mitochondrial DNA depletion syndrome 1

Summary

mitochondrial DNA depletion syndrome 1 (MONDO:0011283) is a disease caused by TYMP (GenCC Strong), with 7 cohort genes.

At a glance

• Causal gene: TYMP (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 303

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome 1
Mondo ID	MONDO:0011283
OMIM	603041
DOID	DOID:0080119
UMLS	C4551995
MedGen	1631838
GARD	0024787
Is cancer (heuristic)	no

Also known as: mitochondrial DNA depletion syndrome 1 · mitochondrial DNA depletion syndrome 1 (MNGIE type) · mitochondrial DNA depletion syndrome type 1 · MTDPS1

Data availability: 303 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › mitochondrial neurogastrointestinal encephalomyopathy › mitochondrial DNA depletion syndrome 1

Related subtypes (3): mitochondrial DNA depletion syndrome 8a, mitochondrial DNA depletion syndrome 4b, mitochondrial DNA depletion syndrome 20 (mngie type)

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

303 retrieved; paginated sample, class counts are floors:

89 uncertain significance, 58 pathogenic, 54 conflicting classifications of pathogenicity, 49 likely pathogenic, 25 pathogenic/likely pathogenic, 15 benign, 10 benign/likely benign, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1332698	NM_001953.5(TYMP):c.1198_1203del (p.Val400_Leu401del)	LOC130067862	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16664	NM_001953.5(TYMP):c.931G>C (p.Gly311Arg)	LOC130067862	Pathogenic	no assertion criteria provided
2138462	NM_001953.5(TYMP):c.1040T>C (p.Leu347Pro)	LOC130067862	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
223049	NM_001953.5(TYMP):c.931G>T (p.Gly311Cys)	LOC130067862	Pathogenic	no assertion criteria provided
223051	NM_001953.5(TYMP):c.1067T>C (p.Leu356Pro)	LOC130067862	Pathogenic	no assertion criteria provided
223053	NM_001953.5(TYMP):c.1159G>A (p.Gly387Ser)	LOC130067862	Pathogenic	no assertion criteria provided
223057	NM_001953.5(TYMP):c.1360G>C (p.Ala454Pro)	LOC130067862	Pathogenic	no assertion criteria provided
223058	NM_001953.5(TYMP):c.1412C>A (p.Ser471Ter)	LOC130067862	Pathogenic	no assertion criteria provided
223062	NM_001953.5(TYMP):c.928+1G>A	LOC130067862	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
223065	NM_001953.5(TYMP):c.1159+2T>A	LOC130067862	Pathogenic	criteria provided, multiple submitters, no conflicts
223067	NM_001953.5(TYMP):c.1160-2A>C	LOC130067862	Pathogenic	no assertion criteria provided
223068	NM_001953.5(TYMP):c.1160-2A>G	LOC130067862	Pathogenic	no assertion criteria provided
223069	NM_001953.5(TYMP):c.1300+1G>A	LOC130067862	Pathogenic	criteria provided, multiple submitters, no conflicts
223070	NM_001953.5(TYMP):c.1300+2T>A	LOC130067862	Pathogenic	no assertion criteria provided
223073	NM_001953.5(TYMP):c.994_1011dup (p.Gly337_Ser338insAlaAlaLeuAspAspGly)	LOC130067862	Pathogenic	no assertion criteria provided
223074	NM_001953.5(TYMP):c.1211dup (p.Gly405fs)	LOC130067862	Pathogenic	no assertion criteria provided
223076	NM_001953.5(TYMP):c.1351dup (p.Gln451fs)	LOC130067862	Pathogenic	no assertion criteria provided
223077	NM_001953.5(TYMP):c.1431dup (p.Leu478fs)	LOC130067862	Pathogenic	no assertion criteria provided
223083	NM_001953.5(TYMP):c.1088del (p.Gly363fs)	LOC130067862	Pathogenic	criteria provided, single submitter
223085	NM_001953.5(TYMP):c.1311del (p.Trp437fs)	LOC130067862	Pathogenic	no assertion criteria provided
223086	NM_001953.5(TYMP):c.1327_1346del (p.Asp443fs)	LOC130067862	Pathogenic	criteria provided, multiple submitters, no conflicts
223087	NM_001953.5(TYMP):c.1395_1400del (p.Pro466_Phe467del)	LOC130067862	Pathogenic	no assertion criteria provided
223088	NM_001953.5(TYMP):c.1010_1019delinsAA (p.Gly337fs)	LOC130067862	Pathogenic	no assertion criteria provided
632392	NM_001953.5(TYMP):c.929-1G>A	LOC130067862	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
817030	NM_001953.5(TYMP):c.1416del (p.Phe473fs)	LOC130067862	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
828126	NM_001953.5(TYMP):c.1048C>T (p.Gln350Ter)	LOC130067862	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
870754	NM_001953.5(TYMP):c.945G>A (p.Trp315Ter)	LOC130067862	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
985706	NM_001953.5(TYMP):c.1159+1G>A	LOC130067862	Pathogenic	criteria provided, multiple submitters, no conflicts
1456105	NM_001953.5(TYMP):c.235C>T (p.Arg79Ter)	LOC130067864	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16662	NM_001953.5(TYMP):c.215-1G>C	LOC130067864	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 16 · 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
TYMP	Strong	Autosomal recessive	mitochondrial DNA depletion syndrome 1	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TYMP	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
SCO2	Orphanet:1561	Fatal infantile cytochrome C oxidase deficiency
SCO2	Orphanet:521411	Autosomal recessive axonal Charcot-Marie-Tooth disease due to copper metabolism defect
SCO2	Orphanet:98619	Rare isolated myopia
FANCI	Orphanet:84	Fanconi anemia
MT-TK	Orphanet:1349	Mitochondrial DNA-related cardiomyopathy and hearing loss
MT-TK	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-TK	Orphanet:551	MERRF
POLG	Orphanet:254881	Spinocerebellar ataxia with epilepsy
POLG	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
POLG	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
POLG	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
POLG	Orphanet:402082	Progressive myoclonic epilepsy type 5
POLG	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
POLG	Orphanet:726	Alpers-Huttenlocher syndrome
POLG	Orphanet:94125	Recessive mitochondrial ataxia syndrome

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TYMP	HGNC:3148	ENSG00000025708	P19971	Thymidine phosphorylase	gencc,clinvar
SCO2	HGNC:10604	ENSG00000284194	O43819	Cytochrome c oxidase assembly factor SCO2	clinvar
NCAPH2	HGNC:25071	ENSG00000025770	Q6IBW4	Condensin-2 complex subunit H2	clinvar
FANCI	HGNC:25568	ENSG00000140525	Q9NVI1	Fanconi anemia group I protein	clinvar
POLGARF	HGNC:56246	ENSG00000291307	A0A3B3IS91	POLG alternative reading frame	clinvar
MT-TK	HGNC:7489	ENSG00000210156		mitochondrially encoded tRNA-Lys (AAA/G)	clinvar
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TYMP	Thymidine phosphorylase	May have a role in maintaining the integrity of the blood vessels.
SCO2	Cytochrome c oxidase assembly factor SCO2	Copper metallochaperone essential for the synthesis and maturation of cytochrome c oxidase subunit II (MT-CO2/COX2); together with SCO1, facilitates the incorporation of copper into the Cu(A) site of MT-CO2/COX2.
NCAPH2	Condensin-2 complex subunit H2	Regulatory subunit of the condensin-2 complex, a complex that seems to provide chromosomes with an additional level of organization and rigidity and in establishing mitotic chromosome architecture.
FANCI	Fanconi anemia group I protein	Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA r…
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 6 · Druggable fraction: 0.14

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	6	1.5×	0.221
Enzyme (other)	1	1.7×	0.456

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TYMP	Enzyme (other)	yes	2.4.2.4	Thymidine/pyrmidine_PPase, Glycosyl_Trfase_fam3, PYNP_C
SCO2	Other/Unknown	no		SCO1/SenC, Thioredoxin_domain, Synth_of_cyt-c-oxidase_Sco1/2
NCAPH2	Other/Unknown	no		H2_N, H2_M, CNDH2_C
FANCI	Other/Unknown	no		FANCI, FANCI_S1-cap, FANCI_S1
POLGARF	Other/Unknown	no
MT-TK	Other/Unknown	no
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf

Expression context

Cohort genes with no expression data: 1.

4 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)	6
unknown	1

Top tissues across cohort

Tissue	Cohort genes
granulocyte	3
right uterine tube	2
monocyte	1
mucosa of transverse colon	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
male germ line stem cell (sensu Vertebrata) in testis	1
secondary oocyte	1
ventricular zone	1
caudate nucleus	1
skeletal muscle tissue	1
sural nerve	1
small intestine Peyer’s patch	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TYMP	251	ubiquitous	marker	right uterine tube, granulocyte, monocyte
SCO2	260	ubiquitous	yes	right uterine tube, granulocyte, mucosa of transverse colon
NCAPH2	260	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
FANCI	221	ubiquitous	marker	ventricular zone, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
POLGARF
MT-TK	118		yes	sural nerve, skeletal muscle tissue, caudate nucleus
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLG	3,400
FANCI	2,312
SCO2	2,043
TYMP	1,972
NCAPH2	1,561
POLGARF	0
MT-TK	0

Intra-cohort edges

A	B	Sources
POLG	TYMP	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG	P54098	36
FANCI	Q9NVI1	8
TYMP	P19971	4
SCO2	O43819	1
NCAPH2	Q6IBW4	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
POLGARF	A0A3B3IS91	40.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 7 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Strand-asynchronous mitochondrial DNA replication	1	228.4×	0.028	POLG
Pyrimidine salvage	1	207.6×	0.028	TYMP
Pyrimidine catabolism	1	175.7×	0.028	TYMP
Fanconi Anemia Pathway	1	55.7×	0.065	FANCI
Complex IV assembly	1	45.7×	0.065	SCO2
TP53 Regulates Transcription of DNA Repair Genes	1	36.2×	0.068	FANCI
Condensation of Prophase Chromosomes	1	31.3×	0.068	NCAPH2
TP53 Regulates Metabolic Genes	1	25.9×	0.071	SCO2
Respiratory electron transport	1	19.0×	0.083	SCO2
Aerobic respiration and respiratory electron transport	1	17.7×	0.083	SCO2
Transcriptional Regulation by TP53	1	12.4×	0.106	SCO2
RNA Polymerase II Transcription	1	4.5×	0.254	SCO2
Gene expression (Transcription)	1	3.6×	0.289	SCO2
Generic Transcription Pathway	1	3.0×	0.311	SCO2
Metabolism	1	2.3×	0.362	SCO2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pyrimidine nucleobase metabolic process	1	1685.2×	0.006	TYMP
female meiosis chromosome separation	1	1685.2×	0.006	NCAPH2
DNA replication proofreading	1	1123.5×	0.006	POLG
muscle system process	1	842.6×	0.006	SCO2
pyrimidine nucleoside metabolic process	1	842.6×	0.006	TYMP
mitotic sister chromatid separation	1	674.1×	0.006	NCAPH2
meiotic chromosome condensation	1	561.7×	0.006	NCAPH2
dTMP catabolic process	1	561.7×	0.006	TYMP
positive regulation of chromosome condensation	1	421.3×	0.008	NCAPH2
positive regulation of chromosome separation	1	337.0×	0.009	NCAPH2
mitochondrial DNA replication	1	306.4×	0.009	POLG
positive regulation of chromosome segregation	1	259.3×	0.009	NCAPH2
base-excision repair, gap-filling	1	224.7×	0.010	POLG
DNA metabolic process	1	210.7×	0.010	POLG
mitotic chromosome condensation	1	198.3×	0.010	NCAPH2
intracellular copper ion homeostasis	1	187.2×	0.010	SCO2
respiratory electron transport chain	1	168.5×	0.010	SCO2
mitochondrial respiratory chain complex IV assembly	1	124.8×	0.013	SCO2
DNA-templated DNA replication	1	112.3×	0.014	POLG
base-excision repair	1	93.6×	0.015	POLG
interstrand cross-link repair	1	86.4×	0.016	FANCI
T cell differentiation in thymus	1	82.2×	0.016	NCAPH2
eye development	1	70.2×	0.018	SCO2
response to activity	1	64.8×	0.019	SCO2
positive regulation of protein ubiquitination	1	42.7×	0.027	FANCI
chemotaxis	1	27.2×	0.040	TYMP
in utero embryonic development	1	14.4×	0.073	SCO2
angiogenesis	1	12.5×	0.080	TYMP
cell differentiation	1	5.8×	0.160	TYMP

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 4 of 7 evidence-associated genes (57%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TYMP	TIPIRACIL
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TYMP	2	4
POLG	1	4
SCO2	0	0
NCAPH2	0	0
FANCI	0	0
POLGARF	0	0
MT-TK	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TIPIRACIL	4	TYMP
TIPIRACIL HYDROCHLORIDE	4	TYMP
ADEFOVIR DIPIVOXIL	4	POLG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TYMP	94	Binding:91, Functional:3
POLG	33	Binding:30, ADMET:2, Functional:1
SCO2	1	Binding:1
FANCI	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TYMP	2.4.2.4	thymidine phosphorylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 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.

Compound	Max phase	Cohort target (bioactivity)
TIPIRACIL	4	TYMP
TIPIRACIL HYDROCHLORIDE	4	TYMP
ADEFOVIR DIPIVOXIL	4	POLG

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TYMP, POLG
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	5	SCO2, NCAPH2, FANCI, POLGARF, MT-TK

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SCO2	1	—
NCAPH2	0	—
FANCI	1	—
POLGARF	0	—
MT-TK	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.