mitochondrial complex I deficiency, nuclear type 4

Summary

mitochondrial complex I deficiency, nuclear type 4 (MONDO:0032609) is a disease caused by NDUFV1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: NDUFV1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 60

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 4
Mondo ID	MONDO:0032609
OMIM	618225
DOID	DOID:0112082
UMLS	C4748753
MedGen	1648324
GARD	0016314
Is cancer (heuristic)	no

Also known as: MC1DN4

Data availability: 60 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 4

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 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

60 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 17 likely pathogenic, 9 pathogenic/likely pathogenic, 9 conflicting classifications of pathogenicity, 4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14056	NM_007103.4(NDUFV1):c.1268C>T (p.Thr423Met)	LOC126861242	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
419230	NM_007103.4(NDUFV1):c.1156C>T (p.Arg386Cys)	LOC126861242	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299402	NM_007103.4(NDUFV1):c.797dup (p.Arg267fs)	NDUFV1	Pathogenic	criteria provided, single submitter
1323338	NM_007103.4(NDUFV1):c.336T>G (p.Tyr112Ter)	NDUFV1	Pathogenic	criteria provided, single submitter
1335076	NM_007103.4(NDUFV1):c.611A>G (p.Tyr204Cys)	NDUFV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14057	NM_007103.4(NDUFV1):c.175C>T (p.Arg59Ter)	NDUFV1	Pathogenic	criteria provided, multiple submitters, no conflicts
14058	NM_007103.4(NDUFV1):c.1022C>T (p.Ala341Val)	NDUFV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14059	NM_007103.4(NDUFV1):c.640G>A (p.Glu214Lys)	NDUFV1	Pathogenic	criteria provided, multiple submitters, no conflicts
1979074	NM_007103.4(NDUFV1):c.520C>T (p.Arg174Ter)	NDUFV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214852	NM_007103.4(NDUFV1):c.365C>T (p.Pro122Leu)	NDUFV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2413150	NM_007103.4(NDUFV1):c.475C>T (p.Arg159Ter)	NDUFV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372716	NM_007103.4(NDUFV1):c.1162+4A>C	NDUFV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496918	NM_007103.4(NDUFV1):c.1157G>A (p.Arg386His)	NDUFV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705562	NM_007103.4(NDUFV1):c.1163G>A (p.Gly388Asp)	LOC126861242	Likely pathogenic	criteria provided, single submitter
2585065	NM_007103.4(NDUFV1):c.1213_1234del (p.Arg405fs)	LOC126861242	Likely pathogenic	criteria provided, single submitter
3776785	NM_007103.4(NDUFV1):c.1378dup (p.Arg460fs)	LOC126861242	Likely pathogenic	criteria provided, single submitter
3600151	NM_007103.4(NDUFV1):c.3G>A (p.Met1Ile)	LOC130006217	Likely pathogenic	criteria provided, single submitter
3600152	NM_007103.4(NDUFV1):c.3G>T (p.Met1Ile)	LOC130006217	Likely pathogenic	criteria provided, single submitter
1324787	NM_007103.4(NDUFV1):c.151_152del (p.Trp51fs)	NDUFV1	Likely pathogenic	criteria provided, single submitter
2137165	NM_007103.4(NDUFV1):c.156-2A>G	NDUFV1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2700690	NM_007103.4(NDUFV1):c.1080+1G>T	NDUFV1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2970239	NM_007103.4(NDUFV1):c.118C>T (p.Arg40Trp)	NDUFV1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3341354	NM_007103.4(NDUFV1):c.450dup (p.Ala151fs)	NDUFV1	Likely pathogenic	criteria provided, single submitter
3600154	NM_007103.4(NDUFV1):c.424del (p.Cys142fs)	NDUFV1	Likely pathogenic	criteria provided, single submitter
3600155	NM_007103.4(NDUFV1):c.437dup (p.Arg147fs)	NDUFV1	Likely pathogenic	criteria provided, single submitter
3600156	NM_007103.4(NDUFV1):c.828del (p.Phe276fs)	NDUFV1	Likely pathogenic	criteria provided, single submitter
3767221	NM_007103.4(NDUFV1):c.344T>A (p.Val115Glu)	NDUFV1	Likely pathogenic	criteria provided, single submitter
431452	NM_007103.4(NDUFV1):c.1118T>C (p.Phe373Ser)	NDUFV1	Likely pathogenic	criteria provided, single submitter
802693	NM_007103.4(NDUFV1):c.1129G>T (p.Glu377Ter)	NDUFV1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4278443	NM_198060.4(NRAP):c.2244+1G>A	NRAP	Likely pathogenic	criteria provided, single submitter

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
NDUFV1	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDUFV1	Orphanet:2609	Isolated complex I deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NDUFV1	HGNC:7716	ENSG00000167792	P49821	NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial	gencc,clinvar
NOL6	HGNC:19910	ENSG00000165271	Q9H6R4	Nucleolar protein 6	clinvar
NRAP	HGNC:7988	ENSG00000197893	Q86VF7	Nebulin-related-anchoring protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDUFV1	NADH dehydrogenase [ubiquinone] flavoprotein 1, 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.
NOL6	Nucleolar protein 6	Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit.
NRAP	Nebulin-related-anchoring protein	May be involved in anchoring the terminal actin filaments in the myofibril to the membrane and in transmitting tension from the myofibrils to the extracellular matrix.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NDUFV1	Other/Unknown	no		NADH-UbQ_OxRdtase_51kDa_CS, NADH-UbQ_OxRdtase_suF, Nuo51_FMN-bd
NOL6	Other/Unknown	no		NOL6/Upt22, Nrap_D1, Nrap_D2
NRAP	Transcription factor	no		Nebulin_repeat, Znf_LIM, Nebulin-like

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	2
metanephros cortex	1
right hemisphere of cerebellum	1
lower esophagus mucosa	1
tongue squamous epithelium	1
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDUFV1	292	ubiquitous	marker	apex of heart, right hemisphere of cerebellum, metanephros cortex
NOL6	278	ubiquitous	marker	tongue squamous epithelium, lower esophagus mucosa, apex of heart
NRAP	157	tissue_specific	marker	skeletal muscle tissue of rectus abdominis, hindlimb stylopod muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFV1	3,982
NOL6	3,427
NRAP	862

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDUFV1	P49821	7
NOL6	Q9H6R4	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NRAP	Q86VF7	51.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 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
rRNA modification in the nucleus and cytosol	1	93.6×	0.036	NOL6
Complex I biogenesis	1	82.8×	0.036	NDUFV1
Mitochondrial protein degradation	1	57.1×	0.036	NDUFV1
Respiratory electron transport	1	47.6×	0.036	NDUFV1
Aerobic respiration and respiratory electron transport	1	44.3×	0.036	NDUFV1
Major pathway of rRNA processing in the nucleolus and cytosol	1	30.9×	0.043	NOL6
Metabolism of proteins	1	6.2×	0.165	NDUFV1
Metabolism	1	5.8×	0.165	NDUFV1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cardiac muscle thin filament assembly	1	1872.4×	0.003	NRAP
tRNA export from nucleus	1	1404.3×	0.003	NOL6
mitochondrial ATP synthesis coupled electron transport	1	624.1×	0.004	NDUFV1
mitochondrial electron transport, NADH to ubiquinone	1	119.5×	0.015	NDUFV1
proton motive force-driven mitochondrial ATP synthesis	1	87.8×	0.015	NDUFV1
aerobic respiration	1	82.6×	0.015	NDUFV1
ribosomal small subunit biogenesis	1	75.9×	0.015	NOL6
rRNA processing	1	47.2×	0.021	NOL6

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NDUFV1	0	0
NOL6	0	0
NRAP	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
NDUFV1	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	NDUFV1, NOL6, NRAP

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NDUFV1	5	—
NOL6	0	—
NRAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.