mitochondrial complex I deficiency, nuclear type 19

Summary

mitochondrial complex I deficiency, nuclear type 19 (MONDO:0032624) is a disease caused by FOXRED1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: FOXRED1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 19
Mondo ID	MONDO:0032624
OMIM	618241
DOID	DOID:0112085
UMLS	C4748791
MedGen	1648450
GARD	0016326
Is cancer (heuristic)	no

Also known as: MC1DN19

Data availability: 34 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 19

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 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

34 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 6 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 6 likely pathogenic, 3 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1705022	NM_017547.4(FOXRED1):c.733+1G>A	FOXRED1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214454	NM_017547.4(FOXRED1):c.86-1G>A	FOXRED1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31048	NM_017547.4(FOXRED1):c.1054C>T (p.Arg352Trp)	FOXRED1	Pathogenic	criteria provided, multiple submitters, no conflicts
3902282	NM_017547.4(FOXRED1):c.1233_1234delinsGA (p.Tyr411_Asp412delinsTer)	FOXRED1	Pathogenic	criteria provided, single submitter
449732	NM_017547.4(FOXRED1):c.874G>A (p.Gly292Arg)	FOXRED1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5	NM_017547.4(FOXRED1):c.694C>T (p.Gln232Ter)	FOXRED1	Pathogenic	criteria provided, multiple submitters, no conflicts
504104	NM_017547.4(FOXRED1):c.1102C>T (p.Gln368Ter)	FOXRED1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
95754	NM_017547.4(FOXRED1):c.612_615dup (p.Ala206fs)	FOXRED1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
981124	NM_017547.4(FOXRED1):c.1057G>T (p.Glu353Ter)	FOXRED1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599142	NM_017547.4(FOXRED1):c.811-1G>A	FOXRED1	Likely pathogenic	criteria provided, single submitter
3599143	NM_017547.4(FOXRED1):c.937C>T (p.Gln313Ter)	FOXRED1	Likely pathogenic	criteria provided, single submitter
3599144	NM_017547.4(FOXRED1):c.1160dup (p.Trp388fs)	FOXRED1	Likely pathogenic	criteria provided, single submitter
4081400	NM_017547.4(FOXRED1):c.972-1G>A	FOXRED1	Likely pathogenic	criteria provided, single submitter
6	NM_017547.4(FOXRED1):c.1289A>G (p.Asn430Ser)	FOXRED1	Likely pathogenic	criteria provided, single submitter
915282	NM_017547.4(FOXRED1):c.209G>C (p.Gly70Ala)	FOXRED1	Likely pathogenic	criteria provided, single submitter
214446	NM_017547.4(FOXRED1):c.682C>T (p.Arg228Trp)	FOXRED1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214447	NM_017547.4(FOXRED1):c.920G>A (p.Gly307Glu)	FOXRED1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214451	NM_017547.4(FOXRED1):c.1171T>G (p.Leu391Val)	FOXRED1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372745	NM_017547.4(FOXRED1):c.406C>T (p.Arg136Trp)	FOXRED1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522718	NM_017547.4(FOXRED1):c.632G>C (p.Gly211Ala)	FOXRED1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
870426	NM_017547.4(FOXRED1):c.1261G>A (p.Val421Met)	FOXRED1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029471	NM_017547.4(FOXRED1):c.943A>G (p.Thr315Ala)	FOXRED1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1505904	NM_017547.4(FOXRED1):c.449T>G (p.Leu150Arg)	FOXRED1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1722932	NM_017547.4(FOXRED1):c.50G>A (p.Arg17Gln)	FOXRED1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1806034	NM_017547.4(FOXRED1):c.1418G>A (p.Arg473His)	FOXRED1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2062015	NM_017547.4(FOXRED1):c.1A>G (p.Met1Val)	FOXRED1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2407341	NM_017547.4(FOXRED1):c.1019C>T (p.Pro340Leu)	FOXRED1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441555	NM_017547.4(FOXRED1):c.1234_1239del (p.Asp412_Tyr413del)	FOXRED1	Uncertain significance	criteria provided, single submitter
2441556	NM_017547.4(FOXRED1):c.677G>A (p.Gly226Glu)	FOXRED1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441557	NM_017547.4(FOXRED1):c.354G>C (p.Gln118His)	FOXRED1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
FOXRED1	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 19	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXRED1	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
FOXRED1	HGNC:26927	ENSG00000110074	Q96CU9	FAD-dependent oxidoreductase domain-containing protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXRED1	FAD-dependent oxidoreductase domain-containing protein 1	Required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I).

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)
FOXRED1	Other/Unknown	no		FAD-dep_OxRdtase, FAD/NAD-bd_sf

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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXRED1	232	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FOXRED1	1,164

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FOXRED1	Q96CU9	90.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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×	0.006	FOXRED1

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
mitochondrial respiratory chain complex I assembly	1	411.0×	0.002	FOXRED1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
FOXRED1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	FOXRED1

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)
FOXRED1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.