GUK1

Summary

GUK1 (guanylate kinase 1, HGNC:4693) is a protein-coding gene on chromosome 1q42.13, encoding Guanylate kinase (Q16774). Catalyzes the phosphorylation of GMP to GDP. It is a common-essential gene (DepMap: required in 97.8% of cancer cell lines).

The protein encoded by this gene is an enzyme that catalyzes the transfer of a phosphate group from ATP to guanosine monophosphate (GMP) to form guanosine diphosphate (GDP). The encoded protein is thought to be a good target for cancer chemotherapy. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2987 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial DNA depletion syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 76 total — 4 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_001159390

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4693
Approved symbol	GUK1
Name	guanylate kinase 1
Location	1q42.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000143774
Ensembl biotype	protein_coding
OMIM	139270
Entrez	2987

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 20 protein_coding, 13 nonsense_mediated_decay, 11 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000312726, ENST00000366716, ENST00000366718, ENST00000366721, ENST00000366722, ENST00000366723, ENST00000366726, ENST00000366728, ENST00000366730, ENST00000412265, ENST00000435153, ENST00000453943, ENST00000460224, ENST00000462807, ENST00000464858, ENST00000465025, ENST00000469973, ENST00000470040, ENST00000471270, ENST00000477206, ENST00000480056, ENST00000484953, ENST00000485083, ENST00000485168, ENST00000485838, ENST00000485859, ENST00000486668, ENST00000491613, ENST00000492871, ENST00000493138, ENST00000493209, ENST00000498092, ENST00000498115, ENST00000885279, ENST00000885280, ENST00000885281, ENST00000885282, ENST00000885283, ENST00000885284, ENST00000885285, ENST00000885286, ENST00000885287, ENST00000940513, ENST00000949976, ENST00000949977, ENST00000949978

RefSeq mRNA: 5 — MANE Select: NM_001159390 NM_000858, NM_001159390, NM_001159391, NM_001242839, NM_001242840

CCDS: CCDS1568, CCDS53481, CCDS55689

Canonical transcript exons

ENST00000453943 — 8 exons

Exon	Start	End
ENSE00003501285	228146842	228146938
ENSE00003552710	228147615	228147699
ENSE00003574427	228147406	228147544
ENSE00003668517	228148371	228148456
ENSE00003694583	228146026	228146067
ENSE00003997472	228145511	228145624
ENSE00003997474	228148665	228148951
ENSE00003997476	228140279	228140363

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 139.9692 / max 3105.1155, expressed in 1829 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8922	134.9285	1829
8921	2.3785	1428
8927	0.9602	30
8923	0.8105	404
8924	0.4524	76
8928	0.2019	72
8926	0.1768	16
8925	0.0604	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	99.58	gold quality
prefrontal cortex	UBERON:0000451	99.45	gold quality
amygdala	UBERON:0001876	99.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.36	gold quality
skin of leg	UBERON:0001511	99.34	gold quality
lower esophagus mucosa	UBERON:0035834	99.34	gold quality
skin of abdomen	UBERON:0001416	99.33	gold quality
nucleus accumbens	UBERON:0001882	99.31	gold quality
right lung	UBERON:0002167	99.30	gold quality
caudate nucleus	UBERON:0001873	99.25	gold quality
ascending aorta	UBERON:0001496	99.24	gold quality
thoracic aorta	UBERON:0001515	99.24	gold quality
tibial nerve	UBERON:0001323	99.23	gold quality
left coronary artery	UBERON:0001626	99.22	gold quality
cingulate cortex	UBERON:0003027	99.20	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.20	gold quality
aorta	UBERON:0000947	99.19	gold quality
popliteal artery	UBERON:0002250	99.19	gold quality
tibial artery	UBERON:0007610	99.19	gold quality
descending thoracic aorta	UBERON:0002345	99.18	gold quality
mucosa of stomach	UBERON:0001199	99.17	gold quality
anterior cingulate cortex	UBERON:0009835	99.17	gold quality
putamen	UBERON:0001874	99.13	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.12	gold quality
adenohypophysis	UBERON:0002196	99.11	gold quality
ectocervix	UBERON:0012249	99.11	gold quality
right coronary artery	UBERON:0001625	99.10	gold quality
upper lobe of left lung	UBERON:0008952	99.10	gold quality
left uterine tube	UBERON:0001303	99.08	gold quality
apex of heart	UBERON:0002098	99.07	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	6969.32
E-HCAD-4	yes	99.46
E-HCAD-1	yes	30.86
E-CURD-122	yes	23.57
E-MTAB-8410	yes	20.46
E-MTAB-9221	yes	17.41
E-MTAB-8271	yes	16.84
E-MTAB-6701	yes	16.10
E-HCAD-9	yes	7.74
E-GEOD-130148	yes	4.45
E-GEOD-75367	no	1369.33
E-GEOD-124858	no	108.35
E-HCAD-8	no	41.63
E-GEOD-137537	no	3.44
E-MTAB-9467	no	2.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

3 targeting GUK1, 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-22-3P	99.93	68.13	917
HSA-MIR-759	96.16	66.77	873
HSA-MIR-6514-5P	95.07	66.02	655

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 2)

• HGS and GUK1 were significantly over expressed in GH-secreting adenomas, compared with ACTH-secreting adenomas and nonfunctioning tumors, and with PRL-secreting adenomas, respectively. (PMID:16832584)
• GUK1 expression in healthy palatal mucosa is strongly negatively correlated with serum cotinine levels (PMID:31682009)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	guk1b	ENSDARG00000005776
danio_rerio	guk1a	ENSDARG00000030340
mus_musculus	Guk1	ENSMUSG00000020444
rattus_norvegicus	Guk1	ENSRNOG00000002928
drosophila_melanogaster	CG11811	FBGN0036099
caenorhabditis_elegans	guk-1	WBGENE00020190

Protein

Protein identifiers

Guanylate kinase — Q16774 (reviewed: Q16774)

Alternative names: GMP kinase, Guanylate kinase 1

All UniProt accessions (17): Q16774, A0A9L9PXH1, A0A9L9PXH5, A0A9L9PXQ5, A0A9L9PY08, A0A9L9PY13, A0A9L9PY17, A0A9L9PY36, A0A9L9PY41, A0A9L9PYH0, A0A9S7JH41, B1ANG9, B1ANH0, B1ANH3, B1ANH5, B1ANH6, Q6IBG8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorylation of GMP to GDP. Essential enzyme for recycling GMP and indirectly, cyclic GMP (cGMP). Involved in the cGMP metabolism in photoreceptors. It may also have a role in the survival and growth progression of some tumors. In addition to its physiological role, GUK1 is essential for converting prodrugs used for the treatment of cancers and viral infections into their pharmacologically active metabolites, most notably acyclovir, ganciclovir, and 6-thioguanine and its closely related analog 6-mercaptopurine.

Subunit / interactions. Monomer. Interacts with RD3.

Subcellular location. Photoreceptor inner segment. Cytoplasm. Cytosol Mitochondrion.

Tissue specificity. Widely expressed.

Disease relevance. Mitochondrial DNA depletion syndrome 21 (MTDPS21) [MIM:621071] An autosomal recessive mitochondrial disorder characterized by ptosis, ophthalmoparesis, myopathic proximal limb weakness, variable hepatopathy, and altered T-lymphocyte profiles. Multiple mtDNA deletions and depletion are detected in muscle, as well as mitochondrial respiratory chain deficiencies. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Up-regulated by RD3.

Miscellaneous. Involved in the activation pathway of bemnifosbuvir (AT-527) and its epimer, AT-752. AT-527 and AT-752 are two guanosine analogs tested in clinical trials against several RNA viruses, which are activated into their common 5’-triphosphate AT-9010 in human cells. Mediates the fourth activation step by catalyzing transformation of AT-8001 into AT-8500.

Similarity. Belongs to the guanylate kinase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q16774-1	1	yes
Q16774-2	2
Q16774-3	3

RefSeq proteins (5): NP_000849, NP_001152862, NP_001152863, NP_001229768, NP_001229769 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008144	Guanylate_kin-like_dom	Domain
IPR008145	GK/Ca_channel_bsu	Domain
IPR017665	Guanylate_kinase	Family
IPR020590	Guanylate_kinase_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00625

Enzyme classification (BRENDA):

• EC 2.7.4.8 — guanylate kinase (BRENDA: 22 organisms, 121 substrates, 63 inhibitors, 85 Km, 28 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
GMP	0.002–1.8	39
DGMP	0.01–0.4	15
ATP	0.12–1	6
MGATP2-	0.2–0.45	5
8-AZAGUANOSINE 5’-MONOPHOSPHATE	0.013–0.091	3
(R)-GANCICLOVIR PHOSPHONATE	0.052	1
6-THIOGUANOSINE 5’-MONOPHOSPHATE	2.1	1
9-(5-PHOSPHONOPENTYL)GUANINE	0.25	1
ADENOSINE TRIPHOSPHATE	23.6	1
CO2+	1.25	1
GANCICLOVIR MONOPHOSPHATE	0.047	1
GDP	0.097	1
GUANOSINE MONOPHOSPHATE	0.0051	1
MG2+	1	1
MGADP-	0.017	1

Catalyzed reactions (Rhea), 1 shown:

• GMP + ATP = GDP + ADP (RHEA:20780)

UniProt features (42 total): strand 9, mutagenesis site 8, helix 7, binding site 4, turn 3, active site 3, splice variant 2, sequence variant 2, initiator methionine 1, chain 1, modified residue 1, domain 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
9JAC	X-RAY DIFFRACTION	1.47
9JAD	X-RAY DIFFRACTION	1.55
9LO3	X-RAY DIFFRACTION	1.75
8PTS	X-RAY DIFFRACTION	1.76
9LO6	X-RAY DIFFRACTION	1.8
9JAF	X-RAY DIFFRACTION	1.9
9JAG	X-RAY DIFFRACTION	1.9
9JAI	X-RAY DIFFRACTION	2.3
9JAJ	X-RAY DIFFRACTION	2.65
9JAB	X-RAY DIFFRACTION	2.75
9JAH	X-RAY DIFFRACTION	2.8
9J8L	X-RAY DIFFRACTION	2.9
9JAE	X-RAY DIFFRACTION	3
6NUI	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16774-F1	94.25	0.93

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 (3): 44; 137; 148

Ligand- & substrate-binding residues (4): 14–19; 37–51; 137; 171–172

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (8):

Position	Phenotype
2	increases in kcat with gmp as substrate.
3	increases in kcat with gmp as substrate.
25	leads to aggregation. increases in kcat with gmp as substrate.
91	increases in kcat with gmp as substrate.
96	increases in kcat with gmp as substrate.
116	increases in kcat with gmp as substrate.
121	increases in kcat with gmp as substrate.
186	increases in kcat with gmp as substrate.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-499943	Interconversion of nucleotide di- and triphosphates
R-HSA-9748787	Azathioprine ADME
R-HSA-1430728	Metabolism
R-HSA-15869	Metabolism of nucleotides
R-HSA-9748784	Drug ADME

MSigDB gene sets: 215 (showing top): GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, RICKMAN_METASTASIS_DN, KESHELAVA_MULTIPLE_DRUG_RESISTANCE, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, MODULE_206

GO Biological Process (11): purine nucleotide metabolic process (GO:0006163), dGDP biosynthetic process (GO:0006185), xenobiotic metabolic process (GO:0006805), nucleobase-containing small molecule interconversion (GO:0015949), GDP-mannose metabolic process (GO:0019673), glycoprotein transport (GO:0034436), dGMP metabolic process (GO:0046054), dATP metabolic process (GO:0046060), GDP biosynthetic process (GO:0046711), GMP metabolic process (GO:0046037), GDP metabolic process (GO:0046710)

GO Molecular Function (6): GMP kinase activity (GO:0004385), ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (4): photoreceptor inner segment (GO:0001917), mitochondrion (GO:0005739), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of nucleotides	1
Drug ADME	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
purine deoxyribonucleotide metabolic process	2
GDP metabolic process	2
purine ribonucleotide metabolic process	2
cytoplasm	2
nucleotide metabolic process	1
purine-containing compound metabolic process	1
purine deoxyribonucleotide biosynthetic process	1
purine deoxyribonucleoside diphosphate biosynthetic process	1
deoxyribonucleoside diphosphate biosynthetic process	1
dGDP metabolic process	1
metabolic process	1
cellular response to xenobiotic stimulus	1
nucleobase-containing small molecule metabolic process	1
nucleotide-sugar metabolic process	1
protein transport	1
carbohydrate derivative transport	1
purine deoxyribonucleoside monophosphate metabolic process	1
deoxyribonucleoside triphosphate metabolic process	1
purine deoxyribonucleoside triphosphate metabolic process	1
purine ribonucleotide biosynthetic process	1
purine ribonucleoside diphosphate biosynthetic process	1
purine ribonucleoside monophosphate metabolic process	1
purine ribonucleoside diphosphate metabolic process	1
GMP metabolic process	1
nucleoside monophosphate kinase activity	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
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

3609 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GUK1	KIF13B	Q9NQT8	921
GUK1	TPI1	P00938	886
GUK1	CACNB3	P54284	835
GUK1	CACNB4	O00305	790
GUK1	DLGAP1	P78335	758
GUK1	SRC	P12931	713
GUK1	GK2	Q14410	683
GUK1	GK	P32189	683
GUK1	GMPS	P49915	613
GUK1	MAPDA	Q6DHV7	613
GUK1	OCLN	Q16625	601
GUK1	DTYMK	P23919	575
GUK1	TBR1	Q16650	569
GUK1	FH	P07954	555
GUK1	EPB41	P11171	551

IntAct

16 interactions, top by confidence:

A	B	Type	Score
GUK1	TTC19	psi-mi:“MI:0915”(physical association)	0.590
TMEM97	STXBP3	psi-mi:“MI:0914”(association)	0.530
C2orf68	PIR	psi-mi:“MI:0914”(association)	0.530
DPY19L2	GUK1	psi-mi:“MI:0915”(physical association)	0.400
LINC02915	GUK1	psi-mi:“MI:0915”(physical association)	0.400
HSPB2	GUK1	psi-mi:“MI:0915”(physical association)	0.370
UBE2Z	GUK1	psi-mi:“MI:0915”(physical association)	0.370
NDUFA4	NUDT19	psi-mi:“MI:0914”(association)	0.350
NDUFA4	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFA4	COX7A2L	psi-mi:“MI:0914”(association)	0.350
IQCB1	PCP4L1	psi-mi:“MI:0914”(association)	0.350
MCEMP1	GUK1	psi-mi:“MI:0914”(association)	0.350
FAHD1	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (61): GUK1 (Affinity Capture-RNA), GUK1 (Affinity Capture-RNA), GUK1 (Affinity Capture-MS), TTC19 (Affinity Capture-MS), GUK1 (Affinity Capture-MS), GUK1 (Affinity Capture-MS), GUK1 (Two-hybrid), GUK1 (Affinity Capture-MS), GUK1 (Affinity Capture-MS), TTC19 (Affinity Capture-MS), TXN2 (Co-fractionation), LYRM2 (Co-fractionation), GUK1 (Co-fractionation), COA7 (Co-fractionation), MSRB3 (Co-fractionation)

ESM2 similar proteins: A4IH68, A5GFY8, B8A5W4, O34932, O74414, O95396, P23919, P34558, Q03941, Q0P4C4, Q13057, Q16774, Q17CA7, Q1JPA0, Q1LZ78, Q2JUC0, Q32PY9, Q3A3D2, Q3SZ73, Q3ZBS0, Q5KWC4, Q5R9W5, Q5T6J7, Q6AY55, Q7Q732, Q7ZV79, Q7ZW24, Q80UN9, Q8AWD2, Q8BHC4, Q8IQF1, Q8MIR4, Q8N5I4, Q8R0J8, Q8TB37, Q8TC12, Q8WVC6, Q91348, Q91WL8, Q94DR2

Diamond homologs: A0A8C0TYJ0, A0A8P0N4K0, B4F7E7, D3ZAA9, E2QY99, E2QYC9, E7FDW2, F1MAD2, G5ECY0, O14910, O15018, O55164, O75970, O84033, O88382, O88951, O88952, P15454, P31006, P31007, P31016, P46195, P57105, P68907, P70175, P78352, P93757, Q0P5F3, Q0SS73, Q0TPK6, Q12959, Q13425, Q13884, Q14160, Q15700, Q16774, Q24210, Q255A8, Q28C55, Q2KIB6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	43
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
3600308	GUK1, 25-BP INS, NT66_67	Pathogenic
3600309	NM_001159390.2(GUK1):c.94G>A (p.Gly32Arg)	Pathogenic
3600311	NM_001159390.2(GUK1):c.139C>T (p.Gln47Ter)	Pathogenic
3600312	NM_001159390.2(GUK1):c.2T>G (p.Met1Arg)	Pathogenic
3600310	NM_001159390.2(GUK1):c.61+1G>T	Likely pathogenic

SpliceAI

1485 predictions. Top by Δscore:

Variant	Effect	Δscore
1:228140157:GAG:G	donor_gain	1.0000
1:228140160:G:C	donor_loss	1.0000
1:228145620:GTCCC:G	donor_gain	1.0000
1:228145625:G:GG	donor_gain	1.0000
1:228146840:A:AG	acceptor_gain	1.0000
1:228146841:G:GG	acceptor_gain	1.0000
1:228146933:C:T	donor_gain	1.0000
1:228146935:CGAG:C	donor_loss	1.0000
1:228146937:AGGTG:A	donor_loss	1.0000
1:228146939:G:GC	donor_loss	1.0000
1:228147401:CCCAG:C	acceptor_loss	1.0000
1:228147402:CCA:C	acceptor_loss	1.0000
1:228147403:CAGCA:C	acceptor_loss	1.0000
1:228147404:A:AG	acceptor_gain	1.0000
1:228147404:A:T	acceptor_loss	1.0000
1:228147405:G:GA	acceptor_gain	1.0000
1:228147405:GCA:G	acceptor_gain	1.0000
1:228147405:GCAA:G	acceptor_gain	1.0000
1:228147407:A:AG	acceptor_gain	1.0000
1:228147407:AAGGT:A	acceptor_gain	1.0000
1:228147610:TTTAG:T	acceptor_loss	1.0000
1:228147613:A:AG	acceptor_gain	1.0000
1:228147613:A:AT	acceptor_loss	1.0000
1:228147613:AG:A	acceptor_gain	1.0000
1:228147614:G:GG	acceptor_gain	1.0000
1:228147614:GG:G	acceptor_gain	1.0000
1:228147614:GGA:G	acceptor_gain	1.0000
1:228147614:GGAGC:G	acceptor_gain	1.0000
1:228147694:A:T	donor_gain	1.0000
1:228147695:GAGCA:G	donor_gain	1.0000

AlphaMissense

1397 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:228146035:G:T	R41M	0.999
1:228146035:G:C	R41T	0.998
1:228146850:T:C	F55L	0.998
1:228146852:T:A	F55L	0.998
1:228146852:T:G	F55L	0.998
1:228146913:T:C	F76L	0.998
1:228146915:C:A	F76L	0.998
1:228146915:C:G	F76L	0.998
1:228145561:A:C	K17Q	0.997
1:228145563:G:C	K17N	0.997
1:228145563:G:T	K17N	0.997
1:228145562:A:T	K17M	0.996
1:228145615:A:C	S35R	0.995
1:228145617:C:A	S35R	0.995
1:228145617:C:G	S35R	0.995
1:228146036:G:C	R41S	0.995
1:228146036:G:T	R41S	0.995
1:228146932:G:A	G82D	0.995
1:228145559:G:A	G16E	0.994
1:228145562:A:C	K17T	0.994
1:228146044:G:C	R44T	0.994
1:228146044:G:T	R44M	0.994
1:228146896:T:C	F70S	0.994
1:228147447:G:A	C98Y	0.994
1:228147448:T:G	C98W	0.994
1:228147633:C:A	R137S	0.994
1:228145544:G:A	G11E	0.993
1:228145558:G:T	G16W	0.993
1:228146844:T:C	Y53H	0.993
1:228146895:T:C	F70L	0.993

dbSNP variants (sampled 300 via entrez): RS1000547808 (1:228149365 C>T), RS1000698950 (1:228145365 C>A,T), RS1000806904 (1:228147317 G>A), RS1001174678 (1:228146221 C>G,T), RS1001269426 (1:228147191 C>T), RS1001412975 (1:228141543 T>A), RS1001675884 (1:228141223 C>T), RS1001864145 (1:228141892 G>A,T), RS1002875544 (1:228138902 G>T), RS1002918550 (1:228141531 G>A), RS1002944489 (1:228145884 T>C), RS1003132198 (1:228140485 G>T), RS1003410354 (1:228139174 T>A), RS1003489228 (1:228140312 C>A,T), RS1004051778 (1:228147336 G>A)

Disease associations

OMIM: gene MIM:139270 | disease phenotypes: MIM:621071, MIM:109730

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial DNA depletion syndrome	Strong	Autosomal recessive
mitochondrial disease	Limited	Autosomal recessive

Mondo (4): mitochondrial dna depletion syndrome 21 (MONDO:0976132), aortic valve disease 1 (MONDO:0024523), mitochondrial disease (MONDO:0044970), mitochondrial DNA depletion syndrome (MONDO:0018158)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005194_206	Coronary artery disease	8.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4989 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	5
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance, increases expression	3
arsenite	affects binding, increases reaction, increases methylation	2
chloropicrin	affects expression, decreases expression	2
Air Pollutants	increases abundance, increases oxidation, affects expression, affects cotreatment	2
Cisplatin	affects reaction, increases expression, affects expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
Cadmium Chloride	increases abundance, increases expression	2
bisphenol F	increases expression	1
bufotalin	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
pirinixic acid	increases activity, affects binding, decreases expression	1
bisphenol A	decreases methylation	1
beta-lapachone	increases expression	1
nickel sulfate	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Ethanol	affects cotreatment, increases abundance, increases expression	1
Aspirin	decreases expression	1
Azacitidine	increases expression	1
Cadmium	increases abundance, increases expression	1
Folic Acid	affects expression, affects reaction	1
Gasoline	increases abundance, increases expression, affects cotreatment	1
Hydralazine	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL686064	Binding	Percent efficiency phosphorylated by guanylate kinase taken from hog brain	Synthesis and antiviral activity of rigid acyclonucleotide analogs — Bioorg Med Chem Lett

Clinical trials (associated diseases)

103 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
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
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
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques
NCT00831948	Not specified	UNKNOWN	Identification of Large-Scale Mutations of POLG Gene by QMPSF in Patients With Mitochondrial DNA Instability.
NCT01001585	Not specified	TERMINATED	Anesthetic Effects in Mitochondrial Disease
NCT01148550	Not specified	SUSPENDED	Longitudinal Study of Mitochondrial Hepatopathies