DNMT3A

Summary

DNMT3A (DNA methyltransferase 3 alpha, HGNC:2978) is a protein-coding gene on chromosome 2p23.3, encoding DNA (cytosine-5)-methyltransferase 3A (Q9Y6K1). Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. In precision oncology, DNMT3A Mutation confers sensitivity to Decitabine in Acute Myeloid Leukemia (CIViC Level B); 3 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase that is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes to the cytoplasm and nucleus and its expression is developmentally regulated.

Source: NCBI Gene 1788 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Tatton-Brown-Rahman overgrowth syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 81
• Clinical variants (ClinVar): 1,318 total — 125 pathogenic, 80 likely-pathogenic
• Phenotypes (HPO): 117
• Druggable target: yes
• Precision-oncology evidence (CIViC): 4 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 9 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 63 downstream targets (CollecTRI)
• MANE Select transcript: NM_022552

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2978
Approved symbol	DNMT3A
Name	DNA methyltransferase 3 alpha
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000119772
Ensembl biotype	protein_coding
OMIM	602769
Entrez	1788

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 13 protein_coding, 6 nonsense_mediated_decay, 4 retained_intron

ENST00000264709, ENST00000321117, ENST00000380746, ENST00000380756, ENST00000402667, ENST00000406659, ENST00000461228, ENST00000466601, ENST00000470983, ENST00000474807, ENST00000474887, ENST00000482935, ENST00000484184, ENST00000491288, ENST00000682842, ENST00000683393, ENST00000683760, ENST00000861234, ENST00000861235, ENST00000861236, ENST00000938699, ENST00000938700, ENST00000960044

RefSeq mRNA: 7 — MANE Select: NM_022552 NM_001320892, NM_001320893, NM_001375819, NM_022552, NM_153759, NM_175629, NM_175630

CCDS: CCDS1718, CCDS33157, CCDS46232, CCDS92718

Canonical transcript exons

ENST00000321117 — 23 exons

Exon	Start	End
ENSE00000808931	25274941	25275087
ENSE00000808934	25300139	25300243
ENSE00001071029	25245253	25245332
ENSE00001071031	25244540	25244652
ENSE00001281418	25244155	25244338
ENSE00001326003	25282441	25282711
ENSE00001408175	25313913	25314161
ENSE00001486208	25275500	25275543
ENSE00001522911	25341826	25341925
ENSE00003460185	25240302	25240450
ENSE00003460672	25248037	25248252
ENSE00003463046	25236936	25237005
ENSE00003465580	25247051	25247158
ENSE00003485430	25235707	25235825
ENSE00003493347	25243898	25243982
ENSE00003505768	25246160	25246309
ENSE00003510462	25241562	25241707
ENSE00003521918	25246620	25246776
ENSE00003587018	25247591	25247749
ENSE00003611481	25239130	25239215
ENSE00003626195	25240640	25240730
ENSE00003639078	25246020	25246064
ENSE00003899866	25227874	25234420

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 93.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.7878 / max 169.1686, expressed in 1630 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27364	3.7845	565
27368	3.6400	1355
27363	1.6074	315
27369	0.5215	294
27371	0.3787	215
27370	0.3588	196
27372	0.2859	131
27365	0.1131	40
27362	0.0981	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	93.70	gold quality
ganglionic eminence	UBERON:0004023	91.93	gold quality
ventricular zone	UBERON:0003053	89.73	gold quality
adrenal tissue	UBERON:0018303	88.87	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.90	silver quality
biceps brachii	UBERON:0001507	87.72	silver quality
cortical plate	UBERON:0005343	87.25	gold quality
embryo	UBERON:0000922	86.66	gold quality
oocyte	CL:0000023	86.47	gold quality
placenta	UBERON:0001987	86.46	gold quality
right ovary	UBERON:0002118	85.82	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.76	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	85.67	silver quality
left ovary	UBERON:0002119	85.54	gold quality
ovary	UBERON:0000992	85.28	gold quality
blood	UBERON:0000178	85.10	gold quality
stromal cell of endometrium	CL:0002255	84.25	gold quality
right adrenal gland	UBERON:0001233	84.24	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.12	gold quality
muscle of leg	UBERON:0001383	84.12	gold quality
granulocyte	CL:0000094	84.10	gold quality
right adrenal gland cortex	UBERON:0035827	84.02	gold quality
gastrocnemius	UBERON:0001388	83.70	gold quality
muscle layer of sigmoid colon	UBERON:0035805	83.40	gold quality
mucosa of stomach	UBERON:0001199	83.37	gold quality
body of uterus	UBERON:0009853	83.12	gold quality
left adrenal gland	UBERON:0001234	83.09	gold quality
adrenal gland	UBERON:0002369	83.00	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.96	gold quality
left adrenal gland cortex	UBERON:0035825	82.93	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	17417.88
E-ANND-3	yes	8.85
E-GEOD-93593	yes	8.49
E-MTAB-7303	no	333.23

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

63 targets.

Target	Regulation
ASCL1
AXIN2	Activation
BRCA1
CCND1	Repression
CDH1	Repression
CDH6	Repression
CDKN1A	Unknown
CDKN2A	Unknown
CDKN2B	Repression
CDKN2C	Repression
CDKN2D	Repression
CXCL8
DNMT3A
DNMT3B
DNMT3L
DPP6	Repression
EHMT2
EPCAM
ESR1
FATE1
FGF21	Repression
FOXP3
GFAP
GH1
HAND1
HLA-DRB1
HOXA9	Repression
IFNG
IGFBP3	Repression
INHA

Upstream regulators (CollecTRI, top): DNMT1, DNMT3A, DNMT3B, DNMT3L, E2F1, ESR2, MDM2, RB1, SALL3, SP1, SP2, SP3, STAT5A, WT1

miRNA regulators (miRDB)

128 targeting DNMT3A, 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-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-6845-3P	99.94	66.88	1439

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• recruited to the RARbeta2 promoter by the PML-RAR fusion protein (PMID:11834837)
• These findings suggest that Dnmt3a and Dnmt3a2 may have distinct DNA targets and different functions in development. (PMID:12138111)
• the human de novo enzymes hDNMT3a and hDNMT3b form complexes with the major maintenance enzyme hDNMT1. (PMID:12145218)
• cloned and characterized the 5’-end of the mRNA and promoter regions (PMID:12359337)
• DNMT3L stimulates de novo methylation by Dnmt3a. (PMID:12481029)
• Over-expressed in squamous cell carcinoma of the mouth. (PMID:12738984)
• Findings are consistent with a model in which Dnmt3a initiates methylation on one of the DNA strands of duplex DNA, and these hemimethylated sites then stimulate Dnmt1 activity for further methylation. (PMID:15799776)
• DNMT3A was shown to have a very pronounced flanking sequence preference for human DNA methylation. (PMID:15854647)
• cDNA microarray analysis identified several genes involved in DNA methylation, such as DNMT2 and DNMT3a that were more highly expressed in LNCaP-r (an androgen sensitive prostate cancer cell line). (PMID:16173030)
• histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells (PMID:16682412)
• In human cells maintenance of XIST methylation is controlled differently than global genomic methylation and in the absence of both DNMT1 and DNMT3B. (PMID:16769694)
• LANA associated with repressed cellular promoters, recruited Dnmt3a to DNA, and facilitated de novo promoter methylation of a down-regulated gene, cadherin 13 (H-cadherin). (PMID:16983096)
• Sex-specific time windows for concomitant upregulation of DNMT3A are associated with prenatal remethylation of the human male and female germ line. (PMID:16998846)
• The genes DNMT1, DNMT3A, and DNMT3B were over-expressed in the ectopic endometrium as compared with normal control subjects or the eutopic endometrium of women with endometriosis (PMID:17081533)
• Progressive up-regulation of the gene encoding DNMT3A was found in the colorectal adenoma-carcinoma sequence. (PMID:17538945)
• Up-regulation of DNMT3A expression is associated with hypomethylation of intron25 in testicular germ cell tumors. (PMID:17548962)
• We found clinically relevant levels of Hcy (0-500 microM) induced elevation of SAH, declination of SAM and SAM/SAH ratio and reduced expression of SAHH and MBD2, but increased activity of DNMT3a and DNMT3b affecting DNA methylation (PMID:17688412)
• Expression of microRNA is inversely correlated with DNMT3A in non-small cell lung cancer. (PMID:17890317)
• the autocrine hGH-stimulated increases in DNMT3A and DNMT3B expression mediate repression of plakoglobin gene transcription by direct hypermethylation of its promoter and consequent phenotypic conversion of mammary carcinoma cells (PMID:17998942)
• DNMT3a was over expressed in gastric neoplasms. (PMID:18253830)
• a negative association of DNMT3a and 3b expression with MDS disease risk (PMID:18829110)
• Epigenetic modification induced by hepatitis B virus X protein via interaction with de novo DNA methyltransferase DNMT3A. (PMID:19070387)
• This functional characterization of SALL3 sheds light on regulatory mechanisms for DNMT3A and provides new strategies to inhibit aberrant methylation in cancer. (PMID:19139273)
• Down-regulation of DNMT3A results from direct interaction of miR-29b with its 3’ untranslated region. (PMID:19211935)
• Loss of the H4 arginine 3 methylation mark through short hairpin RNA-mediated knockdown of PRMT5 leads to reduced DNMT3A binding, loss of DNA methylation and gene activation. (PMID:19234465)
• Data showed that the CD70, perforin and KIR2DL4 promoters are demethylated in CD4(+)CD28(-) T cells, and that DNA methyltransferase 1 (Dnmt1) and Dnmt3a levels are decreased in this subset. (PMID:19394279)
• Results show that folate supplementation enhanced the DNA remethylation through the Sp1/Sp3-mediated transcriptional up-regulation of genes coding for Dnmt3a and Dnmt3b proteins. (PMID:19451595)
• Our results were not able to demonstrate a clear correlation between DNMT1 and DNMT3a immunoexpression and salivary gland neoplasms development. (PMID:19468253)
• nucleosomes containing methylated SINE and LINE elements and CpG islands are the main sites of DNMT3A/3B binding. (PMID:19620278)
• Hypomethylated conditional knockout T helper (Th) type 2 DNMT3a-null cells retain a greater capacity to express IFN-gamma protein when they are subsequently exposed to Th1-cell biasing conditions. (PMID:19625655)
• miR-143 regulates DNA methyltranferase 3A in colorectal cancer (PMID:19638978)
• The expression of DNMT1, DNMT2, DNMT3A and DNMT3B in pediatric acute lymphoblastic leukemia patients, was investigated. (PMID:19763880)
• description of direct interaction between Dnmt3a and/or Dnmt3b and transcription factors provides rational molecular explanation to the mechanisms of targeted DNA (hyper)methylation. (PMID:19786833)
• Np95, Dnmt3a and Dnmt3b in mediating epigenetic silencing through histone modification followed by DNA methylation (PMID:19798101)
• de novo DNA methylation by DNMT3A requires the alteration of chromatin structure (PMID:19834512)
• CG dinucleotide recognized by the Dnmt3a and Dnmt3L complex are distinctive at retroelements and imprinted domains. (PMID:19921333)
• Results show the DNMT3A -448AA SNP homozygotes have a six fold increased risk of gastric cancer over heterozygotes. (PMID:20128888)
• Hepatitis B virus-induced overexpression of DNMTs leads to viral DNA methylation and decreased viral gene expression and also leads to methylation of host CpG islands. (PMID:20147412)
• DNMT3A has a second binding site for DNA. (PMID:20227382)
• Dnmt1 and Dnmt3a transgenes are required for synaptic plasticity, learning and memory through their overlapping roles in maintaining DNA methylation and modulating neuronal gene expression in adult central nervous system neurons. (PMID:20228804)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnmt3aa	ENSDARG00000005394
danio_rerio	dnmt3ab	ENSDARG00000015566
mus_musculus	Dnmt3a	ENSMUSG00000020661
rattus_norvegicus	Dnmt3a	ENSRNOG00000026649

Paralogs (4): DNMT3B (ENSG00000088305), DNMT3L (ENSG00000142182), PWWP2A (ENSG00000170234), PWWP2B (ENSG00000171813)

Protein

Protein identifiers

DNA (cytosine-5)-methyltransferase 3A — Q9Y6K1 (reviewed: Q9Y6K1)

Alternative names: Cysteine methyltransferase DNMT3A, DNA methyltransferase HsaIIIA

All UniProt accessions (9): A0A0C4DG02, A0A8I5KNQ0, A0A8I5KPS0, A0A8I5KTF6, A0A8I5KUD4, A0A8I5KXG9, A0A8I5QKW3, Q9Y6K1, F8WE91

UniProt curated annotations — full annotation on UniProt →

Function. Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNA methylation is coordinated with methylation of histones. It modifies DNA in a non-processive manner and also methylates non-CpG sites. May preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1. Plays a role in paternal and maternal imprinting. Required for methylation of most imprinted loci in germ cells. Acts as a transcriptional corepressor for ZBTB18. Recruited to trimethylated ‘Lys-36’ of histone H3 (H3K36me3) sites. Can actively repress transcription through the recruitment of HDAC activity. Also has weak auto-methylation activity on Cys-710 in absence of DNA.

Subunit / interactions. Heterotetramer composed of 1 DNMT3A homodimer and 2 DNMT3L subunits (DNMT3L-DNMT3A-DNMT3A-DNMT3L). Interacts with UBC9, PIAS1 and PIAS2. Binds the ZBTB18 transcriptional repressor. Interacts with SETDB1. Associates with HDAC1 through its ADD domain. Interacts with UHRF1. Interacts with DNMT1 and DNMT3B. Interacts with the PRC2/EED-EZH2 complex. Interacts with MPHOSPH8. Interacts with histone H3 that is not methylated at ‘Lys-4’ (H3K4). Interacts with SPOCD1. Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression.

Subcellular location. Nucleus. Chromosome. Cytoplasm.

Tissue specificity. Highly expressed in fetal tissues, skeletal muscle, heart, peripheral blood mononuclear cells, kidney, and at lower levels in placenta, brain, liver, colon, spleen, small intestine and lung.

Post-translational modifications. Sumoylated; sumoylation disrupts the ability to interact with histone deacetylases (HDAC1 and HDAC2) and repress transcription. Auto-methylated at Cys-710: auto-methylation takes place in absence of DNA substrate and inactivates the DNA methyltransferase activity. Inactivation by auto-methylation may be used to inactivate unused DNA methyltransferases in the cell.

Disease relevance. Tatton-Brown-Rahman syndrome (TBRS) [MIM:615879] An overgrowth syndrome characterized by a distinctive facial appearance, tall stature and intellectual disability. Facial gestalt is characterized by a round face, heavy horizontal eyebrows and narrow palpebral fissures. Less common features include atrial septal defects, seizures, umbilical hernia, and scoliosis. The disease is caused by variants affecting the gene represented in this entry. Leukemia, acute myelogenous (AML) [MIM:601626] A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. The disease is caused by variants affecting the gene represented in this entry. Heyn-Sproul-Jackson syndrome (HESJAS) [MIM:618724] An autosomal dominant form of microcephalic dwarfism. Affected individuals have intrauterine growth retardation, postnatal growth restrictions, proportionate short stature, microcephaly, severe developmental delay and impaired intellectual development. More variable features include sparse hair, short broad metacarpals and phalanges, and mild recurrent infections. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by binding to the regulatory factor DNMT3L. Auto-methylation at Cys-710 in absence of DNA inactivates the DNA methyltransferase activity.

Domain organisation. The PWWP domain is essential for targeting to pericentric heterochromatin. It specifically recognizes and binds trimethylated ‘Lys-36’ of histone H3 (H3K36me3).

Miscellaneous. It is uncertain whether Met-1 or Met-35 is the initiator. Produced by alternative splicing.

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. C5-methyltransferase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y6K1-1	1	yes
Q9Y6K1-2	2
Q9Y6K1-3	3

RefSeq proteins (7): NP_001307821, NP_001307822, NP_001362748, NP_072046, NP_715640, NP_783328, NP_783329 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000313	PWWP_dom	Domain
IPR001525	C5_MeTfrase	Family
IPR018117	C5_DNA_meth_AS	Active_site
IPR025766	ADD	Domain
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR040552	DNMT3_ADD_GATA1-like	Domain
IPR044108	ADD_DNMT3A	Domain
IPR049554	DNMT3_ADD_PHD	Domain
IPR050390	C5-Methyltransferase	Family
IPR054724	DNM3A_N	Domain

Pfam: PF00145, PF00855, PF17980, PF21255, PF22855

Enzyme classification (BRENDA):

• EC 2.1.1.37 — DNA (cytosine-5-)-methyltransferase (BRENDA: 52 organisms, 225 substrates, 140 inhibitors, 78 Km, 31 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
S-ADENOSYL-L-METHIONINE	0.0001–0.021	28
DNA	0.0003–0.092	4
POLY(DG-DC)-POLY(DG-DC)	0.0009–0.0035	4
POLY(DI-DC)-POLY(DI-DC)	0.0003–0.0015	3
POLY-(DI-DC)/POLY(DI-DC)	0.0005–0.0008	3
DGDC	0.0005–0.0016	2
DIDC	0.0004–0.0012	2
MONONUCLEOSOMAL DNA CONTAINING CYTOSINE	0.52–1.4	2
POLY(DI-DC)*POLY(DI-DC)	0.0005–0.0007	2
UNMETHYLATED 30-MER DNA CONTAINING CYTOSINE	—	2
(CGG*CCG)12	0.0008	1
(CGG*CCG)73	0.0001	1
CPNPG	0.0001	1
CPNPN	—	1
HEMIMETHYLATED CPG	—	1

Catalyzed reactions (Rhea), 2 shown:

• a 2’-deoxycytidine in DNA + S-adenosyl-L-methionine = a 5-methyl-2’-deoxycytidine in DNA + S-adenosyl-L-homocysteine + H(+) (RHEA:13681)
• L-cysteinyl-[protein] + S-adenosyl-L-methionine = S-methyl-L-cysteinyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:66544)

UniProt features (131 total): helix 30, strand 28, sequence variant 21, turn 14, modified residue 10, compositionally biased region 7, region of interest 5, binding site 4, domain 3, splice variant 3, zinc finger region 2, chain 1, active site 1, cross-link 1, mutagenesis site 1

Structure

Experimental structures (PDB)

43 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8BA5	X-RAY DIFFRACTION	1.45
4QBS	X-RAY DIFFRACTION	1.8
4QBR	X-RAY DIFFRACTION	1.9
3A1B	X-RAY DIFFRACTION	2.29
3A1A	X-RAY DIFFRACTION	2.3
3LLR	X-RAY DIFFRACTION	2.3
3SVM	X-RAY DIFFRACTION	2.31
6W8B	X-RAY DIFFRACTION	2.4
4QBQ	X-RAY DIFFRACTION	2.41
6W8J	X-RAY DIFFRACTION	2.44
8TE1	X-RAY DIFFRACTION	2.48
6W89	X-RAY DIFFRACTION	2.5
6W8D	X-RAY DIFFRACTION	2.6
8TE4	X-RAY DIFFRACTION	2.65
5YX2	X-RAY DIFFRACTION	2.65
8UW1	ELECTRON MICROSCOPY	2.88
2QRV	X-RAY DIFFRACTION	2.89
4U7T	X-RAY DIFFRACTION	2.9
6PA7	ELECTRON MICROSCOPY	2.94
6BRR	X-RAY DIFFRACTION	2.97
6F57	X-RAY DIFFRACTION	3.1
8QZM	ELECTRON MICROSCOPY	3.1
9MPP	ELECTRON MICROSCOPY	3.1
9E2Q	ELECTRON MICROSCOPY	3.14
8TE3	X-RAY DIFFRACTION	3.2
8U5H	ELECTRON MICROSCOPY	3.23
8TDR	X-RAY DIFFRACTION	3.32
9LQ1	ELECTRON MICROSCOPY	3.36
9Q7U	ELECTRON MICROSCOPY	3.4
9E0F	ELECTRON MICROSCOPY	3.46

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6K1-F1	73.97	0.51

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): 710

Ligand- & substrate-binding residues (4): 641–645; 664; 686–688; 891–893

Post-translational modifications (11): 105, 124, 171, 243, 255, 261, 267, 390, 393, 710, 162

Mutagenesis-validated functional residues (1):

Position	Phenotype
732	loss of activity due to the incapacity to bind the regulatory subunit dnmt3l.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-212300	PRC2 methylates histones and DNA
R-HSA-3214858	RMTs methylate histone arginines
R-HSA-4655427	SUMOylation of DNA methylation proteins
R-HSA-5334118	DNA methylation
R-HSA-9710421	Defective pyroptosis
R-HSA-9845323	Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)

MSigDB gene sets: 632 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, RRAGTTGT_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, GOBP_RESPONSE_TO_IONIZING_RADIATION, HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_DN, GOBP_RESPONSE_TO_ESTRADIOL, GOBP_RESPONSE_TO_COCAINE, GOBP_RESPONSE_TO_ACID_CHEMICAL, GCANCTGNY_MYOD_Q6, SP3_Q3, KEGG_CYSTEINE_AND_METHIONINE_METABOLISM, AREB6_03, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP

GO Biological Process (32): negative regulation of transcription by RNA polymerase II (GO:0000122), DNA methylation-dependent constitutive heterochromatin formation (GO:0006346), spermatogenesis (GO:0007283), response to xenobiotic stimulus (GO:0009410), response to toxic substance (GO:0009636), post-embryonic development (GO:0009791), response to ionizing radiation (GO:0010212), response to lead ion (GO:0010288), neuron differentiation (GO:0030182), regulatory ncRNA-mediated heterochromatin formation (GO:0031048), methylation (GO:0032259), response to estradiol (GO:0032355), response to vitamin A (GO:0033189), response to cocaine (GO:0042220), negative regulation of gene expression via chromosomal CpG island methylation (GO:0044027), negative regulation of DNA-templated transcription (GO:0045892), oocyte development (GO:0048599), cellular response to amino acid stimulus (GO:0071230), cellular response to ethanol (GO:0071361), cellular response to hypoxia (GO:0071456), hepatocyte apoptotic process (GO:0097284), autosome genomic imprinting (GO:0141068), transposable element silencing by piRNA-mediated DNA methylation (GO:0141196), positive regulation of cellular response to hypoxia (GO:1900039), cellular response to bisphenol A (GO:1903926), chromatin organization (GO:0006325), regulation of gene expression (GO:0010468), heterochromatin formation (GO:0031507), response to nutrient levels (GO:0031667), epigenetic programming of gene expression (GO:0043045), response to ethanol (GO:0045471), genomic imprinting (GO:0071514)

GO Molecular Function (15): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA binding (GO:0003677), chromatin binding (GO:0003682), transcription corepressor activity (GO:0003714), DNA (cytosine-5-)-methyltransferase activity (GO:0003886), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), unmethylated CpG binding (GO:0045322), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), lncRNA binding (GO:0106222), protein-cysteine methyltransferase activity (GO:0106363), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (10): chromosome, centromeric region (GO:0000775), euchromatin (GO:0000791), heterochromatin (GO:0000792), XY body (GO:0001741), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear matrix (GO:0016363), catalytic complex (GO:1902494), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Epigenetic regulation of gene expression	2
Chromatin modifying enzymes	1
SUMO E3 ligases SUMOylate target proteins	1
Diseases of programmed cell death	1
Regulation of endogenous retroelements	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
negative regulation of DNA-templated transcription	2
response to chemical	2
response to lipid	2
response to oxygen-containing compound	2
binding	2
S-adenosylmethionine-dependent methyltransferase activity	2
chromatin	2
nuclear lumen	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
constitutive heterochromatin formation	1
developmental process involved in reproduction	1
male gamete generation	1
multicellular organism development	1
multicellular organismal process	1
response to radiation	1
response to metal ion	1
cell differentiation	1
generation of neurons	1
regulatory ncRNA-mediated gene silencing	1
heterochromatin formation	1
metabolic process	1
response to vitamin	1
response to alkaloid	1
negative regulation of gene expression, epigenetic	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
germ cell development	1
oocyte differentiation	1
response to amino acid	1
cellular response to acid chemical	1
response to ethanol	1
cellular response to alcohol	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

4442 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNMT3A	EZH2	Q15910	998
DNMT3A	SUV39H1	O43463	995
DNMT3A	DNMT1	P26358	995
DNMT3A	SETDB1	Q15047	995
DNMT3A	HDAC1	Q13547	994
DNMT3A	EHMT2	Q96KQ7	991
DNMT3A	H3C1	P02295	990
DNMT3A	H3-3A	P06351	988
DNMT3A	H3-5	Q6NXT2	988
DNMT3A	H3-4	Q16695	987
DNMT3A	H3-7	Q5TEC6	987
DNMT3A	H3C14	Q71DI3	987
DNMT3A	DNMT3L	Q9UJW3	984
DNMT3A	MYC	P01106	983
DNMT3A	HDAC2	Q92769	969

IntAct

120 interactions, top by confidence:

A	B	Type	Score
TCL1A	DNMT3A	psi-mi:“MI:0915”(physical association)	0.830
DNMT3A	TCL1A	psi-mi:“MI:0915”(physical association)	0.830
EZH2	DNMT3B	psi-mi:“MI:0914”(association)	0.830
UHRF1	DNMT1	psi-mi:“MI:0915”(physical association)	0.700
EZH2	DNMT1	psi-mi:“MI:0914”(association)	0.690
DNMT3A	EZH2	psi-mi:“MI:0915”(physical association)	0.680
EZH2	DNMT3A	psi-mi:“MI:0915”(physical association)	0.680
DNMT3A		psi-mi:“MI:0407”(direct interaction)	0.660
DNMT3A		psi-mi:“MI:0915”(physical association)	0.660
DNMT3A	DNMT3L	psi-mi:“MI:0407”(direct interaction)	0.650
DNMT3A	DNMT3B	psi-mi:“MI:0915”(physical association)	0.640
COMMD6	VPS26C	psi-mi:“MI:0914”(association)	0.640
DNMT3A	H3-3A	psi-mi:“MI:0407”(direct interaction)	0.620
H3-3A	DNMT3A	psi-mi:“MI:0407”(direct interaction)	0.620

BioGRID (209): SP100 (Two-hybrid), TCL1A (Two-hybrid), DNMT3A (Reconstituted Complex), DNMT3A (Proximity Label-MS), DNMT3A (Proximity Label-MS), DNMT3A (Affinity Capture-MS), DNMT3A (Co-localization), DNMT3B (Affinity Capture-MS), DNMT3A (Affinity Capture-RNA), DNMT3A (Protein-peptide), DNMT3A (Reconstituted Complex), MYC (Reconstituted Complex), DNMT3A (Reconstituted Complex), MYC (Affinity Capture-Western), DNMT3A (Affinity Capture-Western)

ESM2 similar proteins: A0A8I6G705, A1L3K1, B5DFF2, B5DFI8, G3MWR8, O19048, O19137, O88508, P06730, P29338, P57721, P57722, P60335, Q12800, Q13888, Q15365, Q15366, Q16763, Q1LZ53, Q1RML1, Q28D01, Q2TBV5, Q4W5Z4, Q5E9A3, Q5FVR7, Q5NVP9, Q5TDH0, Q61990, Q6AYU1, Q6DH13, Q6P1K8, Q6ZRY4, Q7RTP6, Q8C6G8, Q8CCI5, Q8CJ19, Q8IY57, Q8N488, Q8VC52, Q921J4

Diamond homologs: A0A1L8GR68, E9Q9M8, F7AQ22, O88508, Q1LZ53, Q4W5Z4, Q69Z61, Q6NUJ5, Q96N64, Q9FNE4, Q9UBC3, Q9Y6K1, A8JR92, B1AYB6, Q3TY92, Q96DN6, Q9P267, O88509, Q923W4, Q9JMG7, Q9Y3E1, P00476, P09915, P0DOY1, P34906, Q10SU5, Q1LZ50, Q2RBJ4, Q9CWR8, Q9LXE5, Q9M548, Q9UJW3, O30868, O33481, O52702, P05102, P05302, P06530, P08455, P09389

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
STAT5A	“up-regulates quantity”	DNMT3A	“transcriptional regulation”
DNMT3A	up-regulates	Differentiation
MYC	“up-regulates activity”	DNMT3A	binding
DNMT3A	“down-regulates quantity by repression”	TIMP2	“transcriptional regulation”
DNMT3A	“down-regulates quantity by repression”	CCND1	“transcriptional regulation”
DNMT3A	“down-regulates quantity by repression”	CDKN2A	“transcriptional regulation”
WT1	“up-regulates quantity by expression”	DNMT3A	“transcriptional regulation”
DNMT3A	“down-regulates quantity by repression”	MEIS1	“transcriptional regulation”
DNMT3A	“down-regulates quantity by repression”	HOXA9	“transcriptional regulation”
DNMT3A	“down-regulates quantity by repression”	CDKN2C	“transcriptional regulation”
DNMT3A	“down-regulates quantity by repression”	CDKN2B	“transcriptional regulation”
DNMT3A	“down-regulates quantity by repression”	CDKN2D	“transcriptional regulation”
DNMT3A	“down-regulates quantity by repression”	FGF21	“transcriptional regulation”
PLK1	“down-regulates activity”	DNMT3A	phosphorylation
DNMT3A	“form complex”	DNMT1/DNMT3A	binding
DNMT3A	“down-regulates quantity by repression”	DPP6	“transcriptional regulation”
miR-29b	“down-regulates quantity by repression”	DNMT3A	“post transcriptional regulation”
MECOM	“up-regulates activity”	DNMT3A	binding
CSNK2A1	“down-regulates activity”	DNMT3A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
DNA methylation	7	48.0×	3e-08
Defective pyroptosis	7	42.1×	3e-08
PRC2 methylates histones and DNA	7	41.0×	3e-08
Negative Regulation of CDH1 Gene Transcription	6	27.7×	6e-06
Regulation of endogenous retroelements by KRAB-ZFP proteins	6	24.6×	1e-05
NoRC negatively regulates rRNA expression	6	24.2×	1e-05
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	5	22.6×	1e-04
Oxidative Stress Induced Senescence	6	20.9×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
DNA methylation-dependent constitutive heterochromatin formation	5	77.7×	2e-06
heterochromatin formation	5	36.5×	3e-05
methylation	5	24.3×	1e-04

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

DNMT3A is one of several epigenetic modifiers identified as recurrently mutated in acute myeloid leukemia (AML). DNMT3A mutations are associated with cytogenetically normal AML. In vitro experiments indicate that the R882H mutation acts in a dominant negative manner to disrupt the de novo methyltransferase activity of wildtype homotetramers. AML patient bone marrow harboring R882 mutations were similarly demonstrated to be hypomethylated compared to patients with wildtype DNMT3A. These studies also indicated that non-R882 DNMT3A mutations may act in a functionally distinct manner from R882 mutations. Alternative mechanisms indicate independent prognostic outcomes and treatment protocols may need to be considered for these two classes of DNMT3A mutations.

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 9 cancer types — AML, BRCA, CCRCC, HCC, LGGNOS, MDS, PCM, PRCC, WDTC.

Clinical variants and AI predictions

ClinVar

1318 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	125
Likely pathogenic	80
Uncertain significance	486
Likely benign	495
Benign	27

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027657	NM_022552.5(DNMT3A):c.427C>T (p.Arg143Ter)	Pathogenic
1098397	NM_022552.5(DNMT3A):c.1299del (p.Glu434fs)	Pathogenic
1173066	NM_022552.5(DNMT3A):c.1757G>T (p.Cys586Phe)	Pathogenic
1183858	NM_022552.5(DNMT3A):c.176dup (p.Val60fs)	Pathogenic
1194481	NM_022552.5(DNMT3A):c.2207G>A (p.Arg736His)	Pathogenic
1298794	NM_022552.5(DNMT3A):c.1346del (p.Ala449fs)	Pathogenic
1320067	NM_022552.5(DNMT3A):c.1555-1G>A	Pathogenic
1330229	NM_022552.5(DNMT3A):c.2322+1G>A	Pathogenic
1332907	NM_022552.5(DNMT3A):c.1647C>A (p.Cys549Ter)	Pathogenic
1342607	NM_022552.5(DNMT3A):c.1791del (p.Arg598fs)	Pathogenic
139615	NM_022552.5(DNMT3A):c.889_891del (p.Trp297del)	Pathogenic
139616	NM_022552.5(DNMT3A):c.1943T>C (p.Leu648Pro)	Pathogenic
139617	NM_022552.5(DNMT3A):c.929T>A (p.Ile310Asn)	Pathogenic
139618	NM_022552.5(DNMT3A):c.1643T>A (p.Met548Lys)	Pathogenic
139619	NM_022552.5(DNMT3A):c.2705T>C (p.Phe902Ser)	Pathogenic
1459355	NC_000002.11:g.(?25458556)(25458714_?)del	Pathogenic
1486678	NM_022552.5(DNMT3A):c.2678G>A (p.Trp893Ter)	Pathogenic
1699425	NM_022552.5(DNMT3A):c.1243C>T (p.Gln415Ter)	Pathogenic
1701889	NM_022552.5(DNMT3A):c.917G>A (p.Trp306Ter)	Pathogenic
1711493	NM_022552.5(DNMT3A):c.1555-1G>T	Pathogenic
2031023	NM_022552.5(DNMT3A):c.629G>A (p.Trp210Ter)	Pathogenic
2032388	NM_022552.5(DNMT3A):c.1004_1011del (p.Lys335fs)	Pathogenic
2073362	NM_022552.5(DNMT3A):c.1342_1343dup (p.Ala449fs)	Pathogenic
208338	NM_022552.5(DNMT3A):c.1204C>T (p.Gln402Ter)	Pathogenic
208714	NM_022552.5(DNMT3A):c.892G>T (p.Gly298Trp)	Pathogenic
2104480	NM_022552.5(DNMT3A):c.853G>T (p.Glu285Ter)	Pathogenic
2203023	NM_022552.5(DNMT3A):c.2245C>T (p.Arg749Cys)	Pathogenic
2255497	NM_022552.5(DNMT3A):c.1405G>T (p.Glu469Ter)	Pathogenic
2423537	NC_000002.11:g.(?25383950)(25523132_?)del	Pathogenic
2427539	NC_000002.11:g.(?25497790)(25498432_?)del	Pathogenic

SpliceAI

3365 predictions. Top by Δscore:

Variant	Effect	Δscore
2:25235710:T:A	donor_gain	1.0000
2:25235821:CTGAA:C	acceptor_gain	1.0000
2:25235826:C:CC	acceptor_gain	1.0000
2:25236931:CTGA:C	donor_loss	1.0000
2:25236932:TGACC:T	donor_loss	1.0000
2:25236933:GACC:G	donor_loss	1.0000
2:25236934:ACC:A	donor_loss	1.0000
2:25236935:C:CG	donor_loss	1.0000
2:25237002:CGGC:C	acceptor_gain	1.0000
2:25239211:TTGGA:T	acceptor_gain	1.0000
2:25239212:TGGA:T	acceptor_gain	1.0000
2:25239216:C:CC	acceptor_gain	1.0000
2:25240447:CCCT:C	acceptor_gain	1.0000
2:25240448:CCTC:C	acceptor_gain	1.0000
2:25240449:CT:C	acceptor_gain	1.0000
2:25240451:C:CC	acceptor_gain	1.0000
2:25240638:A:AC	donor_gain	1.0000
2:25240639:C:CC	donor_gain	1.0000
2:25241560:A:AC	donor_gain	1.0000
2:25241561:C:CC	donor_gain	1.0000
2:25241561:CATG:C	donor_gain	1.0000
2:25241567:T:TA	donor_gain	1.0000
2:25241715:A:T	acceptor_gain	1.0000
2:25244153:A:AC	donor_gain	1.0000
2:25244154:C:CC	donor_gain	1.0000
2:25244154:CA:C	donor_gain	1.0000
2:25244154:CAA:C	donor_gain	1.0000
2:25244154:CAAA:C	donor_gain	1.0000
2:25244154:CAAAT:C	donor_gain	1.0000
2:25244157:ATT:A	donor_gain	1.0000

AlphaMissense

6009 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:25234304:A:G	L905P	1.000
2:25234316:A:G	L901P	1.000
2:25234322:C:G	R899P	1.000
2:25234325:A:T	I898N	1.000
2:25234328:A:T	V897D	1.000
2:25234336:G:C	S894R	1.000
2:25234336:G:T	S894R	1.000
2:25234338:T:G	S894R	1.000
2:25234339:C:A	W893C	1.000
2:25234339:C:G	W893C	1.000
2:25234340:C:G	W893S	1.000
2:25234341:A:G	W893R	1.000
2:25234341:A:T	W893R	1.000
2:25234344:A:G	S892P	1.000
2:25234346:C:G	R891P	1.000
2:25234349:C:A	G890V	1.000
2:25234349:C:T	G890D	1.000
2:25234350:C:A	G890C	1.000
2:25234350:C:G	G890R	1.000
2:25234352:A:G	L889P	1.000
2:25234352:A:T	L889Q	1.000
2:25234355:A:G	L888P	1.000
2:25234360:C:A	Q886H	1.000
2:25234360:C:G	Q886H	1.000
2:25234361:T:G	Q886P	1.000
2:25234363:C:A	R885S	1.000
2:25234363:C:G	R885S	1.000
2:25234364:C:A	R885M	1.000
2:25234364:C:G	R885T	1.000
2:25234365:T:A	R885W	1.000

dbSNP variants (sampled 300 via entrez): RS1000055673 (2:25307782 C>T), RS1000070953 (2:25325698 G>C), RS1000134744 (2:25301795 A>G), RS1000150351 (2:25333658 G>A,C,T), RS1000170414 (2:25254042 A>G), RS1000237871 (2:25336663 G>A), RS1000284997 (2:25253801 C>G,T), RS1000289067 (2:25259155 C>T), RS1000291100 (2:25332005 G>A,T), RS1000364685 (2:25307515 G>C), RS1000376818 (2:25337547 T>A), RS1000428826 (2:25290007 A>C), RS1000445911 (2:25247241 G>A), RS1000471527 (2:25337333 A>T), RS1000493508 (2:25330841 T>C)

Disease associations

OMIM: gene MIM:602769 | disease phenotypes: MIM:615879, MIM:601626, MIM:618724, MIM:615219, MIM:168000, MIM:254500, MIM:123100

GenCC curated gene-disease

Disease	Classification	Inheritance
Tatton-Brown-Rahman overgrowth syndrome	Definitive	Autosomal dominant
Heyn-Sproul-Jackson syndrome	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Heyn-Sproul-Jackson syndrome	Limited	AD
Tatton-Brown-Rahman overgrowth syndrome	Definitive	AD

Mondo (18): intellectual disability (MONDO:0001071), Tatton-Brown-Rahman overgrowth syndrome (MONDO:0014382), autism spectrum disorder (MONDO:0005258), acute myeloid leukemia (MONDO:0018874), Heyn-Sproul-Jackson syndrome (MONDO:0032882), neurodevelopmental disorder (MONDO:0700092), obesity disorder (MONDO:0011122), specific learning disability (MONDO:0016225), hypoparathyroidism (MONDO:0001220), early T cell progenitor acute lymphoblastic leukemia (MONDO:0100291), melanoma (MONDO:0005105), hydrocephalus, nonsyndromic, autosomal recessive 2 (MONDO:0014085), congenital nervous system disorder (MONDO:0002320), hereditary pheochromocytoma-paraganglioma (MONDO:0017366), glioblastoma (MONDO:0018177)

Orphanet (17): Tatton-Brown-Rahman syndrome (Orphanet:404443), Acute myeloid leukemia (Orphanet:519), DNMT3A-related microcephalic dwarfism (Orphanet:658595), Specific learning disability (Orphanet:211047), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Congenital hydrocephalus (Orphanet:2185), Hereditary pheochromocytoma-paraganglioma (Orphanet:29072), Glioblastoma (Orphanet:360), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443), Craniosynostosis (Orphanet:1531), Diffuse large B-cell lymphoma (Orphanet:544), Rare genetic intellectual disability (Orphanet:183757), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

117 total (30 of 117 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000076	Vesicoureteral reflux
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000098	Tall stature
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000405	Conductive hearing impairment
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000574	Thick eyebrow
HP:0000581	Blepharophimosis
HP:0000609	Optic nerve hypoplasia
HP:0000708	Atypical behavior
HP:0000718	Aggressive behavior
HP:0000739	Anxiety
HP:0000740	Episodic paroxysmal anxiety
HP:0000750	Delayed speech and language development
HP:0000790	Hematuria
HP:0000878	11 pairs of ribs
HP:0000980	Pallor
HP:0001069	Episodic hyperhidrosis

GWAS associations

81 associations (top):

Study	Trait	p-value
GCST000175_18	Height	8.000000e-07
GCST000879_17	Crohn’s disease	9.000000e-10
GCST001255_1	Type 1 diabetes	4.000000e-09
GCST002647_19	Height	2.000000e-37
GCST002702_113	Height	4.000000e-11
GCST004063_22	Waist circumference adjusted for body mass index	2.000000e-09
GCST004063_47	Waist circumference adjusted for body mass index	2.000000e-07
GCST004063_7	Waist circumference adjusted for body mass index	6.000000e-14
GCST004131_107	Inflammatory bowel disease	3.000000e-07
GCST004132_38	Crohn’s disease	9.000000e-08
GCST004500_140	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	3.000000e-10
GCST004500_15	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	2.000000e-08
GCST004501_20	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	1.000000e-11
GCST004501_21	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	2.000000e-10
GCST004503_14	Waist circumference adjusted for BMI in smokers	4.000000e-06
GCST004503_3	Waist circumference adjusted for BMI in smokers	2.000000e-07
GCST004504_39	Waist circumference adjusted for BMI in non-smokers	7.000000e-08
GCST004562_12	Waist circumference adjusted for body mass index	9.000000e-08
GCST004562_195	Waist circumference adjusted for body mass index	9.000000e-06
GCST004562_213	Waist circumference adjusted for body mass index	3.000000e-06
GCST004562_260	Waist circumference adjusted for body mass index	2.000000e-10
GCST004562_84	Waist circumference adjusted for body mass index	2.000000e-11
GCST004563_149	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	2.000000e-07
GCST004563_221	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	2.000000e-10
GCST004563_43	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	2.000000e-06
GCST004563_61	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	2.000000e-10
GCST004564_156	Waist circumference adjusted for BMI in active individuals	6.000000e-06
GCST004564_157	Waist circumference adjusted for BMI in active individuals	3.000000e-09
GCST004564_158	Waist circumference adjusted for BMI in active individuals	1.000000e-06
GCST004564_159	Waist circumference adjusted for BMI in active individuals	2.000000e-09

EFO canonical traits (16, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009270	heel bone mineral density
EFO:1002006	treatment-resistant hypertension
EFO:0009819	comparative body size at age 10, self-reported
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004980	appendicular lean mass
EFO:0007986	reticulocyte count

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D005909	Glioblastoma	C04.557.465.625.600.380.080.335; C04.557.470.670.380.080.335; C04.557.580.625.600.380.080.335
D007011	Hypoparathyroidism	C19.642.482
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D015470	Leukemia, Myeloid, Acute	C04.557.337.539.275; C15.378.508.539.275
D016403	Lymphoma, Large B-Cell, Diffuse	C04.557.386.480.150.585; C15.604.515.569.480.150.585; C20.683.515.761.480.150.585
D008545	Melanoma	C04.557.465.625.650.510; C04.557.580.625.650.510; C04.557.665.510; C04.588.805.377; C17.800.882.445
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D065886	Neurodevelopmental Disorders	F03.625
D000067559	Specific Learning Disorder	C10.597.606.150.550.700; C23.888.592.604.150.550.700; F03.625.374.188.700; F03.625.562.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1992 (SINGLE PROTEIN), CHEMBL3137291 (PROTEIN COMPLEX)

Clinical evidence (CIViC)

Drug × variant × indication: 4 predictive associations from 4 curated evidence items; also 24 prognostic, 6 diagnostic.

Variant	Therapy	Indication	Effect	Level	CIViC
DNMT3A Mutation	Decitabine	Acute Myeloid Leukemia	Sensitivity/Response	CIViC B	EID1587
DNMT3A R882	Idarubicin	Acute Myeloid Leukemia	Sensitivity/Response	CIViC B	EID18
DNMT3A Mutation	Atezolizumab + Nivolumab + Pembrolizumab	Cancer	Resistance	CIViC B	EID2926
DNMT3A R882	Daunorubicin	Acute Myeloid Leukemia	Resistance	CIViC B	EID11

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2304429	Dosage	3	warfarin	Heart valve replacement

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2304429	DNMT3A	3	2.25	1	warfarin

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 2.1.1.- Methyltransferases

Binding affinities (BindingDB)

65 measured of 81 human assays (82 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
4-[5-[(Z)-[3-(4-nitrophenyl)-4-oxidanylidene-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl]benzoic acid	IC50	216 nM
4-[[2-bromanyl-4-[(E)-2-cyano-2-(3-fluorophenyl)ethenyl]phenoxy]methyl]benzoic acid	IC50	400 nM
2-[2-chloranyl-6-ethoxy-4-[(E)-[2-(naphthalen-2-ylamino)-4-oxidanylidene-1,3-thiazol-5-ylidene]methyl]phenoxy]ethanoic acid	IC50	440 nM
2-[4-[(E)-[[4-[2-(4-chloroanilino)-1,3-thiazol-4-yl]benzoyl]hydrazinylidene]methyl]phenoxy]acetic acid	IC50	924 nM
3-[(5E)-5-[[4-[(4-chlorophenyl)methoxy]-3-methoxyphenyl]methylidene]-4-oxo-2-sulfanylidene-3-thiazolidinyl]benzoic acid	IC50	953 nM
2-[4-[(Z)-[2-(4-fluoroanilino)-4-keto-2-thiazolin-5-ylidene]methyl]phenoxy]acetic acid methyl ester	IC50	1050 nM
2-[2-chloranyl-6-methoxy-4-[(Z)-[3-[2-[(4-methylphenyl)amino]-2-oxidanylidene-ethyl]-2,4-bis(oxidanylidene)-1,3-thiazolidin-5-ylidene]methyl]phenoxy]ethanoic acid	IC50	1180 nM
2-[2,6-bis(chloranyl)-4-[(Z)-[3-[2-[(4-methylphenyl)amino]-2-oxidanylidene-ethyl]-2,4-bis(oxidanylidene)-1,3-thiazolidin-5-ylidene]methyl]phenoxy]ethanoic acid	IC50	1200 nM
3-[(5E)-5-[1-(2-chlorobenzyl)-2-keto-indolin-3-ylidene]-4-keto-2-thioxo-thiazolidin-3-yl]propionic acid	IC50	1230 nM
4-[3-[(5Z)-4-keto-2-thioxo-5-veratrylidene-thiazolidin-3-yl]propanoylamino]benzoic acid	IC50	1270 nM
cid_9595040	IC50	1490 nM
2-hydroxy-4-({4-[5-(2-methyl-3-phenyl-2-propen-1-ylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]butanoyl}amino)benzoic acid	IC50	1560 nM
4-keto-5-methyl-2-[(E)-2-(4-methyl-3-nitro-phenyl)vinyl]-3H-thieno[2,3-d]pyrimidine-6-carboxylic acid	IC50	1620 nM
MLS-0336006.0001	IC50	1830 nM
3-[[(E)-3-[4-[(4-chlorophenyl)methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]benzoic acid	IC50	2600 nM
MLS-0335096.0001	IC50	2690 nM
3-[[4-[(E)-[3-(3-carboxyphenyl)-4-oxidanylidene-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl]-2-chloranyl-6-methoxy-phenoxy]methyl]benzoic acid	IC50	2810 nM
4-({4-[5-(2-methyl-3-phenyl-2-propen-1-ylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]butanoyl}amino)benzoic acid	EC50	2980 nM
2-[2-chloranyl-4-[(Z)-[2-[(4-ethylphenyl)amino]-4-oxidanylidene-1,3-thiazol-5-ylidene]methyl]phenoxy]ethanoic acid	IC50	3100 nM
2-[4-[[6-carbethoxy-3-keto-7-methyl-5-[4-(methylthio)phenyl]-5H-thiazolo[3,2-a]pyrimidin-2-ylidene]methyl]phenoxy]acetic acid	IC50	3140 nM
2-[4-[[5-(4-chlorophenyl)-6-ethoxycarbonyl-7-methyl-3-oxidanylidene-5H-[1,3]thiazolo[3,2-a]pyrimidin-2-ylidene]methyl]phenoxy]ethanoic acid	IC50	3200 nM
2-[2-bromanyl-4-[(Z)-[2-[(4-ethylphenyl)amino]-4-oxidanylidene-1,3-thiazol-5-ylidene]methyl]-6-methoxy-phenoxy]ethanoic acid	IC50	3620 nM
2-[4-[[6-ethoxycarbonyl-7-methyl-3-oxo-5-(4-propan-2-yloxyphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-2-ylidene]methyl]phenoxy]acetic acid	IC50	3850 nM
2-[2-chloranyl-6-methoxy-4-[(Z)-[3-[2-[(3-methylphenyl)amino]-2-oxidanylidene-ethyl]-2,4-bis(oxidanylidene)-1,3-thiazolidin-5-ylidene]methyl]phenoxy]ethanoic acid	IC50	3960 nM
2-[4-[(Z)-[2-(4-ethylanilino)-4-keto-2-thiazolin-5-ylidene]methyl]phenoxy]acetic acid	IC50	4060 nM
MLS-0313409.0001	IC50	4130 nM
2-[2-ethoxy-6-iodanyl-4-[(E)-(4-oxidanylidene-2-phenylazanyl-1,3-thiazol-5-ylidene)methyl]phenoxy]ethanoic acid	IC50	4840 nM
MLS001172658	IC50	5400 nM
3-[[(E)-3-[4-(4-chlorobenzyl)oxyphenyl]-2-cyano-acryloyl]amino]benzoic acid	IC50	7080 nM
2-[4-[(E)-[2-(3-bromoanilino)-4-keto-2-thiazolin-5-ylidene]methyl]-2-methoxy-phenoxy]acetic acid	IC50	7470 nM
2-[2-chloro-4-[(Z)-[2,4-diketo-3-[2-keto-2-(p-toluidino)ethyl]thiazolidin-5-ylidene]methyl]-6-ethoxy-phenoxy]acetic acid methyl ester	IC50	7510 nM
SMR000646238	IC50	9280 nM
2-[2-chloro-6-ethoxy-4-[(E)-[2-(4-fluoroanilino)-4-keto-2-thiazolin-5-ylidene]methyl]phenoxy]acetic acid ethyl ester	IC50	9980 nM
2-[4-[[5-(4-chlorophenyl)-6-isopropoxycarbonyl-3-keto-7-methyl-5H-thiazolo[3,2-a]pyrimidin-2-ylidene]methyl]phenoxy]acetic acid	IC50	12300 nM
2-[2,6-bis(chloranyl)-4-[(Z)-[6-ethoxycarbonyl-5-(3-methoxyphenyl)-7-methyl-3-oxidanylidene-5H-[1,3]thiazolo[3,2-a]pyrimidin-2-ylidene]methyl]phenoxy]ethanoic acid	IC50	13400 nM
4-[8-[(3-chloranyl-2-methyl-phenyl)sulfamoyl]-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl]benzoic acid	IC50	14200 nM
2-[2-chloranyl-4-[(E)-[5-(2-chlorophenyl)-6-ethoxycarbonyl-7-methyl-3-oxidanylidene-5H-[1,3]thiazolo[3,2-a]pyrimidin-2-ylidene]methyl]-6-methoxy-phenoxy]ethanoic acid	IC50	15100 nM
4-[[1-oxo-4-[(5E)-4-oxo-5-(phenylmethylene)-2-sulfanylidene-3-thiazolidinyl]butyl]amino]benzoic acid	IC50	15800 nM
MLS001034563	IC50	15900 nM
2-chloranyl-5-[5-[(Z)-[3-[(4-methoxyphenyl)methyl]-4-oxidanylidene-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl]furan-2-yl]benzoic acid	IC50	16400 nM
4-[4-[(5Z)-5-benzylidene-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoylamino]-2-hydroxybenzoic acid	IC50	17200 nM
3-[4-[(5Z)-5-[(3,4-dimethoxyphenyl)methylidene]-4-oxidanylidene-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoylamino]benzoic acid	IC50	17700 nM
3-[4-(5-Benzylidene-4-oxo-2-thioxo-thiazolidin-3-yl)-butyrylamino]-benzoic acid	IC50	23700 nM
4-[(E)-[3-(carboxymethyl)-4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene]methyl]benzoic acid	IC50	24500 nM
4-[(E)-2-[3-bromanyl-4-[(4-fluorophenyl)methoxy]phenyl]-1-cyano-ethenyl]benzoic acid	IC50	25100 nM
4-[4-[(5Z)-5-[(3,4-dimethoxyphenyl)methylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoylamino]-2-hydroxybenzoic acid	IC50	26200 nM
4-[[4-[(Z)-2-cyano-2-(4-fluorophenyl)ethenyl]-2-methoxy-phenoxy]methyl]benzoic acid	IC50	27300 nM
4-[4-[(5Z)-5-[(3-methoxyphenyl)methylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoylamino]benzoic acid	IC50	32300 nM
4-[[2-chloranyl-4-[(E)-2-cyano-2-(3-fluorophenyl)ethenyl]-6-ethoxy-phenoxy]methyl]benzoic acid	IC50	33100 nM
cid_4289057	IC50	33500 nM

ChEMBL bioactivities

69 potent at pChembl≥5 of 104 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.04	IC50	92	nM	CHEMBL4208004
6.52	EC50	300	nM	CHEMBL4091463
6.52	IC50	300	nM	CHEMBL4091463
6.41	IC50	390	nM	CHEMBL5425605
6.30	IC50	500	nM	Dichlon
6.16	IC50	700	nM	CHEMBL5415008
6.12	IC50	750	nM	CHEMBL5414585
6.10	IC50	800	nM	CHEMBL5285340
6.05	EC50	900	nM	CHEMBL2336409
6.05	IC50	900	nM	CHEMBL2336409
6.05	IC50	900	nM	CHEMBL5276042
6.03	IC50	930	nM	CHEMBL4878570
6.03	IC50	930	nM	CHEMBL5575739
6.00	EC50	1000	nM	CHEMBL4070517
5.96	EC50	1100	nM	CHEMBL4099197
5.92	EC50	1200	nM	CHEMBL4097685
5.89	IC50	1300	nM	CHEMBL5428173
5.85	EC50	1400	nM	CHEMBL4076088
5.85	IC50	1400	nM	CHEMBL115145
5.80	EC50	1600	nM	CHEMBL4527662
5.80	IC50	1600	nM	CHEMBL6102079
5.76	IC50	1720	nM	CHEMBL2336409
5.75	IC50	1800	nM	CHEMBL5404240
5.75	IC50	1800	nM	CHEMBL4856110
5.72	EC50	1900	nM	CHEMBL4070549
5.72	IC50	1900	nM	CHEMBL2336409
5.68	EC50	2100	nM	CHEMBL3605964
5.68	EC50	2100	nM	CHEMBL4096869
5.62	EC50	2400	nM	CHEMBL4442279
5.55	IC50	2800	nM	CHEMBL3126646
5.55	IC50	2800	nM	CHEMBL6175814
5.52	EC50	3000	nM	CHEMBL3605935
5.50	IC50	3200	nM	CHEMBL6102871
5.50	IC50	3130	nM	CHEMBL6176773
5.47	EC50	3400	nM	CHEMBL4096752
5.43	Ki	3700	nM	CHEMBL2171452
5.40	EC50	4000	nM	CHEMBL3605951
5.40	Kd	4000	nM	CHEMBL6146761
5.40	IC50	4000	nM	CHEMBL6175523
5.36	EC50	4400	nM	CHEMBL4096360
5.34	EC50	4600	nM	CHEMBL4469152
5.32	EC50	4800	nM	CHEMBL4470149
5.31	EC50	4900	nM	CHEMBL4084601
5.30	Ki	5030	nM	CHEMBL2171452
5.29	EC50	5100	nM	CHEMBL4470318
5.28	EC50	5200	nM	CHEMBL4461581
5.27	EC50	5400	nM	CHEMBL4526979
5.27	EC50	5400	nM	CHEMBL4582042
5.27	EC50	5400	nM	CHEMBL4574840
5.22	IC50	6000	nM	CHEMBL4171551

PubChem BioAssay actives

53 with measured affinity, of 446 total; 45 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
N-naphthalen-1-yl-N’-[7-[[1-[2-(quinolin-4-ylamino)ethyl]piperidin-4-yl]methoxy]quinazolin-4-yl]ethane-1,2-diamine	1447857: Inhibition of human DNMT3A catalytic domain using AdoMet assessed as reduction of methylation in 5’-biotin/3’ 6-carboxyfluorescein labeled DNA duplex at CpG site after 1 hr by fluorescence assay	ec50	0.3000	uM
6-methyl-4-oxo-3-(2-pyrrolidin-1-ylethyl)-N-(6-sulfamoyl-3-pyridinyl)furo[2,3-d]pyrimidine-5-carboxamide	1999930: Inhibition of N-terminal His-tagged human DNMT3A (623 to 912 residues)/N-terminal GST-tagged human DNMT3L (160 to 387 residues) co-expressed in baculovirus infected Sf9 cells assessed as DNA methylation using DNA oligonucleotide IDT-01 as substrate preincubated for 15 mins followed by substrate addition in presence of [3H]-SAM and measured after 4 hrs by radioactive methylation assay	ic50	0.3900	uM
2,3-dichloronaphthalene-1,4-dione	1199272: Inhibition of His6-tagged human recombinant DNMT3A/DNMT3L expressed in insect Sf9 cells assessed as reduction in DNA methyltransferase activity using 5’-biotinylated 45-bp unmethylated or hemimethylated oligonucleotide substrates and [3H]-AdoMet by liquid scintillation counting method	ic50	0.5000	uM
6-methyl-4-oxo-3-(2-piperidin-1-ylethyl)-N-(6-sulfamoyl-3-pyridinyl)furo[2,3-d]pyrimidine-5-carboxamide	1999930: Inhibition of N-terminal His-tagged human DNMT3A (623 to 912 residues)/N-terminal GST-tagged human DNMT3L (160 to 387 residues) co-expressed in baculovirus infected Sf9 cells assessed as DNA methylation using DNA oligonucleotide IDT-01 as substrate preincubated for 15 mins followed by substrate addition in presence of [3H]-SAM and measured after 4 hrs by radioactive methylation assay	ic50	0.7000	uM
3-[2-(dimethylamino)ethyl]-6-methyl-4-oxo-N-(6-sulfamoyl-3-pyridinyl)furo[2,3-d]pyrimidine-5-carboxamide	1999930: Inhibition of N-terminal His-tagged human DNMT3A (623 to 912 residues)/N-terminal GST-tagged human DNMT3L (160 to 387 residues) co-expressed in baculovirus infected Sf9 cells assessed as DNA methylation using DNA oligonucleotide IDT-01 as substrate preincubated for 15 mins followed by substrate addition in presence of [3H]-SAM and measured after 4 hrs by radioactive methylation assay	ic50	0.7500	uM
3-(quinolin-4-ylamino)-N-[4-(quinolin-4-ylamino)phenyl]benzamide	1938423: Inhibition of C-terminal biotin-labelled human DNMT3A by multilabel plate reader analysis	ic50	0.8000	uM
N-[4-[(2-amino-6-methylpyrimidin-4-yl)amino]phenyl]-4-(quinolin-4-ylamino)benzamide	1240593: Inhibition of human C-terminal DNMT3A after 1 hr by fluorescence assay	ec50	0.9000	uM
4-(pyridin-4-ylamino)-N-[4-(quinolin-4-ylamino)phenyl]benzamide	1938414: Inhibition of DNMT3A (unknown origin)	ic50	0.9000	uM
1-[3-[1,3-di(carbazol-9-yl)propan-2-yloxy]-2-hydroxypropyl]-N-hydroxypiperidine-4-carboxamide	1760316: Inhibition of DNMT3A (unknown origin) using biotinylated DNA oligonucleotides as substrate in presence of [3H-SAM] preincubated for 15 mins followed by substrate and [3H-SAM] addition and measured after 4 hrs by liquid scintillation counting method	ic50	0.9300	uM
1-[(2R)-3-[1,3-di(carbazol-9-yl)propan-2-yloxy]-2-hydroxypropyl]-N-hydroxypiperidine-4-carboxamide	2092352: Inhibition of DNMT3A/DNMT3L (unknown origin)	ic50	0.9300	uM
N-[2-(3-chlorophenyl)ethyl]-7-[[1-[2-(quinolin-4-ylamino)ethyl]piperidin-4-yl]methoxy]quinazolin-4-amine	1447857: Inhibition of human DNMT3A catalytic domain using AdoMet assessed as reduction of methylation in 5’-biotin/3’ 6-carboxyfluorescein labeled DNA duplex at CpG site after 1 hr by fluorescence assay	ec50	1.0000	uM
N-[(4-phenylphenyl)methyl]-7-[[1-[2-(quinolin-4-ylamino)ethyl]piperidin-4-yl]methoxy]quinazolin-4-amine	1447857: Inhibition of human DNMT3A catalytic domain using AdoMet assessed as reduction of methylation in 5’-biotin/3’ 6-carboxyfluorescein labeled DNA duplex at CpG site after 1 hr by fluorescence assay	ec50	1.1000	uM
N-[2-(4-chlorophenyl)ethyl]-7-[[1-[2-(quinolin-4-ylamino)ethyl]piperidin-4-yl]methoxy]quinazolin-4-amine	1447857: Inhibition of human DNMT3A catalytic domain using AdoMet assessed as reduction of methylation in 5’-biotin/3’ 6-carboxyfluorescein labeled DNA duplex at CpG site after 1 hr by fluorescence assay	ec50	1.2000	uM
6-methyl-4-oxo-3-(3-piperidin-1-ylpropyl)-N-(6-sulfamoyl-3-pyridinyl)furo[2,3-d]pyrimidine-5-carboxamide	1999930: Inhibition of N-terminal His-tagged human DNMT3A (623 to 912 residues)/N-terminal GST-tagged human DNMT3L (160 to 387 residues) co-expressed in baculovirus infected Sf9 cells assessed as DNA methylation using DNA oligonucleotide IDT-01 as substrate preincubated for 15 mins followed by substrate addition in presence of [3H]-SAM and measured after 4 hrs by radioactive methylation assay	ic50	1.3000	uM
7-[[1-[2-[(6,7-dimethoxyquinolin-4-yl)amino]ethyl]piperidin-4-yl]methoxy]-N-(3-phenylpropyl)quinazolin-4-amine	1447857: Inhibition of human DNMT3A catalytic domain using AdoMet assessed as reduction of methylation in 5’-biotin/3’ 6-carboxyfluorescein labeled DNA duplex at CpG site after 1 hr by fluorescence assay	ec50	1.4000	uM
5-[(3-carboxy-4-hydroxyphenyl)methyl]-2-hydroxybenzoic acid	1624429: Inhibition of DNMT3A/3L (unknown origin) using poly(2’-deoxyinosinic-2’-deoxycytidylic acid) as substrate after 1 hr by scintillation proximity assay	ic50	1.4000	uM
N-(1-benzylpiperidin-4-yl)-6-methoxy-7-phenylmethoxy-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine	1530559: Inhibition of recombinant human DNMT3a C-terminal catalytic domain (623 to 908 residues) using 5’-biotinylated/3’-FAM-oligonucleotide as substrate measured after 1 hr in presence of Adomet by fluorescence assay	ec50	1.6000	uM
2-[4-[[[6,7-dimethoxy-2-(5-methylfuran-2-yl)quinolin-4-yl]amino]methyl]piperidin-1-yl]-N-hydroxypyrimidine-5-carboxamide	2127255: Inhibition of DNMT3A (unknown origin)	ic50	1.8000	uM
6-methyl-4-oxo-3-(3-pyrrolidin-1-ylpropyl)-N-(6-sulfamoyl-3-pyridinyl)furo[2,3-d]pyrimidine-5-carboxamide	1999930: Inhibition of N-terminal His-tagged human DNMT3A (623 to 912 residues)/N-terminal GST-tagged human DNMT3L (160 to 387 residues) co-expressed in baculovirus infected Sf9 cells assessed as DNA methylation using DNA oligonucleotide IDT-01 as substrate preincubated for 15 mins followed by substrate addition in presence of [3H]-SAM and measured after 4 hrs by radioactive methylation assay	ic50	1.8000	uM
N-(3-naphthalen-1-ylpropyl)-7-[[1-[2-(quinolin-4-ylamino)ethyl]piperidin-4-yl]methoxy]quinazolin-4-amine	1447857: Inhibition of human DNMT3A catalytic domain using AdoMet assessed as reduction of methylation in 5’-biotin/3’ 6-carboxyfluorescein labeled DNA duplex at CpG site after 1 hr by fluorescence assay	ec50	1.9000	uM
2-(6-aminopurin-7-yl)-1-(4-chlorophenyl)-3-ethoxypropan-1-one	1240593: Inhibition of human C-terminal DNMT3A after 1 hr by fluorescence assay	ec50	2.1000	uM
7-[[1-[2-[(2-methylquinolin-4-yl)amino]ethyl]piperidin-4-yl]methoxy]-N-(3-phenylpropyl)quinazolin-4-amine	1447857: Inhibition of human DNMT3A catalytic domain using AdoMet assessed as reduction of methylation in 5’-biotin/3’ 6-carboxyfluorescein labeled DNA duplex at CpG site after 1 hr by fluorescence assay	ec50	2.1000	uM
N-[1-(naphthalen-2-ylmethyl)piperidin-4-yl]-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine	1530559: Inhibition of recombinant human DNMT3a C-terminal catalytic domain (623 to 908 residues) using 5’-biotinylated/3’-FAM-oligonucleotide as substrate measured after 1 hr in presence of Adomet by fluorescence assay	ec50	2.4000	uM
N-[3-[(2-amino-6-methylpyrimidin-4-yl)amino]phenyl]-3-(quinolin-4-ylamino)benzamide	1073769: Inhibition of human DNMT3A2/3L using unmethylated DNA as substrate in presence of [methyl-3H]-AdoMet	ic50	2.8000	uM
2-(benzimidazol-1-yl)-1-(4-chlorophenyl)-3-ethylsulfanylpropan-1-one	1240593: Inhibition of human C-terminal DNMT3A after 1 hr by fluorescence assay	ec50	3.0000	uM
N-[2-(4-methoxyphenyl)ethyl]-7-[[1-[2-(quinolin-4-ylamino)ethyl]piperidin-4-yl]methoxy]quinazolin-4-amine	1447857: Inhibition of human DNMT3A catalytic domain using AdoMet assessed as reduction of methylation in 5’-biotin/3’ 6-carboxyfluorescein labeled DNA duplex at CpG site after 1 hr by fluorescence assay	ec50	3.4000	uM
2-cycloheptyl-5-[4-methoxy-3-[4-[4-(2H-tetrazol-5-yl)phenoxy]butoxy]phenyl]-4,4-dimethylpyrazol-3-one	1757492: Mixed type inhibition of human DNMT3A using AdoMet as substrate	ki	3.7000	uM
2-(benzimidazol-1-yl)-1-(4-chlorophenyl)prop-2-en-1-one	1240593: Inhibition of human C-terminal DNMT3A after 1 hr by fluorescence assay	ec50	4.0000	uM
N-(3-phenylpropyl)-7-[[1-[2-(quinolin-4-ylamino)ethyl]piperidin-4-yl]methoxy]quinazolin-4-amine	1447857: Inhibition of human DNMT3A catalytic domain using AdoMet assessed as reduction of methylation in 5’-biotin/3’ 6-carboxyfluorescein labeled DNA duplex at CpG site after 1 hr by fluorescence assay	ec50	4.4000	uM
N-(1-benzylpiperidin-4-yl)-7-methoxy-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine	1530559: Inhibition of recombinant human DNMT3a C-terminal catalytic domain (623 to 908 residues) using 5’-biotinylated/3’-FAM-oligonucleotide as substrate measured after 1 hr in presence of Adomet by fluorescence assay	ec50	4.6000	uM
2-N-[(4-fluorophenyl)methyl]-4-N-[1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl]quinazoline-2,4-diamine	1530559: Inhibition of recombinant human DNMT3a C-terminal catalytic domain (623 to 908 residues) using 5’-biotinylated/3’-FAM-oligonucleotide as substrate measured after 1 hr in presence of Adomet by fluorescence assay	ec50	4.8000	uM
N-(2-phenylethyl)-7-[[1-[2-(quinolin-4-ylamino)ethyl]piperidin-4-yl]methoxy]quinazolin-4-amine	1447857: Inhibition of human DNMT3A catalytic domain using AdoMet assessed as reduction of methylation in 5’-biotin/3’ 6-carboxyfluorescein labeled DNA duplex at CpG site after 1 hr by fluorescence assay	ec50	4.9000	uM
2-(4-phenylpiperazin-1-yl)-N-[1-(3-phenylpropyl)piperidin-4-yl]quinazolin-4-amine	1530559: Inhibition of recombinant human DNMT3a C-terminal catalytic domain (623 to 908 residues) using 5’-biotinylated/3’-FAM-oligonucleotide as substrate measured after 1 hr in presence of Adomet by fluorescence assay	ec50	5.1000	uM
2-N-[(4-fluorophenyl)methyl]-6,7-dimethoxy-4-N-[1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl]quinazoline-2,4-diamine	1530559: Inhibition of recombinant human DNMT3a C-terminal catalytic domain (623 to 908 residues) using 5’-biotinylated/3’-FAM-oligonucleotide as substrate measured after 1 hr in presence of Adomet by fluorescence assay	ec50	5.2000	uM
N-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine	1530559: Inhibition of recombinant human DNMT3a C-terminal catalytic domain (623 to 908 residues) using 5’-biotinylated/3’-FAM-oligonucleotide as substrate measured after 1 hr in presence of Adomet by fluorescence assay	ec50	5.4000	uM
N-[1-(2-phenylethyl)piperidin-4-yl]-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine	1530559: Inhibition of recombinant human DNMT3a C-terminal catalytic domain (623 to 908 residues) using 5’-biotinylated/3’-FAM-oligonucleotide as substrate measured after 1 hr in presence of Adomet by fluorescence assay	ec50	5.4000	uM
N-(1-benzylpiperidin-4-yl)-6-methoxy-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine	1530559: Inhibition of recombinant human DNMT3a C-terminal catalytic domain (623 to 908 residues) using 5’-biotinylated/3’-FAM-oligonucleotide as substrate measured after 1 hr in presence of Adomet by fluorescence assay	ec50	5.4000	uM
(4E,5’R,6R,7S,8R,10R,11R,12S,14S,15R,16S,18E,20E,28R,29S)-22-ethyl-7,11,14,15-tetrahydroxy-6’-[(2S)-2-hydroxypropyl]-5’,6,8,10,12,14,16,28,29-nonamethylspiro[2,26-dioxabicyclo[23.3.1]nonacosa-4,18,20-triene-27,2’-oxane]-3,9,13-trione	1664321: Binding affinity to DNMT3A catalytic domain (unknown origin) assessed as inhibition of enzyme-mediated DNA methylation preincubated for 1 hr followed by enzyme addition measured after 1 hr in presence of AdoMet by PAGE analysis	ic50	6.0000	uM
4-[(1-benzylpiperidin-4-yl)amino]-6-methoxy-2-(4-phenylpiperazin-1-yl)quinazolin-7-ol	1530559: Inhibition of recombinant human DNMT3a C-terminal catalytic domain (623 to 908 residues) using 5’-biotinylated/3’-FAM-oligonucleotide as substrate measured after 1 hr in presence of Adomet by fluorescence assay	ec50	6.2000	uM
N-phenyl-N’-[7-[[1-[2-(quinolin-4-ylamino)ethyl]piperidin-4-yl]methoxy]quinazolin-4-yl]ethane-1,2-diamine	1447857: Inhibition of human DNMT3A catalytic domain using AdoMet assessed as reduction of methylation in 5’-biotin/3’ 6-carboxyfluorescein labeled DNA duplex at CpG site after 1 hr by fluorescence assay	ec50	6.8000	uM
(2S,5S)-2-amino-5-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl]-7-(3-carbamoylphenyl)hept-6-ynoic acid	1616798: Inhibition of human DNMT3a expressed in insect sf9 cells assessed as reduction in methylated poly(dI-dC)-Poly(dI-dC) level using poly(dI-dC)-poly(dI-dC) as substrate in presence of [3H] SAM incubated for 10 mins by scintillation counting	ic50	7.6000	uM
tert-butyl 4-[[2-[(4-fluorophenyl)methylamino]-6,7-dimethoxyquinazolin-4-yl]amino]piperidine-1-carboxylate	1530559: Inhibition of recombinant human DNMT3a C-terminal catalytic domain (623 to 908 residues) using 5’-biotinylated/3’-FAM-oligonucleotide as substrate measured after 1 hr in presence of Adomet by fluorescence assay	ec50	8.7000	uM
(4aS,8aR)-2-cycloheptyl-4-[3-[5-[4-(2H-tetrazol-5-yl)phenoxy]pentoxy]phenyl]-4a,5,8,8a-tetrahydrophthalazin-1-one	2144548: Inhibition of DNMT3A (unknown origin) using [3H]-SAM as substrate incubated for 1 hr by scintillation counter analysis	ic50	9.0000	uM
(4aS,8aR)-2-cycloheptyl-4-[4-methoxy-3-[4-[4-(2H-tetrazol-5-yl)phenoxy]butoxy]phenyl]-4a,5,8,8a-tetrahydrophthalazin-1-one	1757494: Uncompetitive inhibition of human DNMT3A using AdoMet as substrate	ki	9.1600	uM
(4aS,8aR)-2-cycloheptyl-4-[3-[4-[4-(2H-tetrazol-5-yl)phenoxy]butoxy]phenyl]-4a,5,8,8a-tetrahydrophthalazin-1-one	2144548: Inhibition of DNMT3A (unknown origin) using [3H]-SAM as substrate incubated for 1 hr by scintillation counter analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, decreases reaction, increases expression, affects expression, decreases expression	13
Decitabine	decreases expression, affects reaction, decreases reaction, increases expression, affects binding	10
Arsenic Trioxide	increases methylation, decreases reaction, decreases activity, decreases expression, increases expression	10
bisphenol A	affects cotreatment, decreases expression, increases methylation, increases expression, decreases abundance (+2 more)	6
hydroquinone	affects expression, decreases expression, increases expression	4
Cadmium Chloride	increases activity, increases expression, affects cotreatment, decreases expression, increases methylation (+1 more)	4
perfluorooctanoic acid	affects cotreatment, increases expression, decreases expression	3
bisphenol S	increases expression, decreases methylation, decreases abundance, increases reaction, decreases expression (+1 more)	3
Resveratrol	affects cotreatment, decreases expression, affects binding, decreases reaction, increases reaction	3
Benzo(a)pyrene	increases methylation, affects methylation, increases expression	3
epigallocatechin gallate	affects expression, decreases reaction, increases expression	2
Fulvestrant	increases methylation, decreases reaction, increases expression, affects cotreatment	2
Glyphosate	increases expression	2
Arsenic	affects response to substance, increases abundance, increases expression	2
Estradiol	decreases expression, decreases reaction, increases expression	2
Hydrogen Peroxide	increases expression	2
Tretinoin	decreases expression	2
Valproic Acid	affects expression, increases expression	2
Aflatoxin B1	increases methylation	2
FR900359	increases phosphorylation	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	decreases expression	1
TAK-243	affects sumoylation	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	increases expression	1
deoxynivalenol	decreases expression	1
withaferin A	decreases expression	1
salinomycin	decreases expression	1
decabromobiphenyl ether	affects cotreatment, decreases expression	1
5-hydroxymethylcytosine	decreases abundance, increases reaction	1
difenacoum	affects binding	1

ChEMBL screening assays

120 unique, capped per target: 118 binding, 1 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1070346	Binding	Binding affinity to DNMT3a in human PC3 cells cytoplasm at 5 uM after 6 hrs by antibody staining	Fluorescent epigenetic small molecule induces expression of the tumor suppressor ras-association domain family 1A and inhibits human prostate xenograft. — J Med Chem
CHEMBL4416348	ADMET	Inhibition of human DNMT3a expressed in insect sf9 cells assessed as reduction in methylated poly(dI-dC)-Poly(dI-dC) level using poly(dI-dC)-poly(dI-dC) as substrate in presence of [3H] SAM incubated for 10 mins by scintillation counting	High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). — J Med Chem
CHEMBL5723123	Functional	Affinity Biochemical interaction: (TR-FRET) EUB0002211a DNMT3A	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

19 cell lines: 14 cancer cell line, 5 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_1294	HT-55	Cancer cell line	Female
CVCL_1321	KO52	Cancer cell line	Male
CVCL_1844	OCI-AML-3	Cancer cell line	Male
CVCL_2187	SET-2	Cancer cell line	Female
CVCL_5227	OCI-AML3/HaABCG2 clone 6.2	Cancer cell line	Male
CVCL_B1QB	Abcam HeLa DNMT3A KO	Cancer cell line	Female
CVCL_D6C9	HyCyte OCI-AML3 KO-hFGL2	Cancer cell line	Male
CVCL_D6NF	OCI-AML3DNR	Cancer cell line	Male
CVCL_D6NG	OCI-AML3/HaABCG2 clone 3.3	Cancer cell line	Male
CVCL_E0BU	Ubigene HeLa DNMT3A KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)