mitochondrial complex I deficiency, nuclear type 5

Summary

mitochondrial complex I deficiency, nuclear type 5 (MONDO:0032610) is a disease caused by NDUFS1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: NDUFS1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 69

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 5
Mondo ID	MONDO:0032610
OMIM	618226
DOID	DOID:0112068
UMLS	C4748754
MedGen	1648292
GARD	0016315
Is cancer (heuristic)	no

Also known as: MC1DN5

Data availability: 69 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 5

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 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

69 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 11 conflicting classifications of pathogenicity, 9 likely pathogenic, 7 pathogenic, 5 benign, 4 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
14230	NM_005006.7(NDUFS1):c.666_668del (p.Ile223del)	NDUFS1	Pathogenic	no assertion criteria provided
14231	NM_005006.7(NDUFS1):c.755A>G (p.Asp252Gly)	NDUFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1945436	NM_005006.7(NDUFS1):c.454C>T (p.Arg152Ter)	NDUFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214772	NM_005006.7(NDUFS1):c.1393-2A>C	NDUFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3254827	NM_005006.7(NDUFS1):c.1880_1881del (p.Leu626_Ser627insTer)	NDUFS1	Pathogenic	criteria provided, single submitter
3254828	NM_005006.7(NDUFS1):c.1298_1325del (p.Gly433fs)	NDUFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3896664	NM_005006.7(NDUFS1):c.2029C>T (p.Gln677Ter)	NDUFS1	Pathogenic	criteria provided, single submitter
429933	NM_005006.7(NDUFS1):c.683T>C (p.Val228Ala)	NDUFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50922	NM_005006.7(NDUFS1):c.1855G>A (p.Asp619Asn)	NDUFS1	Pathogenic	no assertion criteria provided
50923	NM_005006.7(NDUFS1):c.1669C>T (p.Arg557Ter)	NDUFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
626277	NM_005006.7(NDUFS1):c.64C>T (p.Arg22Ter)	NDUFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1324785	NM_005006.7(NDUFS1):c.1810C>T (p.Gln604Ter)	NDUFS1	Likely pathogenic	criteria provided, single submitter
1804014	NM_005006.7(NDUFS1):c.988-2A>C	NDUFS1	Likely pathogenic	criteria provided, single submitter
2690651	NM_005006.7(NDUFS1):c.1119dup (p.Thr374fs)	NDUFS1	Likely pathogenic	criteria provided, single submitter
31914	NM_005006.7(NDUFS1):c.1783A>G (p.Thr595Ala)	NDUFS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3254569	NM_005006.7(NDUFS1):c.548T>G (p.Ile183Ser)	NDUFS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4277428	NM_005006.7(NDUFS1):c.758_761dup (p.Met254fs)	NDUFS1	Likely pathogenic	criteria provided, single submitter
432383	NM_005006.7(NDUFS1):c.1223G>A (p.Arg408His)	NDUFS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4526394	NM_005006.7(NDUFS1):c.1112T>A (p.Val371Asp)	NDUFS1	Likely pathogenic	criteria provided, single submitter
800917	NM_005006.7(NDUFS1):c.2121G>A (p.Met707Ile)	NDUFS1	Likely pathogenic	no assertion criteria provided
138479	NM_005006.7(NDUFS1):c.1291C>G (p.Leu431Val)	NDUFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138480	NM_005006.7(NDUFS1):c.1371G>A (p.Ser457=)	NDUFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14232	NM_005006.7(NDUFS1):c.721C>T (p.Arg241Trp)	NDUFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214770	NM_005006.7(NDUFS1):c.529A>G (p.Ile177Val)	NDUFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2506502	NM_005006.7(NDUFS1):c.2102G>A (p.Ser701Asn)	NDUFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333781	NM_005006.7(NDUFS1):c.1516G>A (p.Val506Ile)	NDUFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
417877	NM_005006.7(NDUFS1):c.908C>G (p.Thr303Ser)	NDUFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
50924	NM_005006.7(NDUFS1):c.1222C>T (p.Arg408Cys)	NDUFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
561062	NM_005006.7(NDUFS1):c.1249A>G (p.Arg417Gly)	NDUFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
801856	NM_005006.7(NDUFS1):c.1256G>A (p.Arg419Gln)	NDUFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
NDUFS1	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 5	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDUFS1	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
NDUFS1	HGNC:7707	ENSG00000023228	P28331	NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDUFS1	NADH-ubiquinone oxidoreductase 75 kDa subunit, 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)
NDUFS1	Other/Unknown	no		NADH_UbQ_OxRdtase_75kDa_su_CS, 2Fe-2S_ferredoxin-type, Mopterin_OxRdtase

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
adrenal tissue	1
corpus callosum	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDUFS1	142	ubiquitous	marker	corpus callosum, skeletal muscle tissue, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFS1	3,899

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDUFS1	P28331	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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×	0.017	NDUFS1
Mitochondrial protein degradation	1	114.2×	0.017	NDUFS1
Respiratory electron transport	1	95.2×	0.017	NDUFS1
Aerobic respiration and respiratory electron transport	1	88.5×	0.017	NDUFS1
Metabolism of proteins	1	12.4×	0.086	NDUFS1
Metabolism	1	11.6×	0.086	NDUFS1

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 respiration	1	432.1×	0.004	NDUFS1
mitochondrial respiratory chain complex I assembly	1	411.0×	0.004	NDUFS1
mitochondrial electron transport, NADH to ubiquinone	1	358.6×	0.004	NDUFS1
proton motive force-driven mitochondrial ATP synthesis	1	263.3×	0.004	NDUFS1
aerobic respiration	1	247.8×	0.004	NDUFS1

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
NDUFS1	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
NDUFS1	5	Binding:5

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	NDUFS1

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)
NDUFS1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.