mitochondrial complex I deficiency, nuclear type 16

Summary

mitochondrial complex I deficiency, nuclear type 16 (MONDO:0032621) is a disease caused by NDUFAF5 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: NDUFAF5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 93

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 16
Mondo ID	MONDO:0032621
OMIM	618238
DOID	DOID:0112096
UMLS	C4748785
MedGen	1648351
GARD	0016324
Is cancer (heuristic)	no

Also known as: MC1DN16

Data availability: 93 ClinVar variants · 2 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 16

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 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

93 retrieved; paginated sample, class counts are floors:

29 likely pathogenic, 27 pathogenic/likely pathogenic, 13 uncertain significance, 13 conflicting classifications of pathogenicity, 5 benign, 3 pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1982970	NM_024120.5(NDUFAF5):c.24G>A (p.Trp8Ter)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1983600	NM_024120.5(NDUFAF5):c.23G>A (p.Trp8Ter)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2073702	NM_024120.5(NDUFAF5):c.46del (p.Ala16fs)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138338	NM_024120.5(NDUFAF5):c.29T>A (p.Leu10Ter)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2139992	NM_024120.5(NDUFAF5):c.44G>A (p.Trp15Ter)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676972	NM_024120.5(NDUFAF5):c.30_31del (p.Cys11fs)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4056399	NM_024120.5(NDUFAF5):c.163C>A (p.Gln55Lys)	LOC130065433	Pathogenic	criteria provided, single submitter
1162277	NM_024120.5(NDUFAF5):c.223-907A>C	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1321429	NM_024120.5(NDUFAF5):c.604C>T (p.Gln202Ter)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722455	NM_024120.5(NDUFAF5):c.712_715del (p.Thr238fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1909379	NM_024120.5(NDUFAF5):c.277_280del (p.Ala93fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1975286	NM_024120.5(NDUFAF5):c.440del (p.Phe147fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1985636	NM_024120.5(NDUFAF5):c.445G>T (p.Glu149Ter)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2078597	NM_024120.5(NDUFAF5):c.183_190dup (p.Glu64fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2141476	NM_024120.5(NDUFAF5):c.204del (p.Phe68fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2141503	NM_024120.5(NDUFAF5):c.826C>T (p.Arg276Ter)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2154677	NM_024120.5(NDUFAF5):c.408dup (p.Ser137fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2200296	NM_024120.5(NDUFAF5):c.33T>A (p.Cys11Ter)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225036	NM_024120.5(NDUFAF5):c.836T>G (p.Met279Arg)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2579156	NM_024120.5(NDUFAF5):c.223-2A>T	NDUFAF5	Pathogenic	criteria provided, single submitter
265061	NM_024120.5(NDUFAF5):c.327G>C (p.Lys109Asn)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676970	NM_024120.5(NDUFAF5):c.552dup (p.Ile185fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676976	NM_024120.5(NDUFAF5):c.165_166del (p.Lys56fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676978	NM_024120.5(NDUFAF5):c.690del (p.Arg231fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676980	NM_024120.5(NDUFAF5):c.489G>A (p.Trp163Ter)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2703746	NM_024120.5(NDUFAF5):c.1A>C (p.Met1Leu)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2775972	NM_024120.5(NDUFAF5):c.529del (p.Ile177fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372253	NM_024120.5(NDUFAF5):c.749G>T (p.Gly250Val)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
421779	NM_024120.5(NDUFAF5):c.583dup (p.Tyr195fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
571	NM_024120.5(NDUFAF5):c.477A>C (p.Leu159Phe)	NDUFAF5	Pathogenic	no assertion criteria provided

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
NDUFAF5	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 16	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDUFAF5	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
NDUFAF5	HGNC:15899	ENSG00000101247	Q5TEU4	Arginine-hydroxylase NDUFAF5, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDUFAF5	Arginine-hydroxylase NDUFAF5, mitochondrial	Arginine hydroxylase that mediates hydroxylation of ‘Arg-111’ of NDUFS7 and is involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) at early stages.

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)
NDUFAF5	Other/Unknown	no		Methyltransf_11, SAM-dependent_MTases_sf, Malonyl-ACP_OMT

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
hindlimb stylopod muscle	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDUFAF5	261	ubiquitous	marker	apex of heart, right atrium auricular region, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFAF5	1,900

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NDUFAF5	Q5TEU4	85.43

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	NDUFAF5
Respiratory electron transport	1	95.2×	0.015	NDUFAF5
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	NDUFAF5
Metabolism	1	11.6×	0.086	NDUFAF5

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×	0.005	NDUFAF5
methylation	1	170.2×	0.006	NDUFAF5

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
NDUFAF5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	NDUFAF5

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)
NDUFAF5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.