0.015	NDUFAF3
Respiratory electron transport	1	95.2×	0.015	NDUFAF3
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	NDUFAF3
Metabolism	1	11.6×	0.086	NDUFAF3

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 respiratory chain complex I assembly	1	411.0×	0.002	NDUFAF3

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
NDUFAF3	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
NDUFAF3	4	Binding:4

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	NDUFAF3

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)
NDUFAF3	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.