mitochondrial complex I deficiency, nuclear type 9

Summary

mitochondrial complex I deficiency, nuclear type 9 (MONDO:0032615) is a disease caused by NDUFS6 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: NDUFS6 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 36

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 9
Mondo ID	MONDO:0032615
OMIM	618232
DOID	DOID:0112073
UMLS	C4748767
MedGen	1648447
GARD	0016319
Is cancer (heuristic)	no

Also known as: MC1DN9

Data availability: 36 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 9

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 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

36 retrieved; paginated sample, class counts are floors:

12 likely pathogenic, 9 pathogenic/likely pathogenic, 5 benign, 5 uncertain significance, 3 conflicting classifications of pathogenicity, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1676852	NM_004553.6(NDUFS6):c.32_33dup (p.Asn12Ter)	NDUFS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1906235	NM_004553.6(NDUFS6):c.309+1G>C	NDUFS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2141323	NM_004553.6(NDUFS6):c.320_323del (p.Thr107fs)	NDUFS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2175361	NM_004553.6(NDUFS6):c.309+2T>C	NDUFS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2212407	NM_004553.6(NDUFS6):c.109G>T (p.Glu37Ter)	NDUFS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677002	NM_004553.6(NDUFS6):c.242del (p.Glu81fs)	NDUFS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677004	NM_004553.6(NDUFS6):c.309+1G>T	NDUFS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2812650	NM_004553.6(NDUFS6):c.309+1G>A	NDUFS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6016	NM_004553.6(NDUFS6):c.186+2T>A	NDUFS6	Pathogenic	criteria provided, single submitter
6017	nsv1197507	NDUFS6	Pathogenic	no assertion criteria provided
983268	NM_004553.6(NDUFS6):c.309+5G>A	NDUFS6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2432093	NM_004553.6(NDUFS6):c.223C>T (p.Gln75Ter)	NDUFS6	Likely pathogenic	criteria provided, single submitter
2677000	NM_004553.6(NDUFS6):c.187-1G>C	NDUFS6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677001	NM_004553.6(NDUFS6):c.314_315del (p.Lys105fs)	NDUFS6	Likely pathogenic	criteria provided, single submitter
2677003	NM_004553.6(NDUFS6):c.182_185del (p.Lys61fs)	NDUFS6	Likely pathogenic	criteria provided, single submitter
2677005	NM_004553.6(NDUFS6):c.302_303del (p.Ile101fs)	NDUFS6	Likely pathogenic	criteria provided, single submitter
2677006	NM_004553.6(NDUFS6):c.186+1G>A	NDUFS6	Likely pathogenic	criteria provided, single submitter
3239851	NM_004553.6(NDUFS6):c.185_186del (p.Glu62fs)	NDUFS6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3239852	NM_004553.6(NDUFS6):c.187-2A>T	NDUFS6	Likely pathogenic	criteria provided, single submitter
3592192	NM_004553.6(NDUFS6):c.334_359delinsAACAAACAAAAA (p.Cys112fs)	NDUFS6	Likely pathogenic	criteria provided, single submitter
4081535	NM_004553.6(NDUFS6):c.187-38_223del	NDUFS6	Likely pathogenic	criteria provided, single submitter
6018	NM_004553.6(NDUFS6):c.344G>A (p.Cys115Tyr)	NDUFS6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
800912	NM_004553.6(NDUFS6):c.80G>A (p.Cys27Tyr)	NDUFS6	Likely pathogenic	no assertion criteria provided
138493	NM_004553.4(NDUFS6):c.-12C>T	MRPL36	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2153173	NM_004553.6(NDUFS6):c.15G>A (p.Met5Ile)	MRPL36	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214820	NM_004553.6(NDUFS6):c.247C>T (p.Arg83Trp)	NDUFS6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
983422	NM_004553.6(NDUFS6):c.2T>G (p.Met1Arg)	MRPL36	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333919	NM_004553.6(NDUFS6):c.356T>A (p.Phe119Tyr)	NDUFS6	Uncertain significance	criteria provided, single submitter
1398895	NM_004553.6(NDUFS6):c.92G>T (p.Arg31Leu)	NDUFS6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1414839	NM_004553.6(NDUFS6):c.83T>A (p.Phe28Tyr)	NDUFS6	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
NDUFS6	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 9	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDUFS6	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
NDUFS6	HGNC:7713	ENSG00000145494	O75380	NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial	gencc,clinvar
MRPL36	HGNC:14490	ENSG00000171421	Q9P0J6	Large ribosomal subunit protein bL36m	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDUFS6	NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NDUFS6	Transcription factor	no		NDUFS6, Znf_CHCC
MRPL36	Other/Unknown	no		Ribosomal_bL36, Ribosomal_bL36_sp, Mitoribosomal_bL36m

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	1
right atrium auricular region	1
tendon of biceps brachii	1
left ventricle myocardium	1
pancreatic ductal cell	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDUFS6	295	ubiquitous	marker	tendon of biceps brachii, apex of heart, right atrium auricular region
MRPL36	255	ubiquitous	marker	pancreatic ductal cell, tibialis anterior, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MRPL36	2,977
NDUFS6	2,955

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL36	Q9P0J6	73
NDUFS6	O75380	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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	1	82.8×	0.031	NDUFS6
Mitochondrial translation	1	68.8×	0.031	MRPL36
Mitochondrial translation initiation	1	63.4×	0.031	MRPL36
Mitochondrial translation elongation	1	63.4×	0.031	MRPL36
Mitochondrial ribosome-associated quality control	1	61.4×	0.031	MRPL36
Mitochondrial translation termination	1	54.9×	0.031	MRPL36
Respiratory electron transport	1	47.6×	0.031	NDUFS6
Aerobic respiration and respiratory electron transport	1	44.3×	0.031	NDUFS6
Translation	1	31.0×	0.039	MRPL36
Metabolism of proteins	1	6.2×	0.165	MRPL36
Metabolism	1	5.8×	0.165	NDUFS6

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
mesenchymal stem cell differentiation	1	4213.0×	0.002	NDUFS6
mesenchymal stem cell proliferation	1	4213.0×	0.002	NDUFS6
reproductive system development	1	1203.7×	0.005	NDUFS6
stem cell division	1	936.2×	0.005	NDUFS6
circulatory system development	1	702.2×	0.006	NDUFS6
regulation of mitochondrial membrane potential	1	271.8×	0.011	NDUFS6
reactive oxygen species metabolic process	1	234.1×	0.011	NDUFS6
mitochondrial respiratory chain complex I assembly	1	205.5×	0.011	NDUFS6
mitochondrial electron transport, NADH to ubiquinone	1	179.3×	0.011	NDUFS6
DNA damage response, signal transduction by p53 class mediator	1	179.3×	0.011	NDUFS6
cellular senescence	1	147.8×	0.012	NDUFS6
proton motive force-driven mitochondrial ATP synthesis	1	131.7×	0.012	NDUFS6
aerobic respiration	1	123.9×	0.012	NDUFS6
muscle contraction	1	104.0×	0.014	NDUFS6
fatty acid metabolic process	1	96.8×	0.014	NDUFS6
mitochondrial translation	1	86.9×	0.014	MRPL36
kidney development	1	70.2×	0.016	NDUFS6
multicellular organism growth	1	68.5×	0.016	NDUFS6
translation	1	51.4×	0.020	MRPL36
gene expression	1	39.9×	0.025	NDUFS6

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
NDUFS6	0	0
MRPL36	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
NDUFS6	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	NDUFS6, MRPL36

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)
NDUFS6	5	—
MRPL36	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.