mitochondrial complex I deficiency, nuclear type 3

Summary

mitochondrial complex I deficiency, nuclear type 3 (MONDO:0032608) is a disease caused by variants in NDUFS7 and NDUFAF5, with 2 cohort genes.

At a glance

• Causal genes: NDUFS7 (GenCC Definitive), NDUFAF5 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 3
Mondo ID	MONDO:0032608
OMIM	618224
DOID	DOID:0112093
UMLS	C4748752
MedGen	1648346
GARD	0016313
Is cancer (heuristic)	no

Also known as: MC1DN3

Data availability: 19 ClinVar variants · 4 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 3

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 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 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

19 retrieved; paginated sample, class counts are floors:

7 likely pathogenic, 5 conflicting classifications of pathogenicity, 2 benign, 2 pathogenic/likely pathogenic, 1 uncertain significance, 1 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2957829	NM_024407.5(NDUFS7):c.339_348del (p.Arg115fs)	NDUFS7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3022568	NM_024407.5(NDUFS7):c.343_352dup (p.Asp118fs)	NDUFS7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7682	NM_024407.5(NDUFS7):c.434G>A (p.Arg145His)	NDUFS7	Pathogenic	no assertion criteria provided
1806253	NM_024407.5(NDUFS7):c.304G>A (p.Asp102Asn)	NDUFS7	Likely pathogenic	criteria provided, single submitter
2442036	NM_024407.5(NDUFS7):c.537C>A (p.Tyr179Ter)	NDUFS7	Likely pathogenic	criteria provided, single submitter
2819120	NM_024407.5(NDUFS7):c.455+2T>C	NDUFS7	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3583495	NM_024407.5(NDUFS7):c.345_354del (p.Gln116fs)	NDUFS7	Likely pathogenic	criteria provided, single submitter
3583496	NM_024407.5(NDUFS7):c.408+1G>C	NDUFS7	Likely pathogenic	criteria provided, single submitter
689475	NM_024407.5(NDUFS7):c.415G>A (p.Asp139Asn)	NDUFS7	Likely pathogenic	criteria provided, single submitter
7683	NM_024407.5(NDUFS7):c.17-1167C>G	NDUFS7	Likely pathogenic	criteria provided, single submitter
1522732	NM_024407.5(NDUFS7):c.180C>T (p.Gly60=)	NDUFS7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1806251	NM_024407.5(NDUFS7):c.256C>G (p.Leu86Val)	NDUFS7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214833	NM_024407.5(NDUFS7):c.456-16G>A	NDUFS7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
423998	NM_024407.5(NDUFS7):c.439G>A (p.Val147Met)	NDUFS7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7681	NM_024407.5(NDUFS7):c.364G>A (p.Val122Met)	NDUFS7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2155247	NM_024407.5(NDUFS7):c.520G>A (p.Val174Met)	NDUFS7	Uncertain significance	criteria provided, multiple submitters, no conflicts
1185398	NM_024407.5(NDUFS7):c.455+71G>A	NDUFS7	Benign	criteria provided, multiple submitters, no conflicts
129702	NM_024407.5(NDUFS7):c.68C>T (p.Pro23Leu)	NDUFS7	Benign	criteria provided, multiple submitters, no conflicts
514399	NM_024407.5(NDUFS7):c.54-19G>A	NDUFS7	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · 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
NDUFS7	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 3	5
NDUFAF5	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 16	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDUFS7	Orphanet:2609	Isolated complex I deficiency
NDUFAF5	Orphanet:2609	Isolated complex I deficiency

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
NDUFS7	HGNC:7714	ENSG00000115286	O75251	NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial	gencc,clinvar
NDUFAF5	HGNC:15899	ENSG00000101247	Q5TEU4	Arginine-hydroxylase NDUFAF5, mitochondrial	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDUFS7	NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
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: 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)
NDUFS7	Other/Unknown	no		NADH_UbQ_OxRdtase-like_20kDa, NADH_UQ_OxRdtase_20Kd_su
NDUFAF5	Other/Unknown	no		Methyltransf_11, SAM-dependent_MTases_sf, Malonyl-ACP_OMT

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
apex of heart	2
hindlimb stylopod muscle	2
gastrocnemius	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDUFS7	286	ubiquitous	marker	hindlimb stylopod muscle, apex of heart, gastrocnemius
NDUFAF5	261	ubiquitous	marker	apex of heart, right atrium auricular region, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFS7	3,621
NDUFAF5	1,900

Intra-cohort edges

A	B	Sources
NDUFAF5	NDUFS7	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDUFS7	O75251	7

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 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
Complex I biogenesis	2	165.5×	1e-04	NDUFS7, NDUFAF5
Respiratory electron transport	2	95.2×	2e-04	NDUFS7, NDUFAF5
Aerobic respiration and respiratory electron transport	2	88.5×	2e-04	NDUFS7, NDUFAF5
Metabolism	2	11.6×	0.007	NDUFS7, 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 2 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	2	411.0×	3e-05	NDUFS7, NDUFAF5
electron transport coupled proton transport	1	2106.5×	0.001	NDUFS7
mitochondrial electron transport, NADH to ubiquinone	1	179.3×	0.010	NDUFS7
proton motive force-driven mitochondrial ATP synthesis	1	131.7×	0.010	NDUFS7
aerobic respiration	1	123.9×	0.010	NDUFS7
methylation	1	85.1×	0.012	NDUFAF5

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
NDUFS7	0	0
NDUFAF5	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
NDUFS7	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	NDUFS7, NDUFAF5

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)
NDUFS7	5	—
NDUFAF5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.