DTYMK

Summary

DTYMK (deoxythymidylate kinase, HGNC:3061) is a protein-coding gene on chromosome 2q37.3, encoding Thymidylate kinase (P23919). Catalyzes the phosphorylation of thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), the immediate precursor for the DNA building block dTTP, with ATP as the preferred phosphoryl donor in the presence of Mg(2+). It is a common-essential gene (DepMap: required in 92.0% of cancer cell lines).

Enables ATP binding activity and dTMP kinase activity. Involved in dTDP biosynthetic process and thymidine biosynthetic process. Located in mitochondrion.

Source: NCBI Gene 1841 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegeneration, childhood-onset, with progressive microcephaly (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 59 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 92.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_012145

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3061
Approved symbol	DTYMK
Name	deoxythymidylate kinase
Location	2q37.3
Locus type	gene with protein product
Status	Approved
Aliases	CDC8, TYMK, TMPK
Ensembl gene	ENSG00000168393
Ensembl biotype	protein_coding
OMIM	188345
Entrez	1841

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000305784, ENST00000400770, ENST00000420144, ENST00000432348, ENST00000445261, ENST00000464603, ENST00000493095, ENST00000858637, ENST00000858638, ENST00000858639, ENST00000858640, ENST00000939420, ENST00000939421, ENST00000939422

RefSeq mRNA: 6 — MANE Select: NM_012145 NM_001165031, NM_001320902, NM_001320903, NM_001320904, NM_001320905, NM_012145

CCDS: CCDS2552

Canonical transcript exons

ENST00000305784 — 5 exons

Exon	Start	End
ENSE00001630292	241685769	241685877
ENSE00001645872	241675747	241676237
ENSE00001748052	241680229	241680319
ENSE00001856557	241686654	241686815
ENSE00003601590	241678452	241678649

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 95.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.7047 / max 122.3534, expressed in 1782 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34938	25.5832	1775
34936	0.6737	314
34937	0.4479	273

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	95.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.52	gold quality
mucosa of transverse colon	UBERON:0004991	94.25	gold quality
ganglionic eminence	UBERON:0004023	93.29	gold quality
embryo	UBERON:0000922	91.66	gold quality
endometrium epithelium	UBERON:0004811	91.33	gold quality
lower esophagus mucosa	UBERON:0035834	90.97	gold quality
stromal cell of endometrium	CL:0002255	89.82	gold quality
right adrenal gland	UBERON:0001233	88.96	gold quality
apex of heart	UBERON:0002098	88.92	gold quality
esophagus mucosa	UBERON:0002469	88.86	gold quality
granulocyte	CL:0000094	88.72	gold quality
right adrenal gland cortex	UBERON:0035827	88.53	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.26	gold quality
left adrenal gland	UBERON:0001234	88.18	gold quality
cerebellar hemisphere	UBERON:0002245	88.01	gold quality
left adrenal gland cortex	UBERON:0035825	88.01	gold quality
cerebellar cortex	UBERON:0002129	87.76	gold quality
metanephros cortex	UBERON:0010533	87.38	gold quality
right lobe of liver	UBERON:0001114	87.12	gold quality
transverse colon	UBERON:0001157	86.92	gold quality
spleen	UBERON:0002106	86.90	gold quality
adrenal cortex	UBERON:0001235	86.84	gold quality
lymph node	UBERON:0000029	86.83	gold quality
body of uterus	UBERON:0009853	86.81	gold quality
ectocervix	UBERON:0012249	86.66	gold quality
body of stomach	UBERON:0001161	86.65	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.62	gold quality
esophagus	UBERON:0001043	86.49	gold quality
adrenal gland	UBERON:0002369	86.38	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	37.11
E-GEOD-125970	yes	26.48
E-HCAD-13	yes	25.16
E-MTAB-6678	yes	8.64
E-MTAB-10553	yes	8.06
E-CURD-88	yes	5.50
E-MTAB-7037	no	365.96
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting DTYMK, 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-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-1909-5P	98.94	64.01	484
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-11399	98.71	65.69	869
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-6890-3P	97.50	65.71	997
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-759	96.16	66.77	873
HSA-MIR-6784-5P	84.56	60.91	126

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 92.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 7)

• Lentiviral delivery of small hairpin RNA targeting TMPK in combination with a low dose of doxorubicin as a new approach to kill colon cancer cells regardless of p53 status. (PMID:18413751)
• these findings suggest that Tip60-ATM signaling has a functional contribution to the recruitment of TMPK to DNA damage sites, thereby increasing local dTTP synthesis for DNA repair. (PMID:30199284)
• The RAMD simulations on product-bound structures of both ttTMPK and hTMPK, revealed that while several exit patterns of the products are permissible, the sequential exit mode is the most preferred pattern for both ttTMPK and hTMPK enzymes. Additionally, the product release from the hTMPK was found to be faster and more directional as compared to ttTMPK (PMID:30447376)
• DTYMK is a novel gene for mitochondrial DNA depletion syndrome (PMID:31271740)
• Genetic effects on planum temporale asymmetry and their limited relevance to neurodevelopmental disorders, intelligence or educational attainment. (PMID:31887566)
• DTYMK is essential for genome integrity and neuronal survival. (PMID:34918187)
• The evolving landscape of involvement of DTYMK enzymes in cancer. (PMID:37358701)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	dtymk	ENSDARG00000052103
mus_musculus	Dtymk	ENSMUSG00000026281
rattus_norvegicus	Dtymk	ENSRNOG00000018904
drosophila_melanogaster	CG5757	FBGN0034299

Paralogs (1): CMPK2 (ENSG00000134326)

Protein

Protein identifiers

Thymidylate kinase — P23919 (reviewed: P23919)

Alternative names: dTMP kinase

All UniProt accessions (6): P23919, G5E9E9, H7BZ20, H7C312, H7C3A4, Q6FGU2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorylation of thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), the immediate precursor for the DNA building block dTTP, with ATP as the preferred phosphoryl donor in the presence of Mg(2+).

Subunit / interactions. Homodimer.

Disease relevance. Neurodegeneration, childhood-onset, with progressive microcephaly (CONPM) [MIM:619847] An autosomal recessive disorder characterized by global developmental delay apparent from infancy. Most severely affected individuals have severe and progressive microcephaly, early-onset seizures, lack of visual tracking, and almost no developmental milestones, resulting in early death. Less severely affected individuals have a small head circumference and severely impaired intellectual development with poor speech and motor delay. Additional features may include poor overall growth, axial hypotonia, limb hypertonia with spasticity, undescended testes, and cerebral atrophy with neuronal loss. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Pyrimidine metabolism; dTTP biosynthesis.

Similarity. Belongs to the thymidylate kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P23919-1	1	yes
P23919-2	2

RefSeq proteins (6): NP_001158503, NP_001307831, NP_001307832, NP_001307833, NP_001307834, NP_036277* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018094	Thymidylate_kinase	Family
IPR018095	Thymidylate_kin_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR039430	Thymidylate_kin-like_dom	Domain

Pfam: PF02223

Enzyme classification (BRENDA):

• EC 2.7.4.9 — dTMP kinase (BRENDA: 31 organisms, 142 substrates, 438 inhibitors, 98 Km, 63 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.0051–1.5	18
DTMP	0.0045–0.25	16
TMP	0.0042–0.0659	13
DGMP	0.0011–0.0969	7
DUMP	0.17–4	6
3’-AZIDO-3’-DEOXYTHYMIDINE MONOPHOSPHATE	0.0038–0.012	4
5-BROMO-2’-DEOXYURIDINE 5’-MONOPHOSPHATE	0.08–0.28	4
2’,3’-DIDEHYDRO-2’,3’-DIDEOXYTHYMIDINE 5’-MONOPH	0.012–0.27	3
3’-AZIDO-3’-DEOXYTHYMIDINE 5’-MONOPHOSPHATE	0.012–0.17	3
N1-[(E)-4-DIHYDROXYPHOSPHONYL-BUT-2-ENYL]-5-CHLO	0.02–0.13	2
(E)-5-(2-BROMOVINYL)-DEOXYURIDINE MONOPHOSPHATE	0.19	1
3’-FLUORO-3’-DEOXYTHYMIDINE 5’-MONOPHOSPHATE	0.008	1
5-BROMO-DUMP	0.01	1
D-2’-FLUOROARABINOSYL-5-METHYLDEOXYURIDINE 5’-MO	0.0044	1
D-DTMP	0.02	1

Catalyzed reactions (Rhea), 1 shown:

• dTMP + ATP = dTDP + ADP (RHEA:13517)

UniProt features (38 total): helix 12, strand 7, sequence conflict 6, binding site 4, sequence variant 3, modified residue 2, initiator methionine 1, chain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
1NN5	X-RAY DIFFRACTION	1.5
1NN3	X-RAY DIFFRACTION	1.55
1E2F	X-RAY DIFFRACTION	1.6
1E9A	X-RAY DIFFRACTION	1.6
1E9C	X-RAY DIFFRACTION	1.6
1E9E	X-RAY DIFFRACTION	1.6
1NMY	X-RAY DIFFRACTION	1.6
1NN0	X-RAY DIFFRACTION	1.6
1E2D	X-RAY DIFFRACTION	1.65
1E2G	X-RAY DIFFRACTION	1.7
1E2Q	X-RAY DIFFRACTION	1.7
1E9B	X-RAY DIFFRACTION	1.7
1E9D	X-RAY DIFFRACTION	1.7
1NMX	X-RAY DIFFRACTION	1.7
1NMZ	X-RAY DIFFRACTION	1.75
1E99	X-RAY DIFFRACTION	1.8
1E98	X-RAY DIFFRACTION	1.9
1E9F	X-RAY DIFFRACTION	1.9
1NN1	X-RAY DIFFRACTION	1.9
1E2E	X-RAY DIFFRACTION	2
2XX3	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23919-F1	95.83	0.90

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 (4): 16–21; 97; 182; 192

Post-translational modifications (2): 2, 169

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-499943	Interconversion of nucleotide di- and triphosphates
R-HSA-1430728	Metabolism
R-HSA-15869	Metabolism of nucleotides

MSigDB gene sets: 335 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, FERRANDO_TAL1_NEIGHBORS, MODULE_52, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, KANG_DOXORUBICIN_RESISTANCE_UP, GNF2_CENPF, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, SEMBA_FHIT_TARGETS_DN, HOFMANN_CELL_LYMPHOMA_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_PYRIMIDINE_NUCLEOSIDE_TRIPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS

GO Biological Process (6): dUDP biosynthetic process (GO:0006227), dTDP biosynthetic process (GO:0006233), dTTP biosynthetic process (GO:0006235), thymidine biosynthetic process (GO:0046105), cellular response to growth factor stimulus (GO:0071363), nucleotide biosynthetic process (GO:0009165)

GO Molecular Function (6): nucleoside diphosphate kinase activity (GO:0004550), dTMP kinase activity (GO:0004798), ATP binding (GO:0005524), nucleotide binding (GO:0000166), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of nucleotides	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
pyrimidine deoxyribonucleotide biosynthetic process	3
pyrimidine deoxyribonucleoside diphosphate biosynthetic process	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
deoxyribonucleoside diphosphate biosynthetic process	1
dUDP metabolic process	1
dTDP metabolic process	1
deoxyribonucleoside triphosphate biosynthetic process	1
pyrimidine deoxyribonucleoside triphosphate biosynthetic process	1
dTTP metabolic process	1
thymidine metabolic process	1
pyrimidine deoxyribonucleoside biosynthetic process	1
response to growth factor	1
cellular response to endogenous stimulus	1
nucleotide metabolic process	1
nucleoside phosphate biosynthetic process	1
phosphotransferase activity, phosphate group as acceptor	1
nucleobase-containing compound kinase activity	1
deoxynucleoside phosphate kinase activity, ATP as phosphate donor	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2396 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DTYMK	CMPK1	P30085	923
DTYMK	CMPK2	Q5EBM0	899
DTYMK	NEU4	Q8WWR8	890
DTYMK	TK2	O00142	851
DTYMK	GAL3ST2	Q9H3Q3	840
DTYMK	TYMS	P04818	821
DTYMK	TK1	P04183	766
DTYMK	DUT	P33316	709
DTYMK	DCTD	P32321	704
DTYMK	UMPS	P11172	665
DTYMK	NME4	O00746	651
DTYMK	NEU2	Q9Y3R4	648
DTYMK	NT5M	Q9NPB1	633
DTYMK	DGUOK	P78532	632
DTYMK	DCK	P27707	598

IntAct

53 interactions, top by confidence:

A	B	Type	Score
HRAS	RAF1	psi-mi:“MI:0914”(association)	0.980
AKR7A3	AKR7A2	psi-mi:“MI:0914”(association)	0.890
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
CHCHD4	ENSA	psi-mi:“MI:0914”(association)	0.530
DTYMK	HSD17B7	psi-mi:“MI:0915”(physical association)	0.370
MAPK6		psi-mi:“MI:0914”(association)	0.350
DLD	NFKBIE	psi-mi:“MI:0914”(association)	0.350
PCMT1	YDJC	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	PSMD3	psi-mi:“MI:0914”(association)	0.350
	SDCBP	psi-mi:“MI:0914”(association)	0.350
	AGPS	psi-mi:“MI:0914”(association)	0.350
S100A6	VWA8	psi-mi:“MI:0914”(association)	0.350
	POLRMT	psi-mi:“MI:0914”(association)	0.350
	SUPT5H	psi-mi:“MI:0914”(association)	0.350
GIP	GNPAT	psi-mi:“MI:0914”(association)	0.350
BBS1	SHTN1	psi-mi:“MI:0914”(association)	0.350
GPR45	VWA8	psi-mi:“MI:0914”(association)	0.350
MFSD4A	UBXN8	psi-mi:“MI:0914”(association)	0.350
NAAA	HAX1	psi-mi:“MI:0914”(association)	0.350
ALPI	RTCA	psi-mi:“MI:0914”(association)	0.350
DNAJB6	SCAMP1	psi-mi:“MI:0914”(association)	0.350
IL12RB1	ZNF185	psi-mi:“MI:0914”(association)	0.350
RASL11A	MBL2	psi-mi:“MI:0914”(association)	0.350
HBS1L	GPX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (59): DTYMK (Affinity Capture-RNA), DTYMK (Affinity Capture-MS), DTYMK (Affinity Capture-MS), DTYMK (Co-fractionation), DTYMK (Affinity Capture-MS), DTYMK (Affinity Capture-MS), DTYMK (Affinity Capture-MS), DTYMK (Affinity Capture-MS), DTYMK (Synthetic Lethality), DTYMK (Affinity Capture-MS), DTYMK (Affinity Capture-MS), DTYMK (Affinity Capture-MS), DTYMK (Affinity Capture-MS), DTYMK (Affinity Capture-MS), DTYMK (Affinity Capture-MS)

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: A0A7H0DNE5, A1ZB29, A2BZV6, A4FXE4, A4J0K6, A4YIC4, A5UKJ7, A6UP44, A6UTV9, A6VFY2, A9AAR4, A9BCY7, B1L821, B4SAG3, B7IHT2, C0R1X1, O30175, O59366, P00572, P0C8F9, P0C8G0, P0C8G1, P0C8G2, P0DSV5, P0DSV6, P23919, P36590, P42490, P59500, P68693, P97930, Q0WW55, Q1QLT8, Q22018, Q3AS37, Q3B752, Q46HP4, Q49UZ1, Q54GN2, Q57741

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FZR1	“down-regulates quantity by destabilization”	DTYMK	binding
APC-c	“down-regulates quantity by destabilization”	DTYMK	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	41
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1686902	NM_012145.4(DTYMK):c.287_320del (p.Asp96fs)	Pathogenic
1686903	NM_012145.4(DTYMK):c.295G>A (p.Ala99Thr)	Pathogenic
1686904	NM_012145.4(DTYMK):c.382G>A (p.Asp128Asn)	Pathogenic
1703652	GRCh37/hg19 2q37.2-37.3(chr2:236472789-242783384)	Pathogenic
562657	GRCh37/hg19 2q37.3(chr2:240076138-242783384)x1	Pathogenic
1686905	NM_012145.4(DTYMK):c.242C>T (p.Pro81Leu)	Likely pathogenic
4277573	NM_012145.4(DTYMK):c.265_270del (p.Gln89_Gly90del)	Likely pathogenic

SpliceAI

1214 predictions. Top by Δscore:

Variant	Effect	Δscore
2:241676236:ATCT:A	acceptor_loss	1.0000
2:241676248:C:CT	acceptor_gain	1.0000
2:241676248:C:T	acceptor_gain	1.0000
2:241676249:G:T	acceptor_gain	1.0000
2:241676256:C:CT	acceptor_gain	1.0000
2:241676257:A:T	acceptor_gain	1.0000
2:241678446:TCTCA:T	donor_loss	1.0000
2:241678447:CTCA:C	donor_loss	1.0000
2:241678448:TCAC:T	donor_loss	1.0000
2:241678449:CA:C	donor_loss	1.0000
2:241678450:A:AG	donor_loss	1.0000
2:241678450:ACCTT:A	donor_gain	1.0000
2:241678451:CCTT:C	donor_gain	1.0000
2:241678451:CCTTC:C	donor_gain	1.0000
2:241685767:A:AC	donor_gain	1.0000
2:241685768:C:CC	donor_gain	1.0000
2:241685768:CA:C	donor_gain	1.0000
2:241686701:T:TA	donor_gain	1.0000
2:241676234:CCAT:C	acceptor_gain	0.9900
2:241676235:CATC:C	acceptor_gain	0.9900
2:241676238:C:CC	acceptor_gain	0.9900
2:241676238:CTGTT:C	acceptor_loss	0.9900
2:241676239:T:G	acceptor_loss	0.9900
2:241676245:C:CT	acceptor_gain	0.9900
2:241676245:C:T	acceptor_gain	0.9900
2:241676252:G:C	acceptor_gain	0.9900
2:241676252:G:GC	acceptor_gain	0.9900
2:241676253:T:C	acceptor_gain	0.9900
2:241676253:T:TC	acceptor_gain	0.9900
2:241678450:A:AC	donor_gain	0.9900

AlphaMissense

1378 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:241680244:G:C	F105L	0.994
2:241680244:G:T	F105L	0.994
2:241680246:A:G	F105L	0.994
2:241685792:A:C	F72L	0.994
2:241685792:A:T	F72L	0.994
2:241685794:A:G	F72L	0.994
2:241685782:G:T	R76S	0.993
2:241686658:G:C	F42L	0.993
2:241686658:G:T	F42L	0.993
2:241686660:A:G	F42L	0.993
2:241686747:C:G	G13R	0.992
2:241685788:C:G	A74P	0.991
2:241680278:A:T	V94D	0.990
2:241685781:C:G	R76P	0.990
2:241686729:T:G	K19Q	0.989
2:241680248:G:T	A104D	0.987
2:241686727:C:A	K19N	0.987
2:241686727:C:G	K19N	0.987
2:241680269:C:A	R97I	0.986
2:241686741:C:G	D15H	0.986
2:241685783:A:C	N75K	0.985
2:241685783:A:T	N75K	0.985
2:241685799:A:G	L70P	0.985
2:241685859:C:T	G50D	0.985
2:241686729:T:C	K19E	0.985
2:241686731:C:T	G18E	0.985
2:241680269:C:G	R97T	0.984
2:241685803:G:C	H69D	0.984
2:241686740:T:A	D15V	0.984
2:241686750:C:T	E12K	0.984

dbSNP variants (sampled 300 via entrez): RS1000242398 (2:241688233 T>C), RS1000405985 (2:241677678 C>T), RS1000472141 (2:241686872 G>A,C), RS1000588761 (2:241682832 G>A), RS1000672993 (2:241682166 T>C), RS1000692742 (2:241687951 C>G,T), RS1001205049 (2:241684023 C>A), RS1001239407 (2:241686059 A>C), RS1001291984 (2:241680591 T>C), RS1001311153 (2:241678894 G>A), RS1001679376 (2:241680852 TAAC>T), RS1001705324 (2:241683927 C>G,T), RS1001851736 (2:241676115 G>A,C), RS1001878692 (2:241685575 G>A,C), RS1001906438 (2:241676567 G>A)

Disease associations

OMIM: gene MIM:188345 | disease phenotypes: MIM:619847, MIM:600430

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegeneration, childhood-onset, with progressive microcephaly	Strong	Autosomal recessive
mitochondrial DNA depletion syndrome	Limited	Autosomal recessive

Mondo (3): neurodegeneration, childhood-onset, with progressive microcephaly (MONDO:0859241), 2q37 microdeletion syndrome (MONDO:0010886), mitochondrial DNA depletion syndrome (MONDO:0018158)

Orphanet (1): 2q37 microdeletion syndrome (Orphanet:1001)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000252	Microcephaly
HP:0000293	Full cheeks
HP:0000341	Narrow forehead
HP:0000407	Sensorineural hearing impairment
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0001518	Small for gestational age
HP:0001561	Polyhydramnios
HP:0001601	Laryngomalacia
HP:0001623	Breech presentation
HP:0002015	Dysphagia
HP:0002059	Cerebral atrophy
HP:0002133	Status epilepticus
HP:0002151	Increased circulating lactate concentration
HP:0002169	Clonus
HP:0002171	Gliosis
HP:0002179	Opisthotonus
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002376	Developmental regression
HP:0002451	Limb dystonia
HP:0002510	Spastic tetraplegia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001942_6	Prostate cancer	5.000000e-09
GCST006479_59	Diverticular disease	3.000000e-07
GCST009798_13	Asthma	5.000000e-36

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009959	diverticular disease

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538317	Chromosome 2q37 deletion syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4388 (SINGLE PROTEIN)

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

ChEMBL bioactivities

10 potent at pChembl≥5 of 15 total, top 10 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.46	IC50	350	nM	CHEMBL4749381
6.33	IC50	470	nM	CHEMBL4758532
5.82	IC50	1530	nM	CHEMBL395814
5.78	IC50	1650	nM	CHEMBL4757635
5.40	IC50	4000	nM	CHEMBL606084
5.22	IC50	6000	nM	CHEMBL605435
5.22	IC50	6000	nM	CHEMBL604405
5.10	IC50	8000	nM	CHEMBL1236157
5.00	Kd	9926	nM	CHEMBL5653589
5.00	ED50	9926	nM	CHEMBL5653589

PubChem BioAssay actives

9 with measured affinity, of 172 total; 9 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
tert-butyl 4-[2-(3-oxo-1,2-benzothiazol-2-yl)acetyl]piperazine-1-carboxylate	1686313: Inhibition of GST-tagged human TMPK expressed in Escherichia coli BL21 incubated for 10 mins by luciferase-coupled TMPK assay	ic50	0.3500	uM
tert-butyl 4-[2-(3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)acetyl]piperazine-1-carboxylate	1686313: Inhibition of GST-tagged human TMPK expressed in Escherichia coli BL21 incubated for 10 mins by luciferase-coupled TMPK assay	ic50	0.4700	uM
5-[(3-carboxy-4-nitrophenyl)disulfanyl]-2-nitrobenzoic acid	649640: Inhibition of human thymidylate kinase using dTMP as substrate after 30 mins by fluorescence analysis	ic50	1.5300	uM
ethyl 4-[2-(4,6-dimethyl-3-oxo-[1,2]thiazolo[5,4-b]pyridin-2-yl)acetyl]piperazine-1-carboxylate	1686313: Inhibition of GST-tagged human TMPK expressed in Escherichia coli BL21 incubated for 10 mins by luciferase-coupled TMPK assay	ic50	1.6500	uM
[[[[[(2R,3S,4R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-[[hydroxy-[[(2R,3S)-3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphoryl]methyl]phosphinic acid	211246: Concentration required to reduce Thymidylate kinase rate by 50% in human blast cells	ic50	4.0000	uM
[[(2R,3S,4R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [hydroxy-[hydroxy-[hydroxy-[hydroxy-[[(2R,3S)-3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphoryl]oxyphosphoryl]oxyphosphoryl]oxyphosphoryl] hydrogen phosphate	211246: Concentration required to reduce Thymidylate kinase rate by 50% in human blast cells	ic50	6.0000	uM
[[[[(2R,3S,4R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-[[hydroxy-[[(2R,3S)-3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphoryl]methyl]phosphinic acid	211246: Concentration required to reduce Thymidylate kinase rate by 50% in human blast cells	ic50	6.0000	uM
[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [hydroxy-[hydroxy-[hydroxy-[[(2R,3S,5R)-3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphoryl]oxyphosphoryl]oxyphosphoryl] hydrogen phosphate	211246: Concentration required to reduce Thymidylate kinase rate by 50% in human blast cells	ic50	8.0000	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148268: Binding affinity to human DTYMK incubated for 45 mins by Kinobead based pull down assay	kd	9.9262	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	5
sodium arsenite	increases expression, affects binding, increases reaction, decreases expression, increases abundance	5
Fluorouracil	increases expression, affects reaction, decreases expression, affects response to substance	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Cisplatin	increases expression, decreases expression, increases reaction	2
Estradiol	decreases expression, increases expression, affects cotreatment	2
Valproic Acid	affects cotreatment, decreases expression	2
Zidovudine	increases phosphorylation, increases response to substance, affects response to substance, affects expression, affects phosphorylation (+1 more)	2
Cyclosporine	decreases expression	2
uranyl acetate	affects expression	1
geraniol	decreases expression	1
methylselenic acid	decreases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
ochratoxin A	increases expression	1
epigallocatechin gallate	decreases expression	1
zidovudine triphosphate	affects chemical synthesis	1
3’-azido-3’-deoxythymidine 5’phosphate	affects metabolic processing	1
3’-azido-3’-deoxythymidine 5’-diphosphate	affects chemical synthesis	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, decreases expression	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1

ChEMBL screening assays

38 unique, capped per target: 36 binding, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1657145	Binding	Activity at human recombinant TMPK by Michaelis-Menten equation analysis	Novel antiviral C5-substituted pyrimidine acyclic nucleoside phosphonates selected as human thymidylate kinase substrates. — J Med Chem
CHEMBL4832959	ADMET	Inhibition of human TMPK at 40 uM	Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors. — Eur J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight