mitochondrial complex I deficiency, nuclear type 8

Summary

mitochondrial complex I deficiency, nuclear type 8 (MONDO:0032613) is a disease caused by NDUFS3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: NDUFS3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 8
Mondo ID	MONDO:0032613
OMIM	618230
DOID	DOID:0112081
UMLS	C4748766
MedGen	1648411
GARD	0016318
Is cancer (heuristic)	no

Also known as: MC1DN8

Data availability: 16 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 8

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 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

16 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 4 conflicting classifications of pathogenicity, 2 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
6019	NM_004551.3(NDUFS3):c.434C>T (p.Thr145Ile)	NDUFS3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6020	NM_004551.3(NDUFS3):c.595C>T (p.Arg199Trp)	NDUFS3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431418	NM_004551.3(NDUFS3):c.382-1del	NDUFS3	Likely pathogenic	criteria provided, single submitter
3776784	NM_004551.3(NDUFS3):c.418C>G (p.Arg140Gly)	NDUFS3	Likely pathogenic	criteria provided, single submitter
138490	NM_004551.3(NDUFS3):c.591T>C (p.Pro197=)	NDUFS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138491	NM_004551.3(NDUFS3):c.628-7C>T	NDUFS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214802	NM_004551.3(NDUFS3):c.475G>C (p.Val159Leu)	NDUFS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
418381	NM_004551.3(NDUFS3):c.374G>A (p.Arg125His)	NDUFS3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030815	NM_004551.3(NDUFS3):c.406C>T (p.Arg136Cys)	NDUFS3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1064536	NM_004551.3(NDUFS3):c.419G>A (p.Arg140Gln)	NDUFS3	Uncertain significance	criteria provided, single submitter
1406925	NM_004551.3(NDUFS3):c.133+3_133+6del	NDUFS3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434093	NM_004551.3(NDUFS3):c.223C>T (p.Gln75Ter)	NDUFS3	Uncertain significance	criteria provided, single submitter
304996	NM_004551.3(NDUFS3):c.381+6T>C	NDUFS3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3599778	NM_004551.3(NDUFS3):c.68G>C (p.Gly23Ala)	NDUFS3	Uncertain significance	criteria provided, single submitter
523006	NM_004551.3(NDUFS3):c.596G>A (p.Arg199Gln)	NDUFS3	Uncertain significance	criteria provided, multiple submitters, no conflicts
638291	NM_004551.3(NDUFS3):c.418C>T (p.Arg140Trp)	NDUFS3	Uncertain significance	criteria provided, multiple submitters, no conflicts

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
NDUFS3	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 8	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDUFS3	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
NDUFS3	HGNC:7710	ENSG00000213619	O75489	NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDUFS3	NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, 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)
NDUFS3	Other/Unknown	no		NADH_UbQ_OxRdtase_30kDa_su, NADH_DH_suC, NADH_UbQ_OxRdtase_CS

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
mucosa of transverse colon	1
putamen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDUFS3	140	ubiquitous	marker	putamen, mucosa of transverse colon, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFS3	5,461

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDUFS3	O75489	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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×	0.025	NDUFS3
RHOG GTPase cycle	1	148.3×	0.025	NDUFS3
Mitochondrial protein degradation	1	114.2×	0.025	NDUFS3
Respiratory electron transport	1	95.2×	0.025	NDUFS3
Aerobic respiration and respiratory electron transport	1	88.5×	0.025	NDUFS3
RHO GTPase cycle	1	60.1×	0.031	NDUFS3
Signaling by Rho GTPases	1	34.2×	0.041	NDUFS3
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.041	NDUFS3
Metabolism of proteins	1	12.4×	0.095	NDUFS3
Metabolism	1	11.6×	0.095	NDUFS3
Signal Transduction	1	10.2×	0.098	NDUFS3

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
reactive oxygen species metabolic process	1	468.1×	0.004	NDUFS3
mitochondrial respiratory chain complex I assembly	1	411.0×	0.004	NDUFS3
substantia nigra development	1	366.4×	0.004	NDUFS3
mitochondrial electron transport, NADH to ubiquinone	1	358.6×	0.004	NDUFS3
proton motive force-driven mitochondrial ATP synthesis	1	263.3×	0.004	NDUFS3
aerobic respiration	1	247.8×	0.004	NDUFS3

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
NDUFS3	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
NDUFS3	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	NDUFS3

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)
NDUFS3	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.