NUDT15

Summary

NUDT15 (nudix hydrolase 15, HGNC:23063) is a protein-coding gene on chromosome 13q14.2, encoding Nucleotide triphosphate diphosphatase NUDT15 (Q9NV35). Catalyzes the hydrolysis of nucleoside triphosphates including dGTP, dTTP, dCTP, their oxidized forms like 8-oxo-dGTP and the prodrug thiopurine derivatives 6-thio-dGTP and 6-thio-GTP.

This gene encodes an enzyme that belongs to the Nudix hydrolase superfamily. Members of this superfamily catalyze the hydrolysis of nucleoside diphosphates, including substrates like 8-oxo-dGTP, which are a result of oxidative damage, and can induce base mispairing during DNA replication, causing transversions. The encoded enzyme is a negative regulator of thiopurine activation and toxicity. Mutations in this gene result in poor metabolism of thiopurines, and are associated with thiopurine-induced early leukopenia. Multiple pseudogenes of this gene have been identified.

Source: NCBI Gene 55270 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 23 total
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_018283

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23063
Approved symbol	NUDT15
Name	nudix hydrolase 15
Location	13q14.2
Locus type	gene with protein product
Status	Approved
Aliases	MTH2, FLJ10956
Ensembl gene	ENSG00000136159
Ensembl biotype	protein_coding
OMIM	615792
Entrez	55270

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000258662, ENST00000875703, ENST00000913136, ENST00000913137

RefSeq mRNA: 1 — MANE Select: NM_018283 NM_018283

CCDS: CCDS9407

Canonical transcript exons

ENST00000258662 — 3 exons

Exon	Start	End
ENSE00000836815	48037726	48037904
ENSE00000836816	48040920	48041116
ENSE00000836817	48045660	48047221

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 92.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.5373 / max 410.1510, expressed in 1807 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
135037	24.0218	1807
135036	0.9182	138
135038	0.5386	276
135035	0.0587	29

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.03	gold quality
endothelial cell	CL:0000115	92.00	gold quality
mucosa of transverse colon	UBERON:0004991	89.82	gold quality
oocyte	CL:0000023	89.79	gold quality
rectum	UBERON:0001052	89.55	gold quality
secondary oocyte	CL:0000655	88.84	gold quality
colonic mucosa	UBERON:0000317	88.69	gold quality
mucosa of sigmoid colon	UBERON:0004993	87.98	gold quality
esophagus squamous epithelium	UBERON:0006920	87.13	gold quality
palpebral conjunctiva	UBERON:0001812	86.77	gold quality
gingival epithelium	UBERON:0001949	86.65	gold quality
endometrium	UBERON:0001295	86.56	gold quality
duodenum	UBERON:0002114	86.44	gold quality
amniotic fluid	UBERON:0000173	86.09	gold quality
gingiva	UBERON:0001828	85.98	gold quality
islet of Langerhans	UBERON:0000006	85.54	gold quality
renal glomerulus	UBERON:0000074	85.45	gold quality
esophagus mucosa	UBERON:0002469	85.25	gold quality
metanephric glomerulus	UBERON:0004736	85.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.91	gold quality
oral cavity	UBERON:0000167	84.71	gold quality
embryo	UBERON:0000922	84.69	gold quality
ganglionic eminence	UBERON:0004023	83.85	gold quality
metanephros	UBERON:0000081	83.74	gold quality
nephron tubule	UBERON:0001231	83.52	gold quality
gastrocnemius	UBERON:0001388	83.29	gold quality
jejunal mucosa	UBERON:0000399	83.28	gold quality
epithelium of esophagus	UBERON:0001976	83.24	gold quality
transverse colon	UBERON:0001157	83.11	gold quality
ventricular zone	UBERON:0003053	83.04	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.49
E-GEOD-124858	no	135.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

71 targeting NUDT15, 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-5011-5P	100.00	83.46	5820
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4447	99.85	67.81	2900

Literature-anchored findings (GeneRIF, showing 40)

• Data demonstrate for the first time that PCNA is protected by this newly identified partner molecule MTH2, which is related to DNA synthesis and cell cycle progression. (PMID:19419956)
• human MTH1, MTH2, and NUDT5 proteins act as a defense against the mutagenesis induced by oxidized dGTP. (PMID:20144704)
• Authros identified a nonsynonymous SNP in NUDT15 (encoding p.Arg139Cys) that was strongly associated with thiopurine-induced early leukopenia (odds ratio (OR) = 35.6; P(combined) = 4.88 x 10(-94)). (PMID:25108385)
• Describe a germline variant in NUDT15 strongly associated with mercaptopurine intolerance in childhood acute lymphoblastic leukemia, which may have implications for treatment individualization in this disease. (PMID:25624441)
• Event-free survival did not significantly differ by NUDT15 genotype. rs116855232 is an important determinant of 6-MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity-related locus in Asians to date. (PMID:26033531)
• NUDT R139C T/T genotype showed complete association with early severe hair loss/leukopenia in Japanese patients with inflammatory bowel diseases. (PMID:26076924)
• Depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA and does not impact cancer cell survival in cell lines tested. NUDT15 is not a biologically relevant 8-oxo-dGTPase (PMID:26238318)
• NUDT15 c.415C>T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia. (PMID:26405151)
• NUDT15 gene polymorphism is related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. (PMID:26503813)
• These results suggest that NUDT15 R139C-related thiopurine-induced leukocytopenia is mediated by a 6-TGN-independent mechanism. (PMID:26590936)
• Mutations of the NUDT15 and TPMT gene accounted for approximately 88% of cases with thiopurine-induced early leukopenia. Extensive hair loss was a recognizable early symptom in patients with the homozygous NUDT15 c.415C>T variant. (PMID:26735160)
• Patients with defective NUDT15 alleles showed excessive levels of thiopurine active metabolites and toxicity. [meta-analysis] (PMID:26878724)
• There was a close association of NUDT15 R139C with early leukopenia associated with thiopurines in patients in Hong Kong (PMID:27095468)
• our study shows that 6-MP reduction is significant in the younger age group in relation to NUDT15 variant (PMID:27193222)
• Letter: discuss role of NUDT15 in complex thiopurine metabolism. (PMID:27308664)
• NUDT15 c.415C>T may be another predictor of AZA-induced leukocytopenia. (PMID:27381176)
• NUDT15 variant as a predictor for thiopurine-induced toxicity in Indian patients. (PMID:27416873)
• our results defined how NUDT15 limits thiopurine efficacy and how genetic ablation via the R139C missense mutation confers sensitivity to thiopurine treatment in patients (PMID:27530327)
• NUDT15 polymorphisms are associated with 6-mercaptopurine intolerance in children treated for acute lymphoblastic leukemia. (PMID:27577869)
• TPMT and NUDT15 genes are both related to mercaptopurine intolerance in acute lymphoblastic leukaemia patients from Uruguay. (PMID:28146264)
• NUDT15 (and ABCC4) variants are major factors for 6-mercaptopurine intolerability in Japanese childhood acute lymphoblastic leukemia patients. (PMID:28418010)
• results of this meta-analysis confirm that NUDT15 c.415C>T may be an important predictor of thiopurine-induced leukocytopenia in Asians (PMID:28470355)
• Study replicated previous findings that the NUDT15 p.R139C variant is a potential predictor for AZA-induced leukopenia, extending this finding to patients with various neurological disorders in Korea and identifying its specific association with early leukopenia and severe alopecia. All of the patients who carried a NUDT15 p.R139C homozygous variant exhibited rapid development of severe leukopenia and extensive hair loss. (PMID:28566182)
• NUDT15 c.415C>T, c.36_37insGGAGTC, and c.52G>A variants were risk factors for thiopurine-induced leukopenia. Combined detection of the 3 variants could increase the predictive sensitivity of thiopurine-induced leukopenia and help to distinguish early leukopenia in heterozygote of c.415C>T in Chinese patients with inflammatory bowel disease. (PMID:28570428)
• 3 novel NUDT15 coding variants (p.R34T, p.K35E, and p.G17_V18del) in 5 children with acute lymphoblastic leukemia enrolled in frontline protocols in Singapore, Taiwan, and at St. Jude Children’s Research Hospital. (PMID:28659275)
• All patients with both NUDT15 rs116855232 heterozygous variants and ABCC4 rs3765534 variants suffered from severe leukopenia and required 6-mercaptopurine dose reduction to less than 35 mg/m(2)/da (PMID:28883280)
• Results show that 6-TGN levels were substantially low in patients with NUDT15 variants who showed highest hematopoietic toxicity. The low ratio of 6-TGN level to 6-mercaptopurine dose in patients with NUDT15 variants seems to be caused by enhanced incorporation of active thiopurine metabolites into DNA. (PMID:28903549)
• Current review highlights the scientific data on NUDT15 enzyme variant in patients with acute lymphoblastic leukaemia and its relation to 6-mercaptopurine toxicity in various ethnic populations. (PMID:28963908)
• Thiopurine treatment should not be recommended to patients with NUDT15 homozygous variant genotype due to severe early leukopenia (PMID:29206869)
• With increasing copy numbers of the risk T allele at NUDT15. (PMID:29210335)
• Mutations in exon 1 of NUDT15 also affect thiopurine-induced leukopenia in patients with inflammatory bowel disease. (PMID:29398872)
• Mutation rate of NUDT15 in Chinese inflammatory bowel disease patients is higher than that of TPMT. NUDT15 polymorphism is a better predictor for AZA-induced leukopenia than TPMT polymorphism. (PMID:29491687)
• we found a significant association between the reported/novel NUDT15 and TPMT SNPs with thiopurine-induced leukopenia, but not hepatotoxicity. (PMID:29519865)
• we report three Japanese patients who developed AZA-induced alopecia and leukopenia associated with homozygous loss-of-function NUDT15 (p.R139C) variants. (PMID:29704867)
• NUDT15 variant is an optimal predictor for 6-MP intolerance in Chinese pediatric acute lymphoblastic leukemia patients (PMID:29720126)
• The genotyping of NUDT15 codon 139 is the best way to predict severe leukopenia and alopecia in Japanese patients with inflammatory bowel disease. (PMID:29923122)
• Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity. (PMID:29967377)
• The present meta-analysis points to rs116855232, rs554405994 and rs186364861 of NUDT15 as clinically relevant predictors of thiopurine-induced leukopenia. (PMID:30048756)
• Retrospective single-center case-control observational study that enrolled a small number of Japanese patients found that NUDT15 R139C homozygosity is a genetic risk of thiopurine (azathioprine)-induced potentially fatal hematological abnormalities. (PMID:30101994)
• As expected TPMT was the main cause of severe hematotoxicity in 31% of patients, who were either TPMT deficient (10%) or heterozygous carriers of TPMT variants (21%). By comparison, NUDT15 genetic polymorphism was identified in 14 (13%) patients including one novel variant (p.Met1Ile). Six percent of patients with severe toxicity carried variants in both TPMT and NUDT15. (PMID:30728528)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nudt15	ENSDARG00000113961
mus_musculus	Nudt15	ENSMUSG00000033405
rattus_norvegicus		ENSRNOG00000082240

Protein

Protein identifiers

Nucleotide triphosphate diphosphatase NUDT15 — Q9NV35 (reviewed: Q9NV35)

Alternative names: MutT homolog 2, Nucleoside diphosphate-linked moiety X motif 15, Nucleoside diphosphate-linked to another moiety X hydrolase 15

All UniProt accessions (1): Q9NV35

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the hydrolysis of nucleoside triphosphates including dGTP, dTTP, dCTP, their oxidized forms like 8-oxo-dGTP and the prodrug thiopurine derivatives 6-thio-dGTP and 6-thio-GTP. Could also catalyze the hydrolysis of some nucleoside diphosphate derivatives. Hydrolyzes oxidized nucleosides triphosphates like 8-oxo-dGTP in vitro, but the specificity and efficiency towards these substrates are low. Therefore, the potential in vivo sanitizing role of this enzyme, that would consist in removing oxidatively damaged forms of nucleosides to prevent their incorporation into DNA, is unclear. Through the hydrolysis of thioguanosine triphosphates may participate in the catabolism of thiopurine drugs. May also have a role in DNA synthesis and cell cycle progression by stabilizing PCNA. Exhibits decapping activity towards dpCoA-capped RNAs in vitro. In vitro, it catalyzes the hydrolysis of isoprene pyrophosphates, including (2E)-geranyl diphosphate, isopentenyl diphosphate, (2E,6E)-farnesyl diphosphate and dimethylallyl diphosphate. It may therefore play a role in the control of cellular levels of these metabolites that are essential for multiple cellular processes, including isoprenoids synthesis and protein isoprenylation.

Subunit / interactions. Homodimer. Interacts with PCNA; interaction is disrupted in response to UV irradiation.

Cofactor. Magnesium may be the real cofactor in vivo.

Polymorphism. Polymorphic NUDT15 variants define the poor metabolism of thiopurines 2 genetic locus (THPM2) [MIM:616903]. Thiopurines are used as immunosuppressants or cytotoxic drugs and are prescribed for a variety of clinical conditions including leukemia, autoimmune disease and organ transplantation. Patients with low NUDT15 activities have an increased risk for toxic effects after receiving standard doses of thiopurine drugs.

Similarity. Belongs to the Nudix hydrolase family.

RefSeq proteins (1): NP_060753* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000086	NUDIX_hydrolase_dom	Domain
IPR015797	NUDIX_hydrolase-like_dom_sf	Homologous_superfamily

Pfam: PF00293

Catalyzed reactions (Rhea), 8 shown:

• a ribonucleoside 5’-triphosphate + H2O = a ribonucleoside 5’-phosphate + diphosphate + H(+) (RHEA:23996)
• dGTP + H2O = dGMP + diphosphate + H(+) (RHEA:28362)
• a 2’-deoxyribonucleoside 5’-triphosphate + H2O = a 2’-deoxyribonucleoside 5’-phosphate + diphosphate + H(+) (RHEA:44644)
• (2E)-geranyl diphosphate + H2O = (2E)-geranyl phosphate + phosphate + H(+) (RHEA:47944)
• (2E,6E)-farnesyl diphosphate + H2O = (2E,6E)-farnesyl phosphate + phosphate + H(+) (RHEA:48128)
• a 5’-end CoA-ribonucleoside in mRNA + H2O = a 5’-end phospho-adenosine-phospho-ribonucleoside in mRNA + (R)-4’-phosphopantetheine + 2 H(+) (RHEA:67592)
• isopentenyl diphosphate + H2O = isopentenyl phosphate + phosphate + H(+) (RHEA:70503)
• dimethylallyl diphosphate + H2O = dimethylallyl phosphate + phosphate + H(+) (RHEA:70507)

UniProt features (30 total): helix 7, strand 7, binding site 5, sequence variant 4, turn 2, chain 1, domain 1, mutagenesis site 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
7B67	X-RAY DIFFRACTION	1.45
7B64	X-RAY DIFFRACTION	1.5
6T5J	X-RAY DIFFRACTION	1.6
7B63	X-RAY DIFFRACTION	1.6
7B65	X-RAY DIFFRACTION	1.6
7B66	X-RAY DIFFRACTION	1.6
7B7V	X-RAY DIFFRACTION	1.6
5LPG	X-RAY DIFFRACTION	1.7
7R0D	X-RAY DIFFRACTION	1.7
5BON	X-RAY DIFFRACTION	1.8
7NR6	X-RAY DIFFRACTION	1.8
7AOM	X-RAY DIFFRACTION	1.95
7AOP	X-RAY DIFFRACTION	2.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NV35-F1	93.12	0.85

Functional residue map

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

Ligand- & substrate-binding residues (5): 47; 49; 63; 67; 67

Mutagenesis-validated functional residues (1):

Position	Phenotype
49	loss of hydrolase activity with (2e)-geranyl diphosphate as substrate. severely decreased hydrolase activity with dgtp a

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2393930	Phosphate bond hydrolysis by NUDT proteins
R-HSA-9748787	Azathioprine ADME

MSigDB gene sets: 152 (showing top): GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MODULE_453, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, WEI_MYCN_TARGETS_WITH_E_BOX, ONKEN_UVEAL_MELANOMA_UP, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS, GOBP_MITOTIC_CELL_CYCLE, FUJII_YBX1_TARGETS_DN

GO Biological Process (11): mitotic cell cycle (GO:0000278), response to reactive oxygen species (GO:0000302), purine nucleotide catabolic process (GO:0006195), dGTP catabolic process (GO:0006203), xenobiotic catabolic process (GO:0042178), DNA protection (GO:0042262), nucleobase-containing small molecule metabolic process (GO:0055086), regulation of proteasomal protein catabolic process (GO:0061136), nucleoside phosphate catabolic process (GO:1901292), response to stress (GO:0006950), purine deoxyribonucleoside triphosphate catabolic process (GO:0009217)

GO Molecular Function (8): 8-oxo-7,8-dihydroguanosine triphosphate pyrophosphatase activity (GO:0008413), 8-oxo-7,8-dihydrodeoxyguanosine triphosphate pyrophosphatase activity (GO:0035539), 8-oxo-dGDP phosphatase activity (GO:0044715), metal ion binding (GO:0046872), nucleoside triphosphate diphosphatase activity (GO:0047429), isoprenoid diphosphate phosphatase activity (GO:0106405), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Purine catabolism	1
Drug ADME	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nucleoside triphosphate diphosphatase activity	2
pyrophosphatase activity	2
cell cycle	1
mitotic nuclear division	1
response to oxidative stress	1
response to oxygen-containing compound	1
purine nucleotide metabolic process	1
nucleotide catabolic process	1
purine-containing compound catabolic process	1
purine deoxyribonucleotide catabolic process	1
deoxyribonucleoside triphosphate catabolic process	1
purine deoxyribonucleoside triphosphate catabolic process	1
dGTP metabolic process	1
xenobiotic metabolic process	1
catabolic process	1
DNA metabolic process	1
cellular response to stress	1
nucleobase-containing compound metabolic process	1
small molecule metabolic process	1
proteasomal protein catabolic process	1
regulation of protein catabolic process	1
nucleoside phosphate metabolic process	1
nucleobase-containing compound catabolic process	1
organophosphate catabolic process	1
response to stimulus	1
purine nucleoside triphosphate catabolic process	1
purine deoxyribonucleoside triphosphate metabolic process	1
nucleoside diphosphate phosphatase activity	1
cation binding	1
binding	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1362 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NUDT15	TPMT	P51580	893
NUDT15	NUDT18	Q6ZVK8	844
NUDT15	ITPA	Q9BY32	823
NUDT15	NUDT5	Q9UKK9	792
NUDT15	NUDT1	P36639	762
NUDT15	NUDT12	Q9BQG2	744
NUDT15	DPYD	Q12882	715
NUDT15	NUDT14	O95848	709
NUDT15	NUDT2	P50583	709
NUDT15	NUDT17	P0C025	693
NUDT15	NUDT19	A8MXV4	637
NUDT15	VKORC1	Q9BQB6	614
NUDT15	NUDT3	O95989	599
NUDT15	NUDT22	Q9BRQ3	586
NUDT15	NUDT8	Q8WV74	583

IntAct

15 interactions, top by confidence:

A	B	Type	Score
GABARAPL2	NUDT15	psi-mi:“MI:0915”(physical association)	0.560
LCN15	POTEF	psi-mi:“MI:0914”(association)	0.530
C1orf220	HCCS	psi-mi:“MI:0914”(association)	0.530
HSPB6	BAG3	psi-mi:“MI:0914”(association)	0.530
CLPSL1	TNFAIP1	psi-mi:“MI:0914”(association)	0.530
SRD5A3	NUDT15	psi-mi:“MI:0915”(physical association)	0.370
LZTS2	MYO9A	psi-mi:“MI:0914”(association)	0.350
CLPSL1	LRP5	psi-mi:“MI:0914”(association)	0.350
BCAS4	SNAPIN	psi-mi:“MI:0914”(association)	0.350
GABARAPL2	NUDT15	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): NUDT15 (Affinity Capture-MS), NUDT15 (Affinity Capture-MS), NUDT15 (Affinity Capture-MS), NUDT15 (Affinity Capture-MS), NUDT15 (Affinity Capture-MS), NUDT15 (Affinity Capture-MS), NUDT15 (Affinity Capture-MS), NUDT15 (Affinity Capture-MS), NUDT15 (Affinity Capture-RNA), NUDT15 (Two-hybrid), NUDT15 (Affinity Capture-MS), NUDT15 (Affinity Capture-MS), NUDT15 (Affinity Capture-MS), NUDT15 (Affinity Capture-MS), NUDT15 (Affinity Capture-MS)

ESM2 similar proteins: A1ADA3, A4WDK7, A6TBV3, A7ZP69, A8A2B8, A9MJC8, A9N5B7, B1IXT6, B1LLK5, B1X8W4, B4SYW7, B4TBG2, B4TPH8, B5BCQ0, B5EZH4, B5FNT5, B5R268, B5RCC0, B5XNX5, B6I7J4, B7LAR6, B7LM80, B7M5T3, B7MG18, B7MXT2, B7N5L6, B7NN72, B7UFR3, C0Q073, C4ZU93, M4I1C6, O06972, P32091, P52006, P96590, Q0T2N2, Q0TFJ1, Q1R9G4, Q3YZV5, Q57M59

Diamond homologs: M4I1C6, Q8BG93, Q8YKE7, Q9CA40, Q9NV35, F1P963, P36639, P41354, P53368, P53369, P59659, P9WIY0, P9WIY1, Q7ZWC3, B0UWT4, P93740, Q0I560, Q58549, Q7NTZ8, Q87KQ7, A1KNJ7, A5F3M9, A5U7L9, A5UA57, A5UGU3, A6VQT1, B2VG76, C1AGW8, C3LR63, P32091, P44710, P46351, P95781, P9WIX4, P9WIX5, Q12KG5, Q19427, Q48IH8, Q4QNB3, Q5PQ04

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

773 predictions. Top by Δscore:

Variant	Effect	Δscore
13:48040914:TTCCA:T	acceptor_loss	1.0000
13:48040915:TCCA:T	acceptor_loss	1.0000
13:48040917:CA:C	acceptor_loss	1.0000
13:48040918:A:AG	acceptor_gain	1.0000
13:48040918:A:T	acceptor_loss	1.0000
13:48040918:AGT:A	acceptor_gain	1.0000
13:48040919:G:GA	acceptor_gain	1.0000
13:48040919:GT:G	acceptor_gain	1.0000
13:48040919:GTG:G	acceptor_gain	1.0000
13:48040919:GTGA:G	acceptor_gain	1.0000
13:48040919:GTGAA:G	acceptor_gain	1.0000
13:48041113:GAAA:G	donor_gain	1.0000
13:48041117:G:GG	donor_gain	1.0000
13:48037849:A:T	donor_gain	0.9900
13:48037948:G:T	donor_gain	0.9900
13:48040910:T:TA	acceptor_gain	0.9900
13:48041112:TGAAA:T	donor_gain	0.9900
13:48041113:GAAAG:G	donor_gain	0.9900
13:48041114:A:T	donor_gain	0.9900
13:48041114:AAAGT:A	donor_loss	0.9900
13:48041115:AAG:A	donor_loss	0.9900
13:48041116:AGTA:A	donor_loss	0.9900
13:48041117:GTAA:G	donor_loss	0.9900
13:48041118:T:G	donor_loss	0.9900
13:48045654:TTCTA:T	acceptor_loss	0.9900
13:48045655:TCTA:T	acceptor_loss	0.9900
13:48045656:CTA:C	acceptor_loss	0.9900
13:48045657:TA:T	acceptor_loss	0.9900
13:48045658:A:AC	acceptor_loss	0.9900
13:48045658:AGGTT:A	acceptor_gain	0.9900

AlphaMissense

1064 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:48045668:T:A	W122R	0.993
13:48045668:T:C	W122R	0.993
13:48045670:G:C	W122C	0.992
13:48045670:G:T	W122C	0.992
13:48037848:G:C	R34S	0.985
13:48037848:G:T	R34S	0.985
13:48037832:T:A	V29D	0.984
13:48041045:T:A	I95K	0.984
13:48045707:T:C	F135L	0.984
13:48045709:C:A	F135L	0.984
13:48045709:C:G	F135L	0.984
13:48040940:C:A	A60D	0.982
13:48045662:T:A	W120R	0.982
13:48045662:T:C	W120R	0.982
13:48040927:T:A	W56R	0.981
13:48040927:T:C	W56R	0.981
13:48040938:T:G	C59W	0.981
13:48045664:G:C	W120C	0.981
13:48045664:G:T	W120C	0.981
13:48040947:G:C	R62S	0.980
13:48040947:G:T	R62S	0.980
13:48041039:T:A	V93D	0.980
13:48037835:T:A	L30H	0.979
13:48045669:G:C	W122S	0.977
13:48041056:G:A	G99R	0.975
13:48041056:G:C	G99R	0.975
13:48040949:A:T	E63V	0.974
13:48040950:A:C	E63D	0.974
13:48040950:A:T	E63D	0.974
13:48037847:G:T	R34M	0.972

dbSNP variants (sampled 300 via entrez): RS1000117988 (13:48036195 C>A,G,T), RS1000170836 (13:48036425 G>A), RS1000746364 (13:48041389 C>T), RS1000854700 (13:48046483 G>C), RS1001088848 (13:48053240 C>T), RS1001342711 (13:48038927 ATCC>A), RS1001392908 (13:48049067 G>A), RS1001457524 (13:48039236 C>T), RS1001640941 (13:48047608 G>A), RS1001696559 (13:48047815 G>C), RS1001763679 (13:48052658 A>G), RS1001846657 (13:48039624 C>T), RS1001917984 (13:48040925 C>A), RS1001976527 (13:48046148 A>C,G), RS1002058647 (13:48046135 T>G)

Disease associations

OMIM: gene MIM:615792 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST003603_2	Thiopurine-induced leukopenia in inflammatory bowel disease	1.000000e-22
GCST006201_2	Thiopurine-induced leukopenia in inflammatory bowel disease	1.000000e-33
GCST006204_1	Thiopurine-induced severe leukopenia in inflammatory bowel disease	1.000000e-08
GCST006205_1	Thiopurine-induced acute severe leukopenia in inflammatory bowel disease	1.000000e-08
GCST006206_5	Thiopurine-induced alopecia in inflammatory bowel disease	4.000000e-29
GCST006207_1	Thiopurine-induced severe alopecia in inflammatory bowel disease	1.000000e-08
GCST007229_1	Thiopurine-induced early leukopenia in Crohn’s disease	5.000000e-94
GCST007876_119	Estimated glomerular filtration rate	5.000000e-09
GCST010916_20	Proportion of activated microglia (inferior temporal cortex)	3.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105827 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

9 annotations.

Variant	Type	Level	Drugs	Phenotypes
NUDT151, NUDT153	Dosage	1A	azathioprine
NUDT151, NUDT153, NUDT154, NUDT155, NUDT156, NUDT157, NUDT158, NUDT159	Dosage	1A	mercaptopurine	Acute lymphoblastic leukemia
NUDT151, NUDT153, NUDT154, NUDT155, NUDT156, NUDT159	Toxicity	1A	mercaptopurine	Leukopenia;Myelosuppression;Neutropenia
NUDT151, NUDT153, NUDT154, NUDT155, NUDT156, NUDT159	Toxicity	1A	azathioprine	Leukopenia;Myelosuppression;Neutropenia
rs116855232	Dosage	1A	mercaptopurine
rs116855232	Toxicity	3	azathioprine;mercaptopurine	Pancytopenia;Thrombocytopenia
rs73189762	Dosage	3	mercaptopurine
rs746071566	Toxicity	3	azathioprine;mercaptopurine	Pancytopenia;Thrombocytopenia
rs746071566	Toxicity	3	thioguanine	Inflammatory Bowel Diseases;Myelosuppression

PharmGKB variants

7 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs116855232	NUDT15	1A	130.38	5	mercaptopurine;azathioprine;mercaptopurine
rs147390019	NUDT15		0.00	2
rs186364861	NUDT15, SUCLA2		0.00	2
rs766023281	NUDT15, SUCLA2		0.00	1
rs746071566	NUDT15, SUCLA2	3	4.00	8	azathioprine;mercaptopurine;thioguanine
rs61973267	NUDT15		0.00	0
rs1238137908	NUDT15		0.00	0

PharmGKB dosing guidelines

6 guidelines.

Source	Drug	Guideline	Dosing?	Recommendation?
CPIC	azathioprine	Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT	yes	yes
CPIC	mercaptopurine	Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT	yes	yes
CPIC	thioguanine	Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT	yes	yes
DPWG	azathioprine	Annotation of DPWG Guideline for azathioprine and NUDT15	yes	yes
DPWG	mercaptopurine	Annotation of DPWG Guideline for mercaptopurine and NUDT15	yes	yes
DPWG	thioguanine	Annotation of DPWG Guideline for thioguanine and NUDT15	yes	yes

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.60	IC50	25	nM	CHEMBL5723328
7.24	IC50	57	nM	CHEMBL5723328

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
lasiocarpine	increases expression	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
NCS 382	increases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Atrazine	increases expression	1
Doxorubicin	affects response to substance	1
Ethyl Methanesulfonate	increases expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methyl Methanesulfonate	increases expression	1
Oxygen	decreases expression	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Dronabinol	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects expression	1
Vinblastine	affects response to substance	1
Mercaptopurine	increases response to substance	1
Aflatoxin B1	decreases methylation, increases expression	1
Paclitaxel	affects response to substance	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 3 functional, 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4008390	Binding	Inhibition of human His-tagged NUDT15 expressed in bacterial expression system after 1 hr by malachite green reagent based assay	Identification of Triazolothiadiazoles as Potent Inhibitors of the dCTP Pyrophosphatase 1. — J Med Chem
CHEMBL5723175	Functional	Affinity Biochemical interaction: (enzyme-coupled MG (Malachite Green) assay with dGDP) EUB0002330a NUDT15	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TB32	HAP1 NUDT15 (-) 1	Cancer cell line	Male
CVCL_TB33	HAP1 NUDT15 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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