mitochondrial complex I deficiency, nuclear type 6

Summary

mitochondrial complex I deficiency, nuclear type 6 (MONDO:0032611) is a disease caused by NDUFS2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: NDUFS2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 38

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 6
Mondo ID	MONDO:0032611
OMIM	618228
DOID	DOID:0112066
UMLS	C4748759
MedGen	1648496
GARD	0016316
Is cancer (heuristic)	no

Also known as: MC1DN6

Data availability: 38 ClinVar variants · 5 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 6

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 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

38 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 6 conflicting classifications of pathogenicity, 5 benign/likely benign, 5 likely benign, 4 benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
6710	NM_001377299.1(NDUFS2):c.686C>A (p.Pro229Gln)	NDUFS2	Pathogenic	no assertion criteria provided
6711	NM_001377299.1(NDUFS2):c.1237T>C (p.Ser413Pro)	NDUFS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
214787	NM_001377299.1(NDUFS2):c.968G>A (p.Arg323Gln)	NDUFS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214795	NM_001377299.1(NDUFS2):c.1138C>G (p.His380Asp)	NDUFS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214799	NM_001377299.1(NDUFS2):c.158A>G (p.Tyr53Cys)	NDUFS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293273	NM_001377299.1(NDUFS2):c.337A>G (p.Ile113Val)	NDUFS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6709	NM_001377299.1(NDUFS2):c.683G>A (p.Arg228Gln)	NDUFS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
985317	NM_001377299.1(NDUFS2):c.1324C>T (p.His442Tyr)	NDUFS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2136289	NM_001377299.1(NDUFS2):c.59C>T (p.Pro20Leu)	LOC129931761	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030813	NM_001377299.1(NDUFS2):c.422A>G (p.Tyr141Cys)	NDUFS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1303015	NM_001377299.1(NDUFS2):c.998G>A (p.Arg333Gln)	NDUFS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1422418	NM_001377299.1(NDUFS2):c.412C>T (p.Arg138Trp)	NDUFS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709667	NM_001377299.1(NDUFS2):c.860G>A (p.Gly287Asp)	NDUFS2	Uncertain significance	criteria provided, single submitter
1967017	NM_001377299.1(NDUFS2):c.845A>C (p.Glu282Ala)	NDUFS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1973021	NM_001377299.1(NDUFS2):c.1342G>A (p.Val448Ile)	NDUFS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214796	NM_001377299.1(NDUFS2):c.1212G>A (p.Lys404=)	NDUFS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214800	NM_001377299.1(NDUFS2):c.393+5G>A	NDUFS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2413148	NM_001377299.1(NDUFS2):c.245T>A (p.Leu82Gln)	NDUFS2	Uncertain significance	criteria provided, single submitter
293271	NM_001377299.1(NDUFS2):c.98G>A (p.Gly33Asp)	NDUFS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3254825	NM_001377299.1(NDUFS2):c.442G>C (p.Glu148Gln)	NDUFS2	Uncertain significance	criteria provided, single submitter
638369	NM_001377299.1(NDUFS2):c.934G>C (p.Asp312His)	NDUFS2	Uncertain significance	criteria provided, single submitter
876337	NM_001377299.1(NDUFS2):c.1367T>C (p.Ile456Thr)	NDUFS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
928840	NM_001377299.1(NDUFS2):c.1105G>A (p.Ala369Thr)	NDUFS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
973096	NM_001377299.1(NDUFS2):c.662G>A (p.Arg221Gln)	NDUFS2	Uncertain significance	no assertion criteria provided
293269	NM_001377299.1(NDUFS2):c.58C>A (p.Pro20Thr)	LOC129931761	Benign	criteria provided, multiple submitters, no conflicts
516382	NM_001377299.1(NDUFS2):c.39C>A (p.Val13=)	LOC129931761	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
129697	NM_001377299.1(NDUFS2):c.1054C>G (p.Pro352Ala)	NDUFS2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
129698	NM_001377299.1(NDUFS2):c.1290C>T (p.Ala430=)	NDUFS2	Benign	criteria provided, multiple submitters, no conflicts
138486	NM_001377299.1(NDUFS2):c.986+12A>G	NDUFS2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1589328	NM_001377299.1(NDUFS2):c.777G>A (p.Glu259=)	NDUFS2	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
NDUFS2	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 6	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDUFS2	Orphanet:104	Leber hereditary optic neuropathy
NDUFS2	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
NDUFS2	HGNC:7708	ENSG00000158864	O75306	NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDUFS2	NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, 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.

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)
NDUFS2	Other/Unknown	no		NADH_Q_OxRdtase_suD, NADH_UbQ_OxRdtase_49kDa_CS, NDH1_su_D/H

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
gastrocnemius	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDUFS2	292	ubiquitous	marker	apex of heart, gastrocnemius, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFS2	4,412

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDUFS2	O75306	8

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	NDUFS2
Respiratory electron transport	1	95.2×	0.015	NDUFS2
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	NDUFS2
Metabolism	1	11.6×	0.086	NDUFS2

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
cellular response to oxygen levels	1	4213.0×	0.002	NDUFS2
gliogenesis	1	2808.7×	0.002	NDUFS2
mitochondrial ATP synthesis coupled electron transport	1	1872.4×	0.002	NDUFS2
neural precursor cell proliferation	1	674.1×	0.003	NDUFS2
mitochondrial respiratory chain complex I assembly	1	411.0×	0.004	NDUFS2
mitochondrial electron transport, NADH to ubiquinone	1	358.6×	0.004	NDUFS2
proton motive force-driven mitochondrial ATP synthesis	1	263.3×	0.005	NDUFS2
aerobic respiration	1	247.8×	0.005	NDUFS2
neurogenesis	1	208.1×	0.005	NDUFS2

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
NDUFS2	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
NDUFS2	11	Binding:10, Functional:1

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	NDUFS2

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)
NDUFS2	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.