mitochondrial complex I deficiency, nuclear type 31

Summary

mitochondrial complex I deficiency, nuclear type 31 (MONDO:0032634) is a disease caused by TIMMDC1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TIMMDC1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 31
Mondo ID	MONDO:0032634
OMIM	618251
DOID	DOID:0112071
UMLS	C4748838
MedGen	1648395
GARD	0016331
Is cancer (heuristic)	no

Also known as: MC1DN31

Data availability: 16 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 31

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 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 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

16 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 2 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1723290	NM_016589.4(TIMMDC1):c.1A>G (p.Met1Val)	TIMMDC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
429020	NM_016589.4(TIMMDC1):c.597-1340A>G	TIMMDC1	Pathogenic	criteria provided, multiple submitters, no conflicts
4848998	NM_016589.4(TIMMDC1):c.631_635delinsTAGTT (p.Lys211_Tyr212delinsTer)	TIMMDC1	Pathogenic	criteria provided, single submitter
983214	NM_016589.4(TIMMDC1):c.385C>T (p.Arg129Ter)	TIMMDC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709036	NM_016589.4(TIMMDC1):c.596+1del	TIMMDC1	Likely pathogenic	criteria provided, single submitter
2501222	NM_016589.4(TIMMDC1):c.194+2T>C	TIMMDC1	Likely pathogenic	criteria provided, single submitter
3391305	NM_016589.4(TIMMDC1):c.414G>A (p.Trp138Ter)	TIMMDC1	Likely pathogenic	criteria provided, single submitter
1691015	NM_016589.4(TIMMDC1):c.410G>A (p.Arg137His)	TIMMDC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807710	NM_016589.4(TIMMDC1):c.524C>T (p.Thr175Met)	TIMMDC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030567	NM_016589.4(TIMMDC1):c.-2C>T	TIMMDC1	Uncertain significance	criteria provided, single submitter
1030568	NM_016589.4(TIMMDC1):c.361-5T>G	TIMMDC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709042	NM_016589.4(TIMMDC1):c.751G>T (p.Glu251Ter)	TIMMDC1	Uncertain significance	criteria provided, single submitter
1723291	NM_016589.4(TIMMDC1):c.814del (p.Leu272fs)	TIMMDC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3897996	NM_016589.4(TIMMDC1):c.360+3A>G	TIMMDC1	Uncertain significance	criteria provided, single submitter
809523	NM_016589.4(TIMMDC1):c.598A>G (p.Thr200Ala)	TIMMDC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1342212	NM_016589.4(TIMMDC1):c.597-35G>T	TIMMDC1	Benign	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
TIMMDC1	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 31	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TIMMDC1	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
TIMMDC1	HGNC:1321	ENSG00000113845	Q9NPL8	Complex I assembly factor TIMMDC1, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TIMMDC1	Complex I assembly factor TIMMDC1, mitochondrial	Chaperone protein involved in the assembly of the mitochondrial NADH:ubiquinone oxidoreductase complex (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)
TIMMDC1	Other/Unknown	no		TIMMDC1

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
cardiac muscle of right atrium	1
left ventricle myocardium	1
myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TIMMDC1	259	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TIMMDC1	1,569

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TIMMDC1	Q9NPL8	72.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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×	0.015	TIMMDC1
Respiratory electron transport	1	95.2×	0.015	TIMMDC1
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	TIMMDC1
Metabolism	1	11.6×	0.086	TIMMDC1

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	TIMMDC1

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
TIMMDC1	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	TIMMDC1

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)
TIMMDC1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.