mitochondrial complex I deficiency, nuclear type 21

Summary

mitochondrial complex I deficiency, nuclear type 21 (MONDO:0032625) is a disease caused by NUBPL (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: NUBPL (GenCC Definitive)
• Cohort genes: 3
• 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 21
Mondo ID	MONDO:0032625
OMIM	618242
DOID	DOID:0112088
UMLS	C4748792
MedGen	1648383
GARD	0016327
Is cancer (heuristic)	no

Also known as: MC1DN21

Data availability: 36 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 21

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 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 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:

10 uncertain significance, 8 conflicting classifications of pathogenicity, 6 likely pathogenic, 6 pathogenic, 3 pathogenic/likely pathogenic, 2 benign, 1 pathogenic; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
7	NM_025152.2(NUBPL):c.[166G>A;815-27T>C]		Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
929501	NUBPL, 240-KB DEL AND 130-KB DUP	DTD2	Pathogenic	criteria provided, single submitter
209179	NM_025152.3(NUBPL):c.311T>C (p.Leu104Pro)	NUBPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2682369	NC_000014.8:g.(32142781_32256985)_(32257080_32295834)del	NUBPL	Pathogenic	criteria provided, single submitter
50214	NM_025152.3(NUBPL):c.667_668insCCTTGTGCTG (p.Glu223delinsAlaLeuCysTer)	NUBPL	Pathogenic	no assertion criteria provided
50216	NM_025152.3(NUBPL):c.693+1G>A	NUBPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50217	NM_025152.3(NUBPL):c.579A>C (p.Leu193Phe)	NUBPL	Pathogenic	no assertion criteria provided
635348	NM_025152.3(NUBPL):c.726C>G (p.Phe242Leu)	NUBPL	Pathogenic	criteria provided, single submitter
915894	NM_025152.3(NUBPL):c.351G>A (p.Met117Ile)	NUBPL	Pathogenic	no assertion criteria provided
17975	NM_001127701.1(SERPINA1):c.839A>T (p.Asp280Val)	SERPINA1	Pathogenic; other	criteria provided, multiple submitters, no conflicts
2627223	NM_025152.3(NUBPL):c.423-1G>A	NUBPL	Likely pathogenic	criteria provided, single submitter
3764546	NM_025152.3(NUBPL):c.448del (p.Glu150fs)	NUBPL	Likely pathogenic	criteria provided, single submitter
3899261	GRCh37/hg19 14q12(chr14:32317254-32323465)x1	NUBPL	Likely pathogenic	criteria provided, single submitter
3906930	NM_025152.3(NUBPL):c.261del (p.Ala89fs)	NUBPL	Likely pathogenic	criteria provided, single submitter
432144	NM_025152.3(NUBPL):c.526C>T (p.Gln176Ter)	NUBPL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4845507	NM_025152.3(NUBPL):c.622_623del (p.Ser208fs)	NUBPL	Likely pathogenic	criteria provided, single submitter
1935073	NM_025152.3(NUBPL):c.201A>G (p.Lys67=)	NUBPL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214874	NM_025152.3(NUBPL):c.545T>C (p.Val182Ala)	NUBPL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214875	NM_025152.3(NUBPL):c.593A>C (p.Asn198Thr)	NUBPL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214885	NM_025152.3(NUBPL):c.166G>A (p.Gly56Arg)	NUBPL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
50215	NM_025152.3(NUBPL):c.313G>T (p.Asp105Tyr)	NUBPL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
50317	NM_025152.3(NUBPL):c.815-27T>C	NUBPL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
517222	NM_025152.3(NUBPL):c.2T>C (p.Met1Thr)	NUBPL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
881212	NM_025152.3(NUBPL):c.4G>C (p.Gly2Arg)	NUBPL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2434461	NM_025152.3(NUBPL):c.386A>G (p.Asn129Ser)	NUBPL	Uncertain significance	criteria provided, single submitter
2434462	NM_025152.3(NUBPL):c.308T>A (p.Leu103Ter)	NUBPL	Uncertain significance	criteria provided, single submitter
2434463	NM_025152.3(NUBPL):c.514-19835C>A	NUBPL	Uncertain significance	criteria provided, single submitter
2671721	NM_025152.3(NUBPL):c.893A>C (p.Asp298Ala)	NUBPL	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065262	NM_025152.3(NUBPL):c.468G>T (p.Trp156Cys)	NUBPL	Uncertain significance	criteria provided, single submitter
4081993	NM_025152.3(NUBPL):c.907T>A (p.Tyr303Asn)	NUBPL	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 4 · 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
NUBPL	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 21	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NUBPL	Orphanet:2609	Isolated complex I deficiency
SERPINA1	Orphanet:178396	Hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation
SERPINA1	Orphanet:586	Cystic fibrosis
SERPINA1	Orphanet:60	Alpha-1-antitrypsin 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
NUBPL	HGNC:20278	ENSG00000151413	Q8TB37	Iron-sulfur cluster transfer protein NUBPL	gencc,clinvar
DTD2	HGNC:20277	ENSG00000129480	Q96FN9	D-aminoacyl-tRNA deacylase 2	clinvar
SERPINA1	HGNC:8941	ENSG00000197249	P01009	Alpha-1-antitrypsin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NUBPL	Iron-sulfur cluster transfer protein NUBPL	Iron-sulfur cluster transfer protein involved in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I).
DTD2	D-aminoacyl-tRNA deacylase 2	Deacylates mischarged D-aminoacyl-tRNAs.
SERPINA1	Alpha-1-antitrypsin	Inhibitor of serine proteases.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NUBPL	Other/Unknown	no		Mrp-like_CS, Mrp/NBP35_ATP-bd, P-loop_NTPase
DTD2	Other/Unknown	no		Daa-tRNA_deacyls_DTD, DTD-like_sf
SERPINA1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
calcaneal tendon	1
skeletal muscle tissue of biceps brachii	1
epithelial cell of pancreas	1
oviduct epithelium	1
ventricular zone	1
blood	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NUBPL	267	ubiquitous	marker	calcaneal tendon, adrenal tissue, skeletal muscle tissue of biceps brachii
DTD2	239	ubiquitous	yes	oviduct epithelium, epithelial cell of pancreas, ventricular zone
SERPINA1	133	ubiquitous	marker	right lobe of liver, liver, blood

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SERPINA1	3,617
NUBPL	1,696
DTD2	530

Intra-cohort edges

A	B	Sources
DTD2	NUBPL	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SERPINA1	P01009	46

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DTD2	Q96FN9	96.31
NUBPL	Q8TB37	85.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. 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
Cargo concentration in the ER	1	167.9×	0.044	SERPINA1
Complex I biogenesis	1	82.8×	0.044	NUBPL
COPII-mediated vesicle transport	1	81.6×	0.044	SERPINA1
Response to elevated platelet cytosolic Ca2+	1	81.6×	0.044	SERPINA1
ER to Golgi Anterograde Transport	1	66.4×	0.044	SERPINA1
Platelet activation, signaling and aggregation	1	52.9×	0.044	SERPINA1
Transport to the Golgi and subsequent modification	1	51.4×	0.044	SERPINA1
Post-translational protein phosphorylation	1	50.1×	0.044	SERPINA1
Platelet degranulation	1	43.9×	0.044	SERPINA1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.044	SERPINA1
Asparagine N-linked glycosylation	1	30.1×	0.057	SERPINA1
Membrane Trafficking	1	18.5×	0.077	SERPINA1
Hemostasis	1	18.0×	0.077	SERPINA1
Vesicle-mediated transport	1	17.4×	0.077	SERPINA1
Innate Immune System	1	12.8×	0.097	SERPINA1
Neutrophil degranulation	1	11.5×	0.101	SERPINA1
Post-translational protein modification	1	9.6×	0.113	SERPINA1
Immune System	1	6.5×	0.155	SERPINA1
Metabolism of proteins	1	6.2×	0.155	SERPINA1

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
aminoacyl-tRNA metabolism involved in translational fidelity	1	5617.3×	0.001	DTD2
tRNA metabolic process	1	1123.5×	0.003	DTD2
iron-sulfur cluster assembly	1	200.6×	0.010	NUBPL
acute-phase response	1	140.4×	0.010	SERPINA1
mitochondrial respiratory chain complex I assembly	1	137.0×	0.010	NUBPL
blood coagulation	1	57.9×	0.020	SERPINA1
mitochondrion organization	1	50.6×	0.020	NUBPL

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NUBPL	0	0
DTD2	0	0
SERPINA1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	NUBPL, DTD2, SERPINA1

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)
NUBPL	0	—
DTD2	0	—
SERPINA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.