mitochondrial complex I deficiency, nuclear type 2

Summary

mitochondrial complex I deficiency, nuclear type 2 (MONDO:0032606) is a disease caused by NDUFS8 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: NDUFS8 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 25

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 2
Mondo ID	MONDO:0032606
OMIM	618222
DOID	DOID:0112083
UMLS	C4748737
MedGen	1648466
GARD	0016312
Is cancer (heuristic)	no

Also known as: MC1DN2

Data availability: 25 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 2

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 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 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

25 retrieved; paginated sample, class counts are floors:

7 likely pathogenic, 6 uncertain significance, 6 conflicting classifications of pathogenicity, 4 pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2577373	NM_002496.4(NDUFS8):c.160C>T (p.Arg54Trp)	NDUFS8	Pathogenic	criteria provided, single submitter
39834	NM_002496.4(NDUFS8):c.476C>A (p.Ala159Asp)	NDUFS8	Pathogenic	no assertion criteria provided
39835	NM_002496.4(NDUFS8):c.187G>C (p.Glu63Gln)	NDUFS8	Pathogenic	no assertion criteria provided
7513	NM_002496.4(NDUFS8):c.254C>T (p.Pro85Leu)	NDUFS8	Pathogenic	no assertion criteria provided
1804015	NM_002496.4(NDUFS8):c.170G>C (p.Arg57Pro)	NDUFS8	Likely pathogenic	criteria provided, single submitter
1806071	NM_002496.4(NDUFS8):c.325G>A (p.Glu109Lys)	NDUFS8	Likely pathogenic	criteria provided, single submitter
3063712	NM_002496.4(NDUFS8):c.372+1G>A	NDUFS8	Likely pathogenic	criteria provided, single submitter
3254824	NM_002496.4(NDUFS8):c.501+5G>A	NDUFS8	Likely pathogenic	criteria provided, single submitter
3767218	NM_002496.4(NDUFS8):c.304C>T (p.Arg102Cys)	NDUFS8	Likely pathogenic	criteria provided, single submitter
3767219	NM_002496.4(NDUFS8):c.342C>A (p.Cys114Ter)	NDUFS8	Likely pathogenic	criteria provided, single submitter
7511	NM_002496.4(NDUFS8):c.236C>T (p.Pro79Leu)	NDUFS8	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2084627	NM_002496.4(NDUFS8):c.307C>T (p.Arg103Trp)	NDUFS8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214836	NM_002496.4(NDUFS8):c.4C>T (p.Arg2Cys)	NDUFS8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
446006	NM_002496.4(NDUFS8):c.460G>A (p.Gly154Ser)	NDUFS8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7512	NM_002496.4(NDUFS8):c.305G>A (p.Arg102His)	NDUFS8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7514	NM_002496.4(NDUFS8):c.413G>A (p.Arg138His)	NDUFS8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
990509	NM_006019.4(TCIRG1):c.59C>T (p.Ala20Val)	TCIRG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1503645	NM_002496.4(NDUFS8):c.585G>A (p.Trp195Ter)	NDUFS8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709288	NM_002496.4(NDUFS8):c.499G>A (p.Glu167Lys)	NDUFS8	Uncertain significance	criteria provided, single submitter
2434095	NM_002496.4(NDUFS8):c.367G>T (p.Ala123Ser)	NDUFS8	Uncertain significance	criteria provided, multiple submitters, no conflicts
2689554	NM_002496.4(NDUFS8):c.329G>A (p.Arg110His)	NDUFS8	Uncertain significance	criteria provided, single submitter
39833	NM_002496.4(NDUFS8):c.229C>T (p.Arg77Trp)	NDUFS8	Uncertain significance	criteria provided, multiple submitters, no conflicts
917536	NM_002496.4(NDUFS8):c.384C>G (p.Ile128Met)	NDUFS8	Uncertain significance	no assertion criteria provided
1241165	NM_002496.4(NDUFS8):c.59-22C>G	NDUFS8	Benign	criteria provided, multiple submitters, no conflicts
305765	NM_002496.4(NDUFS8):c.199+15T>G	NDUFS8	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
NDUFS8	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDUFS8	Orphanet:2609	Isolated complex I deficiency
TCIRG1	Orphanet:1782	Dysosteosclerosis
TCIRG1	Orphanet:210110	Intermediate osteopetrosis
TCIRG1	Orphanet:486	Autosomal dominant severe congenital neutropenia
TCIRG1	Orphanet:667	Autosomal recessive malignant osteopetrosis

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
NDUFS8	HGNC:7715	ENSG00000110717	O00217	NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial	gencc,clinvar
TCIRG1	HGNC:11647	ENSG00000110719	Q13488	V-type proton ATPase 116 kDa subunit a 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDUFS8	NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, 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.
TCIRG1	V-type proton ATPase 116 kDa subunit a 3	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NDUFS8	Other/Unknown	no		NADH_quinone_OxRdtase_chainI, 4Fe4S_Fe-S-bd, 4Fe4S_Fe_S_CS
TCIRG1	Other/Unknown	no		V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka

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 adrenal gland	1
right adrenal gland cortex	1
blood	1
granulocyte	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDUFS8	294	ubiquitous	marker	apex of heart, right adrenal gland, right adrenal gland cortex
TCIRG1	148	ubiquitous	marker	granulocyte, blood, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFS8	5,298
TCIRG1	1,931

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDUFS8	O00217	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCIRG1	Q13488	83.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Insulin receptor recycling	1	190.3×	0.020	TCIRG1
Transferrin endocytosis and recycling	1	184.2×	0.020	TCIRG1
ROS and RNS production in phagocytes	1	167.9×	0.020	TCIRG1
Amino acids regulate mTORC1	1	100.2×	0.024	TCIRG1
Complex I biogenesis	1	82.8×	0.024	NDUFS8
Ion channel transport	1	48.0×	0.028	TCIRG1
Respiratory electron transport	1	47.6×	0.028	NDUFS8
Aerobic respiration and respiratory electron transport	1	44.3×	0.028	NDUFS8
Neutrophil degranulation	1	11.5×	0.094	TCIRG1
Metabolism	1	5.8×	0.165	NDUFS8

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
response to silver ion	1	8426.0×	0.003	TCIRG1
dentin mineralization	1	8426.0×	0.003	TCIRG1
protein catabolic process in the vacuole	1	4213.0×	0.003	TCIRG1
memory T cell activation	1	4213.0×	0.003	TCIRG1
regulation of proton transport	1	2808.7×	0.003	TCIRG1
T-helper 1 cell activation	1	2808.7×	0.003	TCIRG1
osteoclast proliferation	1	1685.2×	0.003	TCIRG1
tooth eruption	1	1685.2×	0.003	TCIRG1
pH reduction	1	1203.7×	0.003	TCIRG1
establishment of vesicle localization	1	1203.7×	0.003	TCIRG1
phagosome acidification	1	1203.7×	0.003	TCIRG1
ruffle organization	1	648.1×	0.005	TCIRG1
regulation of osteoblast differentiation	1	648.1×	0.005	TCIRG1
optic nerve development	1	601.9×	0.005	TCIRG1
enamel mineralization	1	601.9×	0.005	TCIRG1
vacuolar acidification	1	366.4×	0.007	TCIRG1
immunoglobulin mediated immune response	1	351.1×	0.007	TCIRG1
lysosomal lumen acidification	1	337.0×	0.007	TCIRG1
bone resorption	1	290.6×	0.008	TCIRG1
hematopoietic stem cell homeostasis	1	280.9×	0.008	TCIRG1
cellular response to cytokine stimulus	1	271.8×	0.008	TCIRG1
T cell homeostasis	1	227.7×	0.009	TCIRG1
mitochondrial respiratory chain complex I assembly	1	205.5×	0.009	NDUFS8
regulation of insulin secretion	1	195.9×	0.009	TCIRG1
establishment of cell polarity	1	191.5×	0.009	TCIRG1
T cell differentiation	1	191.5×	0.009	TCIRG1
mitochondrial electron transport, NADH to ubiquinone	1	179.3×	0.009	NDUFS8
osteoclast differentiation	1	172.0×	0.009	TCIRG1
cellular defense response	1	159.0×	0.009	TCIRG1
proton transmembrane transport	1	156.0×	0.009	TCIRG1

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
NDUFS8	0	0
TCIRG1	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
NDUFS8	4	Binding:4

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	NDUFS8, TCIRG1

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)
NDUFS8	4	—
TCIRG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.