DGUOK

Summary

DGUOK (deoxyguanosine kinase, HGNC:2858) is a protein-coding gene on chromosome 2p13.1, encoding Deoxyguanosine kinase, mitochondrial (Q16854). Phosphorylates deoxyguanosine and deoxyadenosine in the mitochondrial matrix, with the highest efficiency for deoxyguanosine.

In mammalian cells, the phosphorylation of purine deoxyribonucleosides is mediated predominantly by two deoxyribonucleoside kinases, cytosolic deoxycytidine kinase and mitochondrial deoxyguanosine kinase. The protein encoded by this gene is responsible for phosphorylation of purine deoxyribonucleosides in the mitochondrial matrix. In addition, this protein phosphorylates several purine deoxyribonucleoside analogs used in the treatment of lymphoproliferative disorders, and this phosphorylation is critical for the effectiveness of the analogs. Alternative splice variants encoding different protein isoforms have been described for this gene.

Source: NCBI Gene 1716 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 391 total — 42 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 78
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_080916

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2858
Approved symbol	DGUOK
Name	deoxyguanosine kinase
Location	2p13.1
Locus type	gene with protein product
Status	Approved
Aliases	dGK
Ensembl gene	ENSG00000114956
Ensembl biotype	protein_coding
OMIM	601465
Entrez	1716

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 10 protein_coding, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000264093, ENST00000348222, ENST00000418996, ENST00000462551, ENST00000462685, ENST00000489796, ENST00000493055, ENST00000629438, ENST00000893377, ENST00000893378, ENST00000893379, ENST00000893380, ENST00000893381, ENST00000915416, ENST00000915417, ENST00000915418

RefSeq mRNA: 7 — MANE Select: NM_080916 NM_001318859, NM_001318860, NM_001318861, NM_001318862, NM_001318863, NM_080916, NM_080918

CCDS: CCDS1931, CCDS1932

Canonical transcript exons

ENST00000264093 — 7 exons

Exon	Start	End
ENSE00001670855	73957125	73957240
ENSE00001740843	73950585	73950732
ENSE00003534571	73946719	73946906
ENSE00003550783	73958146	73958245
ENSE00003565535	73938910	73939022
ENSE00003842845	73926880	73927052
ENSE00003847359	73958710	73958946

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 96.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 82.7498 / max 342.6173, expressed in 1827 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20990	73.1704	1826
20991	9.5794	1787

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	96.74	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.44	gold quality
pituitary gland	UBERON:0000007	96.13	gold quality
ascending aorta	UBERON:0001496	96.11	gold quality
thoracic aorta	UBERON:0001515	96.10	gold quality
descending thoracic aorta	UBERON:0002345	96.08	gold quality
ganglionic eminence	UBERON:0004023	96.05	gold quality
mucosa of transverse colon	UBERON:0004991	95.95	gold quality
cortical plate	UBERON:0005343	95.95	gold quality
aorta	UBERON:0000947	95.87	gold quality
popliteal artery	UBERON:0002250	95.78	gold quality
tibial artery	UBERON:0007610	95.78	gold quality
left ovary	UBERON:0002119	95.77	gold quality
left coronary artery	UBERON:0001626	95.70	gold quality
granulocyte	CL:0000094	95.68	gold quality
right ovary	UBERON:0002118	95.59	gold quality
mucosa of stomach	UBERON:0001199	95.53	gold quality
body of uterus	UBERON:0009853	95.34	gold quality
endocervix	UBERON:0000458	95.20	gold quality
left uterine tube	UBERON:0001303	95.20	gold quality
ectocervix	UBERON:0012249	95.18	gold quality
stromal cell of endometrium	CL:0002255	95.16	gold quality
right adrenal gland cortex	UBERON:0035827	95.13	gold quality
nucleus accumbens	UBERON:0001882	95.12	gold quality
right adrenal gland	UBERON:0001233	95.11	gold quality
ventricular zone	UBERON:0003053	95.08	gold quality
coronary artery	UBERON:0001621	95.06	gold quality
left adrenal gland	UBERON:0001234	95.05	gold quality
skin of abdomen	UBERON:0001416	95.03	gold quality
skin of leg	UBERON:0001511	95.03	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR2

miRNA regulators (miRDB)

7 targeting DGUOK, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-1287-3P	99.63	66.93	492
HSA-MIR-92A-1-5P	98.28	64.51	631
HSA-MIR-7113-5P	97.88	67.33	1735

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 21)

• Low level of mitochondrial deoxyguanosine kinase is the dominant factor in acquired resistance to 9-beta-D-arabinofuranosylguanine cytotoxicity (PMID:12054684)
• A novel mutation in the deoxyguanosine kinase gene causing depletion of mitochondrial DNA. Homozygous nonsense mutation in exon 3 of DGUOK (313C–>T). (PMID:12210798)
• Data show that inorganic tripolyphosphate (PPP(i)) is a good donor for human ceoxycytidine kinase and deoxyguanosine kinase. (PMID:12535661)
• Neurological symptoms appeared later and were mild, in agreement with the limited brain pathology. Molecular analysis of the dGK gene should be performed in infants with cirrhosis even in the absence of CNS involvement. (PMID:15150663)
• This study identified 2 novel homozygous mutations, G352A and C269T, that lead to truncated proteins in the hepatocerebral form of mitochondrial DNA depletion syndrome. (PMID:15883261)
• deoxycytidine kinase, deoxyguanosine kinase, and cytosolic 5’-nucleotidase I are regulated in a cell cycle-dependent manner in MOLT-4 cells (PMID:17065091)
• DGUOK activity may play a crucial role in the phenotype reversal (PMID:17073823)
• DGUOK is required for mitochondrial DNA replication in resting cells and that small changes in expression of this enzyme may cause mitochondrial DNA depletion. (PMID:17490647)
• 15 different mutations in the DGUOK gene from 9 kindreds, were identified. (PMID:18205204)
• dCK and dGK were downregulated by approximately 70% in CEM cells and tested against six nucleoside (PMID:18600530)
• study reports the first founder DGUOK mutation (c.444-62C>A) in two North-African families with hepatocerebral syndrome and severe combined respiratory chain deficiency (PMID:19394258)
• a viral infection can trigger fulminant liver failure in the context of a genetic predisposition associated with mutations in DGUOK (PMID:19502998)
• c.592-4_c.592-3delTT mutation causes exon skipping and is and responsible for the DGUOK deficiency (PMID:19900589)
• Deoxyguanosine kinase gene mutations combined with impaired glucose homeostasis and iron overload features are associated with severe progressive liver failure. (PMID:21107780)
• study expands the spectrum of disorders caused by mutations in DGUOK. (PMID:23043144)
• thymidine kinase 2 but not deoxyguanosine kinase is up-regulated during the stationary growth phase of cultured cells (PMID:24940680)
• The goals of this work are to characterize the DGUOK rat in terms of mitochondrial dysfunction and pathological outcome, and to evaluate EPR as a new and additional technique in an integrated characterization of mitochondrial disease . (PMID:26773591)
• rare homozygous p.N46S mutation associated with idiopathic noncirrhotic portal hypertension (PMID:26874653)
• sequencing results showed that the patient was a compound heterozygote for c.679G>A and c.817delT in the DGUOK gene (PMID:27324545)
• DGUOK deficiency and mutation is associated with mitochondrial DNA depletion syndromes. (PMID:28493820)
• Case report: Two unexpected cases of DGUOK-related mitochondrial DNA depletion syndrome presenting with hyperinsulinemic hypoglycemia. (PMID:38027095)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dguok	ENSDARG00000075395
mus_musculus	Dguok	ENSMUSG00000014554
rattus_norvegicus	Dguok	ENSRNOG00000011617

Paralogs (3): NDUFA10 (ENSG00000130414), DCK (ENSG00000156136), TK2 (ENSG00000166548)

Protein

Protein identifiers

Deoxyguanosine kinase, mitochondrial — Q16854 (reviewed: Q16854)

Alternative names: Deoxyadenosine kinase, mitochondrial

All UniProt accessions (4): A0A0S2Z3N1, E5KSL5, E5KSL6, Q16854

UniProt curated annotations — full annotation on UniProt →

Function. Phosphorylates deoxyguanosine and deoxyadenosine in the mitochondrial matrix, with the highest efficiency for deoxyguanosine. In non-replicating cells, where cytosolic dNTP synthesis is down-regulated, mtDNA synthesis depends solely on DGUOK and TK2. Phosphorylates certain nucleoside analogs. Widely used as target of antiviral and chemotherapeutic agents.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion.

Tissue specificity. Ubiquitous. Highest expression in muscle, brain, liver and lymphoid tissues.

Disease relevance. Mitochondrial DNA depletion syndrome 3 (MTDPS3) [MIM:251880] A disorder due to mitochondrial dysfunction characterized by onset in infancy of progressive liver failure, hypoglycemia, increased lactate in body fluids, and neurologic abnormalities including hypotonia, encephalopathy, peripheral neuropathy. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes and mtDNA depletion. The disease is caused by variants affecting the gene represented in this entry. Portal hypertension, non-cirrhotic, 1 (NCPH1) [MIM:617068] An autosomal recessive disorder characterized by portal hypertension associated with hepatosplenomegaly, in absence of cirrhosis, extrahepatic diseases, and splanchnic venous thrombosis. Portal hypertension is defined by a portal venous system pressure that is at least 5 mm Hg higher than the pressure in the inferior vena cava. High pressure in the portal venous system leads to shunting of blood through vessels that are poorly suited to carrying large blood volumes, resulting in collateral circulation and splenomegaly. NCPH1 patients show normal liver function. The disease is caused by variants affecting the gene represented in this entry. Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 (PEOB4) [MIM:617070] A form of progressive external ophthalmoplegia, a mitochondrial myopathy characterized by progressive paralysis of the levator palpebrae, orbicularis oculi, and extraocular muscles. PEOB4 patients manifest clinically variable features including mitochondrial myopathy with or without progressive external ophthalmoplegia, recurrent rhabdomyolysis, and adult-onset lower motor neuron syndrome with mild cognitive impairment. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DCK/DGK family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q16854-1	1	yes
Q16854-2	2
Q16854-3	3
Q16854-4	4
Q16854-5	5
Q16854-6	6

RefSeq proteins (7): NP_001305788, NP_001305789, NP_001305790, NP_001305791, NP_001305792, NP_550438, NP_550440 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002624	DCK/DGK	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031314	DNK_dom	Domain
IPR050566	Deoxyribonucleoside_kinase	Family

Pfam: PF01712

Enzyme classification (BRENDA):

• EC 2.7.1.113 — deoxyguanosine kinase (BRENDA: 10 organisms, 123 substrates, 93 inhibitors, 99 Km, 23 kcat entries)

Substrate kinetics (BRENDA)

22 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0085–3.3	22
2’-DEOXYGUANOSINE	0.0006–0.123	20
DEOXYGUANOSINE	0.0003–0.76	17
2’-DEOXYADENOSINE	0.0026–0.5	9
DEOXYADENOSINE	0.206–2.689	4
DTTP	0.08–2.2	3
UTP	0.006–0.125	3
2-CHLORODEOXYADENOSINE	0.008–0.062	2
CTP	0.035	2
DEOXYCYTIDINE	0.34–4.424	2
DEOXYINOSINE	0.012–0.021	2
GTP	0.046	2
1-(2-DEOXY-BETA-D-RIBOFURANOSYL)-7-IODOISOCARBOS	0.019	1
2-CHLORO-2’-ARABINO-FLUORO-2’-DEOXYADENOSINE	0.056	1
2-CHLORO-2’-DEOXYADENOSINE	0.078	1

Catalyzed reactions (Rhea), 2 shown:

• 2’-deoxyguanosine + ATP = dGMP + ADP + H(+) (RHEA:19201)
• 2’-deoxyadenosine + ATP = dAMP + ADP + H(+) (RHEA:23452)

UniProt features (50 total): helix 13, binding site 10, sequence variant 8, splice variant 5, strand 5, sequence conflict 3, turn 2, transit peptide 1, chain 1, modified residue 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2OCP	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16854-F1	87.27	0.77

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 141 (proton acceptor)

Ligand- & substrate-binding residues (10): 206–208; 211; 254–256; 45–53; 70; 100; 111; 118; 142; 147

Post-translational modifications (1): 275

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-74217	Purine salvage

MSigDB gene sets: 337 (showing top): KANG_FLUOROURACIL_RESISTANCE_UP, KAAB_FAILED_HEART_ATRIUM_DN, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, GOBP_NEUROGENESIS, DARWICHE_PAPILLOMA_RISK_HIGH_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, MORF_HDAC2, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PURINE_CONTAINING_COMPOUND_SALVAGE, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, PUJANA_CHEK2_PCC_NETWORK

GO Biological Process (9): guanosine metabolic process (GO:0008617), negative regulation of neuron projection development (GO:0010977), mitochondrial ATP synthesis coupled electron transport (GO:0042775), dGTP metabolic process (GO:0046070), purine deoxyribonucleoside metabolic process (GO:0046122), dAMP salvage (GO:0106383), nucleobase-containing compound metabolic process (GO:0006139), deoxyribonucleoside monophosphate biosynthetic process (GO:0009157), carbohydrate derivative metabolic process (GO:1901135)

GO Molecular Function (8): deoxyadenosine kinase activity (GO:0004136), deoxyguanosine kinase activity (GO:0004138), ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), deoxynucleoside kinase activity (GO:0019136)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nucleotide salvage	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
dAMP biosynthetic process	2
deoxynucleoside kinase activity	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
purine ribonucleoside metabolic process	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
ATP synthesis coupled electron transport	1
purine deoxyribonucleotide metabolic process	1
deoxyribonucleoside triphosphate metabolic process	1
purine deoxyribonucleoside triphosphate metabolic process	1
purine nucleoside metabolic process	1
purine deoxyribonucleotide salvage	1
primary metabolic process	1
nucleoside monophosphate biosynthetic process	1
metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
deoxyribonucleoside monophosphate biosynthetic process	1
nucleobase-containing compound kinase activity	1
intracellular anatomical structure	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

10 interactions, top by confidence:

A	B	Type	Score
DCK	DGUOK	psi-mi:“MI:0914”(association)	0.620
DGUOK	DCK	psi-mi:“MI:0915”(physical association)	0.620
PXN	DGUOK	psi-mi:“MI:0915”(physical association)	0.370
DGUOK	BIN1	psi-mi:“MI:0914”(association)	0.350
TMEM184A	NRDC	psi-mi:“MI:0914”(association)	0.350
MTPN	PLCG1	psi-mi:“MI:0914”(association)	0.350
DCK	KLK3	psi-mi:“MI:0914”(association)	0.350

BioGRID (191): NCAM1 (Affinity Capture-MS), DPYSL5 (Affinity Capture-MS), STXBP1 (Affinity Capture-MS), ATP4A (Affinity Capture-MS), ATP2B2 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ELAVL4 (Affinity Capture-MS), GPM6B (Affinity Capture-MS), HIST1H1B (Affinity Capture-MS), HIST1H2BL (Affinity Capture-MS), CNTN1 (Affinity Capture-MS), DCLK1 (Affinity Capture-MS), SNAP91 (Affinity Capture-MS), SYT1 (Affinity Capture-MS), HPCAL4 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8HV70, A0A7H0DNE5, A1ZB29, A6QQL3, P00572, P07884, P0DSV5, P0DSV6, P21974, P27707, P34254, P43346, P48769, P49915, P68693, P91929, Q16854, Q197D1, Q22018, Q2M197, Q3MHR2, Q3THK7, Q4V339, Q4V7C6, Q5F3Z1, Q5JTY5, Q5ZJM7, Q5ZMF3, Q61E36, Q6DD33, Q6GPW6, Q6RZD4, Q76RA8, Q77TG7, Q80DS7, Q80HT9, Q8IUF1, Q8JL72, Q8QMQ7, Q8QQ21

Diamond homologs: A0A1L8HV70, O00142, P21974, P27707, P43346, P48769, Q16854, Q3MHR2, Q5ZJM7, Q5ZMF3, Q6DD33, Q6GPW6, Q9J579, Q9N0C5, Q9QX60, Q9R088, Q9XZT6, Q8FKZ1, P28855, Q6GZP0, Q197D1, Q54YL2, Q54UT2

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
DGUOK	“down-regulates quantity”	ATP(4-)	“chemical modification”
DGUOK	“up-regulates quantity”	ADP(3-)	“chemical modification”
DGUOK	“down-regulates quantity”	2’-deoxyadenosine	“chemical modification”
DGUOK	“up-regulates quantity”	“2’-deoxyadenosine 5’-monophosphate(2-)”	“chemical modification”
DGUOK	“down-regulates quantity”	2’-deoxyguanosine	“chemical modification”
DGUOK	“up-regulates quantity”	“2’-deoxyguanosine 5’-monophosphate(2-)”	“chemical modification”
DGUOK	“down-regulates quantity”	2’-deoxyinosine	“chemical modification”
DGUOK	“up-regulates quantity”	“2’-deoxyinosine 5’-phosphate(2-)”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

391 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	42
Likely pathogenic	14
Uncertain significance	120
Likely benign	156
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1322207	NM_080916.3(DGUOK):c.235C>T (p.Gln79Ter)	Pathogenic
1324223	NM_080916.3(DGUOK):c.3G>A (p.Met1Ile)	Pathogenic
1968811	NM_080916.3(DGUOK):c.225G>A (p.Trp75Ter)	Pathogenic
2020035	NM_080916.3(DGUOK):c.226C>T (p.Gln76Ter)	Pathogenic
214286	NM_080916.3(DGUOK):c.591G>A (p.Gln197=)	Pathogenic
214287	NM_080916.3(DGUOK):c.658G>T (p.Glu220Ter)	Pathogenic
214288	NM_080916.3(DGUOK):c.605_606del (p.Arg202fs)	Pathogenic
2203104	NM_080916.3(DGUOK):c.1A>G (p.Met1Val)	Pathogenic
2203105	NM_080916.3(DGUOK):c.677A>G (p.His226Arg)	Pathogenic
2216459	NM_080916.3(DGUOK):c.487del (p.Asp163fs)	Pathogenic
253068	NM_080916.3(DGUOK):c.186C>A (p.Tyr62Ter)	Pathogenic
2572386	NM_080916.3(DGUOK):c.173_176del (p.Leu58fs)	Pathogenic
2706426	NM_080916.3(DGUOK):c.54_57dup (p.Lys20fs)	Pathogenic
2734235	NM_080916.3(DGUOK):c.2T>C (p.Met1Thr)	Pathogenic
2734237	NM_080916.3(DGUOK):c.80_81dup (p.Ser28fs)	Pathogenic
2734238	NM_080916.3(DGUOK):c.318G>A (p.Trp106Ter)	Pathogenic
2758034	NM_080916.3(DGUOK):c.589del (p.Gln197fs)	Pathogenic
2790322	NM_080916.3(DGUOK):c.66_78del (p.Leu23fs)	Pathogenic
2802719	NM_080916.3(DGUOK):c.94_106del (p.Leu32fs)	Pathogenic
2853002	NM_080916.3(DGUOK):c.498G>A (p.Trp166Ter)	Pathogenic
2990374	NM_080916.3(DGUOK):c.476_477del (p.Gly159fs)	Pathogenic
3007048	NM_080916.3(DGUOK):c.601_602del (p.Lys201fs)	Pathogenic
3247576	NC_000002.11:g.(?74166017)(74166169_?)del	Pathogenic
3247579	NC_000002.11:g.(?74173826)(74177879_?)del	Pathogenic
3247581	NC_000002.11:g.(?74177650)(74185863_?)del	Pathogenic
3247582	NC_000002.11:g.(?74184232)(74185863_?)del	Pathogenic
3247583	NC_000002.11:g.(?74185253)(74185863_?)del	Pathogenic
3381837	NM_080916.3(DGUOK):c.505_508del (p.Tyr169fs)	Pathogenic
3384060	NM_080916.3(DGUOK):c.760GAT[1] (p.Asp255del)	Pathogenic
3616078	NM_080916.3(DGUOK):c.746del (p.Val249fs)	Pathogenic

SpliceAI

1144 predictions. Top by Δscore:

Variant	Effect	Δscore
2:73946865:G:GT	donor_gain	1.0000
2:73958125:A:AG	acceptor_gain	1.0000
2:73958125:AAAC:A	acceptor_gain	1.0000
2:73958126:A:G	acceptor_gain	1.0000
2:73958128:C:CA	acceptor_gain	1.0000
2:73958128:C:G	acceptor_gain	1.0000
2:73958134:C:CA	acceptor_gain	1.0000
2:73958134:C:G	acceptor_gain	1.0000
2:73958141:TATA:T	acceptor_loss	1.0000
2:73958143:TA:T	acceptor_loss	1.0000
2:73958144:A:AG	acceptor_gain	1.0000
2:73958145:G:GA	acceptor_gain	1.0000
2:73958213:G:GT	donor_gain	1.0000
2:73958241:GAGAG:G	donor_gain	1.0000
2:73958242:AGAGG:A	donor_loss	1.0000
2:73958243:GAG:G	donor_gain	1.0000
2:73958243:GAGGT:G	donor_loss	1.0000
2:73958244:AGGTG:A	donor_loss	1.0000
2:73958245:GG:G	donor_loss	1.0000
2:73958247:T:A	donor_loss	1.0000
2:73958250:G:T	donor_gain	1.0000
2:73927049:ATTGG:A	donor_loss	0.9900
2:73927051:TGGTA:T	donor_loss	0.9900
2:73927052:GGTAA:G	donor_loss	0.9900
2:73927053:G:GC	donor_loss	0.9900
2:73927053:G:GG	donor_gain	0.9900
2:73927054:T:A	donor_loss	0.9900
2:73938909:GCT:G	acceptor_gain	0.9900
2:73939023:G:GG	donor_gain	0.9900
2:73946708:T:G	acceptor_gain	0.9900

AlphaMissense

1822 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:73950592:T:C	F151L	0.996
2:73950594:T:A	F151L	0.996
2:73950594:T:G	F151L	0.996
2:73938920:G:C	K51N	0.992
2:73938920:G:T	K51N	0.992
2:73927043:G:C	G45R	0.991
2:73946899:A:C	S146R	0.991
2:73946901:T:A	S146R	0.991
2:73946901:T:G	S146R	0.991
2:73938919:A:T	K51M	0.989
2:73957130:T:G	C199W	0.988
2:73938918:A:C	K51Q	0.987
2:73938919:A:C	K51T	0.987
2:73957218:T:A	W229R	0.986
2:73957218:T:C	W229R	0.986
2:73927043:G:T	G45C	0.985
2:73927048:C:A	N46K	0.985
2:73927048:C:G	N46K	0.985
2:73946816:G:C	R118P	0.985
2:73946819:T:C	L119P	0.985
2:73950637:T:A	W166R	0.984
2:73950637:T:C	W166R	0.984
2:73950593:T:C	F151S	0.983
2:73950593:T:G	F151C	0.983
2:73946885:A:T	E141V	0.982
2:73957151:G:C	R206S	0.982
2:73957151:G:T	R206S	0.982
2:73927044:G:T	G45V	0.981
2:73938916:G:A	G50E	0.981
2:73938916:G:T	G50V	0.981

dbSNP variants (sampled 300 via entrez): RS1000083488 (2:73954867 C>T), RS1000149821 (2:73955999 T>A,C), RS1000226473 (2:73949812 T>C), RS1000241925 (2:73948022 A>G,T), RS1000396717 (2:73934039 G>A), RS1000500953 (2:73956322 T>A,C), RS1000522280 (2:73937128 T>G), RS1000573309 (2:73936878 T>C), RS1000576786 (2:73929191 G>A), RS1000683737 (2:73934366 A>G), RS1000742184 (2:73943557 A>C), RS1000989179 (2:73930795 T>C), RS1001058890 (2:73929912 AAC>A), RS1001105421 (2:73954673 G>A), RS1001137133 (2:73935574 A>G)

Disease associations

OMIM: gene MIM:601465 | disease phenotypes: MIM:251880, MIM:617070, MIM:617068

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial DNA depletion syndrome 3 (hepatocerebral type)	Definitive	Autosomal recessive
mitochondrial disease	Strong	Autosomal recessive
progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4	Supportive	Autosomal recessive
portal hypertension, noncirrhotic	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (8): mitochondrial disease (MONDO:0044970), mitochondrial DNA depletion syndrome 3 (hepatocerebral type) (MONDO:0009636), progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 (MONDO:0014899), portal hypertension, noncirrhotic, 1 (MONDO:8000013), portal hypertension, noncirrhotic (MONDO:0024193), portal hypertension (MONDO:0005080), migraine with aura (MONDO:0005475), (MONDO:0014897)

Orphanet (3): Mitochondrial disease (Orphanet:68380), Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency (Orphanet:279934), Adult-onset multiple mitochondrial DNA deletion syndrome due to DGUOK deficiency (Orphanet:329314)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000549	Abnormal conjugate eye movement
HP:0000590	Progressive external ophthalmoplegia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000716	Depression
HP:0000726	Dementia
HP:0000952	Jaundice
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001265	Hyporeflexia
HP:0001271	Polyneuropathy
HP:0001298	Encephalopathy
HP:0001347	Hyperreflexia
HP:0001397	Hepatic steatosis
HP:0001399	Hepatic failure
HP:0001404	Hepatocellular necrosis
HP:0001405	Periportal fibrosis
HP:0001409	Portal hypertension
HP:0001413	Micronodular cirrhosis
HP:0001488	Bilateral ptosis
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001541	Ascites

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001066_14	Dialysis-related mortality	3.000000e-06
GCST001795_1	Systemic lupus erythematosus	7.000000e-17
GCST001795_2	Systemic lupus erythematosus	6.000000e-14

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006975	Hypertension, Portal	C06.552.494
D020325	Migraine with Aura	C10.228.140.546.399.750.250

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5997 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
Valproic Acid	affects expression, decreases expression	2
triphenyl phosphate	affects expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
abrine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Lead	affects splicing	1
Phthalic Acids	increases methylation	1
Sarin	decreases expression, increases expression	1
Smoke	decreases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	increases expression	1
Cadmium Chloride	increases expression	1
Lactic Acid	decreases expression	1
Genistein	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL886787	Binding	Inhibition of human fibroblast mitochondrial deoxyguanosine kinase	Novel selective human mitochondrial kinase inhibitors: design, synthesis and enzymatic activity. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2VV	Abcam HEK293T DGUOK KO	Transformed cell line	Female
CVCL_B5JU	HAP1 DGUOK (-) 2	Cancer cell line	Male
CVCL_B5JV	HAP1 DGUOK (-) 3	Cancer cell line	Male
CVCL_D9DD	Ubigene HEK293 DGUOK KO	Transformed cell line	Female
CVCL_XN22	HAP1 DGUOK (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

193 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00332904	PHASE4	UNKNOWN	Effect of Betablocker or Aldosterone Antagonist Therapy on Patients With Liver Cirrhosis
NCT00369694	PHASE4	COMPLETED	Short Course Terlipressin for Control of Acute Variceal Bleeding
NCT00414713	PHASE4	UNKNOWN	Transfusion Requirements in Gastrointestinal (GI) Bleeding
NCT00450164	PHASE4	COMPLETED	Secondary Prophylaxis After Variceal Bleeding in Non-Responders
NCT00534677	PHASE4	COMPLETED	The Safety & Efficacy of Terlipressin vs Octreotide for the Control of Variceal Bleed
NCT00563602	PHASE4	UNKNOWN	Treatment for Prevention of Variceal Rebleeding Guided by the Hemodynamic Response
NCT00570622	PHASE4	COMPLETED	Effect of Pioglitazone on Portal and Systemic Hemodynamics in Patients With Advanced Cirrhosis
NCT01070641	PHASE4	UNKNOWN	RCT of Carvedilol Versus Variceal Band Ligation in the Primary Prophylaxis of Oesophageal Variceal Haemorrhage
NCT01842113	PHASE4	TERMINATED	Quality of Life and Nutritional Improvements in Cirrhotic Patients
NCT02344719	PHASE4	COMPLETED	Effect of Taurine on Portal Hemodynamics in Patients With Advanced Liver Cirrhosis
NCT02489045	PHASE4	COMPLETED	Noninvasive Subharmonic Aided Pressure Estimation of Portal Hypertension
NCT02907749	PHASE4	COMPLETED	Spironolactone on Fibrosis Progrssion-Portal Hypertension(FP-PH)in Cirrhosis
NCT02925975	PHASE4	UNKNOWN	Early Precise Diagnosis and Intervention of CPT Based on a Noninvasive 3D-vHPS
NCT02945956	PHASE4	UNKNOWN	Treatment of Low-grade Cirrhotic Portal Hypertension Due to Hepatitis B Virus With Fuzheng Huayu and Entecavir
NCT02945982	PHASE4	UNKNOWN	Treatment of Moderate and Severe Cirrhotic Portal Hypertension Due to HBV With Fuzheng Huayu and Entecavir
NCT02994485	PHASE4	COMPLETED	Evaluation Of The Portal Pressure By Doppler Ultrasound In Cirrhotic Patients Before And After Simvastatin
NCT04073290	PHASE4	RECRUITING	Prevention of Post-TIPS Hepatic Encephalopathy by Administration of Rifaximin and Lactulose
NCT04107428	PHASE4	UNKNOWN	Somatostatin in Living Donor Liver Transplantation
NCT05872698	PHASE4	ACTIVE_NOT_RECRUITING	Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of Oesophageal Varices Trial.
NCT06449339	PHASE4	RECRUITING	Non-selective Beta-blocker in Compensated Advanced Chronic Liver Disease
NCT07521332	PHASE4	RECRUITING	Apixaban-PK Trial: Preventing Portal Hypertension Complications in Cirrhosis
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT00006398	PHASE3	COMPLETED	Prevention of Esophageal Varices by Beta-Adrenergic Blockers
NCT00331188	PHASE3	COMPLETED	Use of Sanvar® With Endoscopic Treatment for the Control of Acute Variceal Bleeding
NCT00493480	PHASE3	COMPLETED	Danish Carvedilol Study in Portal Hypertension
NCT00787436	PHASE3	WITHDRAWN	Secondary Prophylaxis of Gastrointestinal Bleeding in Cirrhotic Patients Using THALIDOMIDE
NCT01131962	PHASE3	COMPLETED	Comparing Two Methods to Stop Vomiting of Blood Using the Endoscope
NCT02134626	PHASE3	COMPLETED	Simvastatin Effect on Portal Hypertension
NCT02508623	PHASE3	UNKNOWN	Effect of Administration of Rifaximin on the Portal Pressure of Patients With Liver Cirrhosis and Esophageal Varices
NCT02975323	PHASE3	UNKNOWN	Doppler Ultrasound Hepatic Vein Waveform as a Non-invasive Tool in the Assessment of Severity of Portal Hypertension
NCT04010669	PHASE3	UNKNOWN	The Role of Somatostatin in the Hemodynamics of the Hepatic Circulation in Patients Undergoing Liver Resection
NCT05227833	PHASE3	COMPLETED	Vonoprazan Efficacy to Prevent Post Variceal Band Ligation Ulcer
NCT05470205	PHASE3	RECRUITING	Noninvasive Subharmonic Aided Pressure Estimation of Portal Hypertension; Renewal
NCT05794555	PHASE3	COMPLETED	LiveSMART Trial to Prevent Falls in Patients With Cirrhosis
NCT06434753	PHASE3	RECRUITING	Zinc Supplementation to Improve Prognosis in Patients With Compensated Advanced Chronic Liver Disease.
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease