mitochondrial DNA depletion syndrome

Summary

mitochondrial DNA depletion syndrome (MONDO:0018158) is a disease (an umbrella term covering 21 Mondo subtypes) caused by GUK1 (GenCC Strong), with 7 cohort genes. The dominant Reactome pathway is Metabolism of nucleotides (3 cohort genes).

At a glance

• Prevalence: 1-9 / 1 000 000 (Israel) [Orphanet-validated]
• Causal gene: GUK1 (GenCC Strong)
• Umbrella term: 21 Mondo subtypes
• Cohort genes: 7
• ClinVar variants: 65

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.5	Israel	Validated
Prevalence at birth	1-9 / 100 000	1.1	Specific population	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome
Mondo ID	MONDO:0018158
OMIM	603041
Orphanet	35698
DOID	DOID:0070329
ICD-11	1159345506
UMLS	C0342782
MedGen	452449
GARD	0013643
MedDRA	10059396
Is cancer (heuristic)	no

Also known as: mtDNA depletion syndrome

Data availability: 65 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 21 Mondo subtypes.

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 DNA depletion syndrome

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

Subtypes (21): Sengers syndrome, mitochondrial DNA depletion syndrome 1, mitochondrial DNA depletion syndrome, myopathic form, mitochondrial DNA depletion syndrome 4b, mitochondrial DNA depletion syndrome 11, mitochondrial DNA deletion syndrome with progressive myopathy, mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive, mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type), mitochondrial DNA depletion syndrome 15 (hepatocerebral type), mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant, mitochondrial DNA depletion syndrome, encephalomyopathic form, mitochondrial dna depletion syndrome 16B (neuroophthalmic type), mitochondrial DNA depletion syndrome 20 (mngie type), mitochondrial DNA depletion syndrome 16 (hepatic type), mitochondrial DNA depletion syndrome 17, mitochondrial DNA depletion syndrome 18, mitochondrial DNA depletion syndrome 19, mitochondrial DNA depletion syndrome, hepatocerebral form, AFG3L2-related optic atrophy and/or spastic ataxia spectrum, mitochondrial dna depletion syndrome 21, mitochondrial dna depletion syndrome 14A (encephalomyopathic 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

65 retrieved; paginated sample, class counts are floors:

22 pathogenic, 18 pathogenic/likely pathogenic, 14 conflicting classifications of pathogenicity, 10 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
66091	NM_001278716.2(FBXL4):c.1303C>T (p.Arg435Ter)	FBXL4	Pathogenic	criteria provided, multiple submitters, no conflicts
16160	NM_002437.5(MPV17):c.149G>A (p.Arg50Gln)	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
16162	NM_002437.5(MPV17):c.148C>T (p.Arg50Trp)	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
16164	NM_002437.5(MPV17):c.359G>A (p.Trp120Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2581455	NM_002437.5(MPV17):c.70+5G>A	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3063945	NC_000002.11:g.(27535977_27545314)(27545965?)del	MPV17	Pathogenic	criteria provided, single submitter
3384706	NM_002437.5(MPV17):c.125del (p.Gly42fs)	MPV17	Pathogenic	criteria provided, single submitter
381523	NM_002437.5(MPV17):c.191C>G (p.Pro64Arg)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38355	NM_002437.5(MPV17):c.293C>T (p.Pro98Leu)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
626263	NM_002437.5(MPV17):c.122G>A (p.Arg41Gln)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13495	NM_002693.3(POLG):c.2864A>G (p.Tyr955Cys)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13499	NM_002693.3(POLG):c.1879C>T (p.Arg627Trp)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
13500	NM_002693.3(POLG):c.2794C>T (p.His932Tyr)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
13502	NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
13506	NM_002693.3(POLG):c.2591A>G (p.Asn864Ser)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
13515	NM_002693.3(POLG):c.679C>T (p.Arg227Trp)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13516	NM_002693.3(POLG):c.3218C>T (p.Pro1073Leu)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
206529	NM_002693.3(POLG):c.2558G>A (p.Arg853Gln)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21319	NM_002693.3(POLG):c.695G>A (p.Arg232His)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
2736252	NM_002693.3(POLG):c.2420G>C (p.Arg807Pro)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
280016	NM_002693.3(POLG):c.2870C>T (p.Ala957Val)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372472	NM_002693.3(POLG):c.823C>T (p.Arg275Ter)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
3896091	NM_002693.3(POLG):c.731T>C (p.Leu244Pro)	POLG	Pathogenic	criteria provided, multiple submitters, no conflicts
4525746	NM_002693.3(POLG):c.132_133insTAGCAGCAG (p.Gln45Ter)	POLG	Pathogenic	criteria provided, single submitter
458687	NM_002693.3(POLG):c.1276G>A (p.Gly426Ser)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4848601	NM_002693.3(POLG):c.1984G>T (p.Glu662Ter)	POLG	Pathogenic	criteria provided, single submitter
619395	NM_002693.3(POLG):c.2551A>G (p.Thr851Ala)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12708	NM_004614.5(TK2):c.361C>A (p.His121Asn)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
12710	NM_004614.5(TK2):c.323C>T (p.Thr108Met)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
1410181	NM_004614.5(TK2):c.415G>A (p.Ala139Thr)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 13 · 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
GUK1	Strong	Autosomal recessive	mitochondrial DNA depletion syndrome	2
POLG2	Strong	Autosomal dominant	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4	8
DTYMK	Limited	Autosomal recessive	mitochondrial DNA depletion syndrome	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLG2	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
TK2	Orphanet:254875	Mitochondrial DNA depletion syndrome, myopathic form
TK2	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
FBXL4	Orphanet:369897	Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies
MPV17	Orphanet:255229	Navajo neurohepatopathy
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, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DTYMK	HGNC:3061	ENSG00000168393	P23919	Thymidylate kinase	gencc
GUK1	HGNC:4693	ENSG00000143774	Q16774	Guanylate kinase	gencc
POLG2	HGNC:9180	ENSG00000256525	Q9UHN1	DNA polymerase subunit gamma-2	gencc
TK2	HGNC:11831	ENSG00000166548	O00142	Thymidine kinase 2, mitochondrial	clinvar
FBXL4	HGNC:13601	ENSG00000112234	Q9UKA2	F-box/LRR-repeat protein 4	clinvar
MPV17	HGNC:7224	ENSG00000115204	P39210	Mitochondrial inner membrane protein Mpv17	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)
DTYMK	Thymidylate kinase	Catalyzes the phosphorylation of thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), the immediate precursor for the DNA building block dTTP, with ATP as the preferred phosphoryl donor in the presence of Mg(2+).
GUK1	Guanylate kinase	Catalyzes the phosphorylation of GMP to GDP.
POLG2	DNA polymerase subunit gamma-2	Accessory subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).
TK2	Thymidine kinase 2, mitochondrial	Phosphorylates thymidine, deoxycytidine, and deoxyuridine in the mitochondrial matrix.
FBXL4	F-box/LRR-repeat protein 4	Substrate-recognition component of the mitochondria-localized SCF-FBXL4 ubiquitin E3 ligase complex that plays a role in the restriction of mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors.
MPV17	Mitochondrial inner membrane protein Mpv17	Non-selective channel that modulates the membrane potential under normal conditions and oxidative stress, and is involved in mitochondrial homeostasis.
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.57

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
Kinase	3	11.9×	0.004
Enzyme (other)	1	1.7×	0.685
Other/Unknown	3	0.8×	0.858

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DTYMK	Kinase	yes	2.7.4.9	Thymidylate_kinase, Thymidylate_kin_CS, P-loop_NTPase
GUK1	Kinase	yes	2.7.4.8	Guanylate_kin-like_dom, GK/Ca_channel_bsu, Guanylate_kinase
POLG2	Enzyme (other)	yes	2.7.7.7	Anticodon-bd, Gly-tRNA_synthase/POLG2, Anticodon-bd_dom_sf
TK2	Kinase	yes	2.7.1.21	DCK/DGK, P-loop_NTPase, DNK_dom
FBXL4	Other/Unknown	no		F-box_dom, Leu-rich_rpt_Cys-con_subtyp, LRR_dom_sf
MPV17	Other/Unknown	no		Mpv17_PMP22
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: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	2
calcaneal tendon	2
mucosa of transverse colon	1
primordial germ cell in gonad	1
ventricular zone	1
amygdala	1
prefrontal cortex	1
right frontal lobe	1
left testis	1
oocyte	1
secondary oocyte	1
sural nerve	1
corpus epididymis	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
granulocyte	1
small intestine Peyer’s patch	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DTYMK	224	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, mucosa of transverse colon
GUK1	300	ubiquitous	marker	right frontal lobe, prefrontal cortex, amygdala
POLG2	249	ubiquitous	marker	secondary oocyte, oocyte, left testis
TK2	280	ubiquitous	marker	calcaneal tendon, sural nerve, adrenal tissue
FBXL4	265	ubiquitous	marker	adrenal tissue, corpus epididymis, calcaneal tendon
MPV17	283	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 9.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GUK1	3,686
POLG	3,400
DTYMK	2,508
TK2	2,031
FBXL4	1,620
POLG2	1,557
MPV17	1,251

Intra-cohort edges

A	B	Sources
DTYMK	GUK1	string_interaction
DTYMK	TK2	string_interaction
FBXL4	MPV17	string_interaction
FBXL4	POLG	string_interaction
FBXL4	POLG2	string_interaction
MPV17	POLG	string_interaction
MPV17	POLG2	string_interaction
MPV17	TK2	string_interaction
POLG	POLG2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG2	Q9UHN1	38
POLG	P54098	36
DTYMK	P23919	21
GUK1	Q16774	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MPV17	P39210	90.23
FBXL4	Q9UKA2	86.50
TK2	O00142	85.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 7 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Metabolism of nucleotides	3	128.8×	2e-05	TK2, DTYMK, GUK1
Strand-asynchronous mitochondrial DNA replication	2	326.3×	9e-05	POLG, POLG2
Interconversion of nucleotide di- and triphosphates	2	102.0×	7e-04	DTYMK, GUK1
Nucleotide salvage	1	163.1×	0.017	TK2
Pyrimidine salvage	1	148.3×	0.017	TK2
Azathioprine ADME	1	70.9×	0.030	GUK1
Metabolism	3	5.0×	0.032	TK2, DTYMK, GUK1
Drug ADME	1	32.6×	0.047	GUK1
Transcriptional activation of mitochondrial biogenesis	1	29.1×	0.047	POLG2
Protein localization	1	27.2×	0.047	MPV17
Peroxisomal protein import	1	24.7×	0.047	MPV17
Neddylation	1	6.8×	0.150	FBXL4
Antigen processing: Ubiquitination & Proteasome degradation	1	5.3×	0.174	FBXL4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial DNA replication	2	437.7×	3e-04	POLG, POLG2
DNA-templated DNA replication	2	160.5×	0.001	POLG, POLG2
dGDP biosynthetic process	1	2407.4×	0.002	GUK1
dATP metabolic process	1	2407.4×	0.002	GUK1
deoxycytidine metabolic process	1	2407.4×	0.002	TK2
GDP biosynthetic process	1	2407.4×	0.002	GUK1
dUDP biosynthetic process	1	1203.7×	0.003	DTYMK
dTDP biosynthetic process	1	1203.7×	0.003	DTYMK
pyrimidine nucleoside salvage	1	1203.7×	0.003	TK2
thymidine metabolic process	1	1203.7×	0.003	TK2
regulation of mitochondrial DNA metabolic process	1	1203.7×	0.003	MPV17
purine nucleotide metabolic process	1	802.5×	0.003	GUK1
glycoprotein transport	1	802.5×	0.003	GUK1
DNA replication proofreading	1	802.5×	0.003	POLG
dGMP metabolic process	1	802.5×	0.003	GUK1
thymidine biosynthetic process	1	802.5×	0.003	DTYMK
dTTP biosynthetic process	1	481.5×	0.004	DTYMK
GDP-mannose metabolic process	1	401.2×	0.005	GUK1
positive regulation of DNA-directed DNA polymerase activity	1	300.9×	0.006	POLG2
nucleobase-containing small molecule interconversion	1	240.7×	0.007	GUK1
glomerular basement membrane development	1	218.9×	0.007	MPV17
negative regulation of mitophagy	1	218.9×	0.007	FBXL4
base-excision repair, gap-filling	1	160.5×	0.009	POLG
DNA metabolic process	1	150.5×	0.010	POLG
DNA biosynthetic process	1	114.6×	0.012	TK2
autophagy of mitochondrion	1	104.7×	0.013	FBXL4
nucleobase-containing compound metabolic process	1	75.2×	0.017	TK2
base-excision repair	1	66.9×	0.019	POLG
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	1	53.5×	0.022	FBXL4
inner ear development	1	53.5×	0.022	MPV17

Therapeutics

Drug target analysis

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

Druggability breadth: 5 of 7 evidence-associated genes (71%) 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
TK2	SORIVUDINE
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TK2	1	4
POLG	1	4
DTYMK	0	0
GUK1	0	0
POLG2	0	0
FBXL4	0	0
MPV17	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SORIVUDINE	4	TK2
ADEFOVIR DIPIVOXIL	4	POLG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
DTYMK	38	Binding:36, ADMET:2
POLG	33	Binding:30, ADMET:2, Functional:1
TK2	17	Binding:17
GUK1	6	Binding:6
POLG2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DTYMK	2.7.4.9	dTMP kinase
GUK1	2.7.4.8	guanylate kinase
POLG2	2.7.7.7	DNA-directed DNA polymerase
TK2	2.7.1.21	thymidine kinase

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

2 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)
SORIVUDINE	4	TK2
ADEFOVIR DIPIVOXIL	4	POLG

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TK2, POLG
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	DTYMK, GUK1, POLG2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FBXL4, MPV17

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)
DTYMK	38	TK2
POLG2	1	POLG
MPV17	0	POLG
GUK1	6	—
FBXL4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.