DNMT3L

Summary

DNMT3L (DNA methyltransferase 3 like, HGNC:2980) is a protein-coding gene on chromosome 21q22.3, encoding DNA (cytosine-5)-methyltransferase 3-like (Q9UJW3). Catalytically inactive regulatory factor of DNA methyltransferases that can either promote or inhibit DNA methylation depending on the context.

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 nuclear protein with similarity to DNA methyltransferases, but is not thought to function as a DNA methyltransferase as it does not contain the amino acid residues necessary for methyltransferase activity. However, it does stimulate de novo methylation by DNA cytosine methyltransferase 3 alpha and is thought to be required for the establishment of maternal genomic imprints. This protein also mediates transcriptional repression through interaction with histone deacetylase 1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 29947 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 86 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_175867

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2980
Approved symbol	DNMT3L
Name	DNA methyltransferase 3 like
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC1090
Ensembl gene	ENSG00000142182
Ensembl biotype	protein_coding
OMIM	606588
Entrez	29947

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000270172, ENST00000431166, ENST00000436357, ENST00000628202

RefSeq mRNA: 2 — MANE Select: NM_175867 NM_013369, NM_175867

CCDS: CCDS13705, CCDS46650

Canonical transcript exons

ENST00000628202 — 12 exons

Exon	Start	End
ENSE00000952757	44261154	44261266
ENSE00000952758	44260795	44260839
ENSE00000952759	44259632	44259711
ENSE00000952760	44259437	44259549
ENSE00000952766	44249026	44249111
ENSE00001286863	44258523	44258694
ENSE00001291091	44251623	44251698
ENSE00001297260	44256067	44256154
ENSE00001311957	44254617	44254705
ENSE00003767744	44246339	44246562
ENSE00003768543	44261740	44261897
ENSE00003790618	44250810	44250949

Expression profiles

Bgee: expression breadth broad, 77 present calls, max score 84.68.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7925 / max 527.2078, expressed in 66 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190740	0.4636	38
190738	0.2331	36
190741	0.0475	9
190739	0.0330	8
190742	0.0152	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.68	gold quality
liver	UBERON:0002107	73.68	gold quality
right lobe of liver	UBERON:0001114	70.23	gold quality
adult mammalian kidney	UBERON:0000082	69.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	62.37	gold quality
kidney	UBERON:0002113	62.30	gold quality
lower esophagus mucosa	UBERON:0035834	59.68	gold quality
lymph node	UBERON:0000029	53.43	gold quality
cortex of kidney	UBERON:0001225	49.34	gold quality
granulocyte	CL:0000094	44.95	silver quality
tonsil	UBERON:0002372	43.98	gold quality
mucosa of transverse colon	UBERON:0004991	41.83	silver quality
colonic epithelium	UBERON:0000397	41.70	gold quality
bone marrow cell	CL:0002092	41.43	gold quality
blood	UBERON:0000178	41.11	gold quality
metanephros cortex	UBERON:0010533	41.10	gold quality
endocervix	UBERON:0000458	39.80	gold quality
bone marrow	UBERON:0002371	39.78	gold quality
spleen	UBERON:0002106	39.76	gold quality
duodenum	UBERON:0002114	38.97	gold quality
vermiform appendix	UBERON:0001154	37.75	gold quality
uterine cervix	UBERON:0000002	37.61	gold quality
skeletal muscle tissue	UBERON:0001134	37.04	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
corpus callosum	UBERON:0002336	36.20	gold quality
small intestine	UBERON:0002108	35.99	gold quality
small intestine Peyer’s patch	UBERON:0003454	35.97	gold quality
ectocervix	UBERON:0012249	35.62	silver quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
primary visual cortex	UBERON:0002436	35.46	silver quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10018	yes	1757.79
E-GEOD-36552	yes	1330.45
E-ANND-3	no	1.13

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
DNMT3A
DNMT3B
DNMT3L
TDG	Repression

Upstream regulators (CollecTRI, top): DNMT3A, DNMT3B, DNMT3L, WT1

Literature-anchored findings (GeneRIF, showing 32)

• DNMT3L stimulates de novo methylation by Dnmt3a. (PMID:12481029)
• The carboxyl-terminal half of DNMT3L was found to be responsible for the stimulation of the DNA methylation activity of Dnmt3a and Dnmt3b. (PMID:15105426)
• Regulates germ cell-specific gene expression and intracisternal A-particle suppression, which are critical for male germ cell proliferation and meiosis. (PMID:16211598)
• Dnmt3L-Dnmt3b interactions play an important role in the regulation of DNA methylation during mammalian development. (PMID:16543361)
• The acquisition of DNMT3L by a common ancestor of eutherians and marsupials might have been closely related to the evolution of imprinting. (PMID:16575165)
• Data show that binding of DNMT3L to DNMT3A2 promotes reorganization of DNMT3A2 subunits and leads to formation of specific complexes with enhanced DNA methyltransferase activity and increased S-adenosyl-L-methionine binding. (PMID:16829525)
• Crystallographic studies of human DNMT3L showed that the protein has a carboxy-terminal methyltransferase-like domain and an N-terminal cysteine-rich domain (PMID:17687327)
• the carboxy-terminal domain of human Dnmt3L interacts with the catalytic domain of Dnmt3a, demonstrating that Dnmt3L has dual functions of binding the unmethylated histone tail and activating DNA methyltransferase (PMID:17713477)
• Importance of DNA methylation profile at DNMT3L promoter not only as a promising biomarker for cervical cancer but also provides insight into the possible role of DNMT3L in cancer development. (PMID:17965599)
• DNMT3L(R271Q) is impaired in its ability to stimulate de novo DNA methylation by DNMT3A. (PMID:19246518)
• Overexpression of DNMT3L, which functions by regulating the activity of DNMT3A and DNMT3B, increased cellular proliferation and anchorage-independent growth. (PMID:19625766)
• CG dinucleotide recognized by the Dnmt3a and Dnmt3L complex are distinctive at retroelements and imprinted domains. (PMID:19921333)
• DNMT3L exerts a major effect on the transcriptional regulation of a specific target gene, such as thymine DNA glycosylase (PMID:20428781)
• DNMT3L is a novel marker and is essential for the growth of human embryonal carcinoma. (PMID:20460473)
• Processive methylation is enhanced 3-fold in the presence of DNMT3L, an inactive homolog of DNMT3A, therefore providing a mechanism for the previously described DNMT3L activation of DNMT3A. (PMID:20630873)
• We have identified loss of methylation at the DNMT3L promoter in ocular surface squamous neoplasia cases. (PMID:20670142)
• This study offers insights into the manner by which DNA methylation patterns are deposited and reveals a new level of interplay between members of the de novo DNMT family. (PMID:20838592)
• mutation analysis of SYCP3, DNMT3L and MSH4 in patients with maturation arrest of spermatogenesis and couples with recurrent miscarriages. (PMID:21126912)
• SNP rs2070565, as well as haplotypes AAA and GAA, may be associated with male infertility; DNMT3L may contribute to azoospermia susceptibility in humans (PMID:22116073)
• Genetic polymorphisms of DNMT3L involved in hypermethylation of chromosomal ends are associated with greater risk of developing ovarian endometriosis. (PMID:22401780)
• DNMT3L is one of the key players in de novo DNA methylation of imprinting control elements and retrotransposons, which occurs after genome-wide epigenetic erasure during germ cell development. (Review) (PMID:22671959)
• CpG island encompassing the promoter and first exon of human DNMT3L gene is a PcG/TrX response element (PMID:24743422)
• DNMT3L rs2070565 (genotype P = 0.007, allele P = 0.0026) confers an increased risk of developing schizophrenia at an early age in individuals with family history. (PMID:24859147)
• DNMT3L can address DNMT3A/B to specific sites by directly interacting with TFs that do not directly interact with DNMT3A/B (PMID:24952347)
• crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 A resolution, respectively (PMID:25383530)
• the present study has demonstrated that variations in the DNMT3L gene do not contribute to stage I-II endometriosis-associated infertility. (PMID:26647998)
• DNMT3L overexpression is associated with Down syndrome. (PMID:26911678)
• Nutrition and its DNA methylation influence cognitive decline. (PMID:30877840)
• EGR1 interacts with DNMT3L to inhibit the transcription of miR-195 and plays an anti-apoptotic role in the development of gastric cancer. (PMID:31515938)
• Decoding the Genetic Alterations in Genes of DNMT Family (DNA Methyl-Transferase) and their Association with Head and Neck Squamous Cell Carcinoma. (PMID:33369458)
• Stable DNMT3L overexpression in SH-SY5Y neurons recreates a facet of the genome-wide Down syndrome DNA methylation signature. (PMID:33750431)
• DNMT3L inhibits hepatocellular carcinoma progression through DNA methylation of CDO1: insights from big data to basic research. (PMID:38308276)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnmt3ba	ENSDARG00000052402
danio_rerio	dnmt3bb.2	ENSDARG00000057830
danio_rerio	dnmt3bb.3	ENSDARG00000057863
mus_musculus	Dnmt3l	ENSMUSG00000000730
rattus_norvegicus	Dnmt3l	ENSRNOG00000001212

Paralogs (4): DNMT3B (ENSG00000088305), DNMT3A (ENSG00000119772), PWWP2A (ENSG00000170234), PWWP2B (ENSG00000171813)

Protein

Protein identifiers

DNA (cytosine-5)-methyltransferase 3-like — Q9UJW3 (reviewed: Q9UJW3)

All UniProt accessions (2): Q9UJW3, C9J0T5

UniProt curated annotations — full annotation on UniProt →

Function. Catalytically inactive regulatory factor of DNA methyltransferases that can either promote or inhibit DNA methylation depending on the context. Essential for the function of DNMT3A and DNMT3B: activates DNMT3A and DNMT3B by binding to their catalytic domain. Acts by accelerating the binding of DNA and S-adenosyl-L-methionine (AdoMet) to the methyltransferases and dissociates from the complex after DNA binding to the methyltransferases. Recognizes unmethylated histone H3 lysine 4 (H3K4me0) and induces de novo DNA methylation by recruitment or activation of DNMT3. Plays a key role in embryonic stem cells and germ cells. In germ cells, required for the methylation of imprinted loci together with DNMT3A. In male germ cells, specifically required to methylate retrotransposons, preventing their mobilization. Plays a key role in embryonic stem cells (ESCs) by acting both as an positive and negative regulator of DNA methylation. While it promotes DNA methylation of housekeeping genes together with DNMT3A and DNMT3B, it also acts as an inhibitor of DNA methylation at the promoter of bivalent genes. Interacts with the EZH2 component of the PRC2/EED-EZH2 complex, preventing interaction of DNMT3A and DNMT3B with the PRC2/EED-EZH2 complex, leading to maintain low methylation levels at the promoters of bivalent genes. Promotes differentiation of ESCs into primordial germ cells by inhibiting DNA methylation at the promoter of RHOX5, thereby activating its expression.

Subunit / interactions. Homodimer. Heterotetramer composed of 1 DNMT3A homodimer and 2 DNMT3L subunits (DNMT3L-DNMT3A-DNMT3A-DNMT3L). Interacts with histone H3 (via N-terminus); interaction is strongly inhibited by methylation at lysine 4 (H3K4me). Interacts with EZH2; the interaction is direct. Interacts with SPOCD1.

Subcellular location. Nucleus.

Tissue specificity. Expressed at low levels in several tissues including testis, ovary, and thymus.

Miscellaneous. Interaction with histone H3 is strongly inhibited by methylation at lysine 4 (H3K4me).

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UJW3-1	1	yes
Q9UJW3-2	2

RefSeq proteins (2): NP_037501, NP_787063* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR025766	ADD	Domain
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR040552	DNMT3_ADD_GATA1-like	Domain
IPR049554	DNMT3_ADD_PHD	Domain
IPR050390	C5-Methyltransferase	Family

Pfam: PF17980, PF21255

UniProt features (42 total): helix 16, strand 11, turn 6, zinc finger region 2, sequence conflict 2, chain 1, domain 1, splice variant 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

29 structures.

PDB	Method	Resolution (Å)
6W8B	X-RAY DIFFRACTION	2.4
6W8J	X-RAY DIFFRACTION	2.44
6W89	X-RAY DIFFRACTION	2.5
6W8D	X-RAY DIFFRACTION	2.6
5YX2	X-RAY DIFFRACTION	2.65
6KDB	X-RAY DIFFRACTION	2.86
6KDT	X-RAY DIFFRACTION	2.87
2QRV	X-RAY DIFFRACTION	2.89
4U7T	X-RAY DIFFRACTION	2.9
6KDA	X-RAY DIFFRACTION	2.91
6KDP	X-RAY DIFFRACTION	2.93
6U8W	X-RAY DIFFRACTION	2.95
6U8X	X-RAY DIFFRACTION	2.95
6BRR	X-RAY DIFFRACTION	2.97
6U91	X-RAY DIFFRACTION	3
6U8V	X-RAY DIFFRACTION	3
6U90	X-RAY DIFFRACTION	3
8XEE	X-RAY DIFFRACTION	3.03
6U8P	X-RAY DIFFRACTION	3.05
7X9D	X-RAY DIFFRACTION	3.08
6F57	X-RAY DIFFRACTION	3.1
9MPP	ELECTRON MICROSCOPY	3.1
8TCI	X-RAY DIFFRACTION	3.19
6KDL	X-RAY DIFFRACTION	3.27
2PV0	X-RAY DIFFRACTION	3.3
9MP0	ELECTRON MICROSCOPY	3.66
9PRW	ELECTRON MICROSCOPY	3.66
2PVC	X-RAY DIFFRACTION	3.69
4U7P	X-RAY DIFFRACTION	3.82

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UJW3-F1	87.47	0.70

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
261	loss of binding to dnmt3a.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5334118	DNA methylation
R-HSA-9845323	Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)

MSigDB gene sets: 113 (showing top): KEGG_CYSTEINE_AND_METHIONINE_METABOLISM, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_MALE_GAMETE_GENERATION, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_DNA_METHYLATION_DEPENDENT_CONSTITUTIVE_HETEROCHROMATIN_FORMATION, GOBP_ORGANELLE_FISSION, GOBP_MALE_MEIOSIS_I, GOBP_GENOMIC_IMPRINTING, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_REGULATION_OF_CHROMATIN_ORGANIZATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_MEIOTIC_CELL_CYCLE_PROCESS

GO Biological Process (21): placenta development (GO:0001890), DNA methylation-dependent constitutive heterochromatin formation (GO:0006346), male meiosis I (GO:0007141), spermatogenesis (GO:0007283), post-embryonic development (GO:0009791), methylation (GO:0032259), negative regulation of gene expression via chromosomal CpG island methylation (GO:0044027), epigenetic programing of female pronucleus (GO:0044726), negative regulation of gene expression, epigenetic (GO:0045814), negative regulation of DNA-templated transcription (GO:0045892), oocyte development (GO:0048599), stem cell differentiation (GO:0048863), chorionic trophoblast cell differentiation (GO:0060718), genomic imprinting (GO:0071514), negative regulation of DNA methylation-dependent heterochromatin formation (GO:0090310), transposable element silencing by heterochromatin formation (GO:0141005), autosome genomic imprinting (GO:0141068), transposable element silencing by piRNA-mediated DNA methylation (GO:0141196), regulation of gene expression (GO:0010468), negative regulation of macromolecule biosynthetic process (GO:0010558), cell differentiation (GO:0030154)

GO Molecular Function (5): enzyme activator activity (GO:0008047), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): heterochromatin (GO:0000792), condensed nuclear chromosome (GO:0000794), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), ESC/E(Z) complex (GO:0035098), catalytic complex (GO:1902494)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Epigenetic regulation of gene expression	1
Regulation of endogenous retroelements	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
constitutive heterochromatin formation	2
male gamete generation	2
germ cell development	2
cell differentiation	2
regulation of macromolecule biosynthetic process	2
cellular anatomical structure	2
animal organ development	1
meiosis I	1
male meiotic nuclear division	1
meiotic cell cycle	1
developmental process involved in reproduction	1
multicellular organism development	1
multicellular organismal process	1
metabolic process	1
negative regulation of gene expression, epigenetic	1
epigenetic programming in the zygotic pronuclei	1
negative regulation of gene expression	1
epigenetic regulation of gene expression	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
oocyte differentiation	1
chorion development	1
epigenetic programming of gene expression	1
DNA methylation-dependent constitutive heterochromatin formation	1
negative regulation of heterochromatin formation	1
transposable element silencing	1
genomic imprinting	1
transposable element silencing by heterochromatin formation	1
gene silencing by piRNA-directed DNA methylation	1
gene expression	1
macromolecule biosynthetic process	1
negative regulation of biosynthetic process	1
negative regulation of macromolecule metabolic process	1
catalytic activity	1
enzyme regulator activity	1
molecular function activator activity	1
transition metal ion binding	1
protein binding	1
binding	1

Protein interactions and networks

STRING

1450 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNMT3L	H3-3A	P06351	994
DNMT3L	H3C1	P02295	994
DNMT3L	H3-4	Q16695	994
DNMT3L	H3-7	Q5TEC6	994
DNMT3L	H3-5	Q6NXT2	994
DNMT3L	H3C14	Q71DI3	994
DNMT3L	DNMT3A	Q9Y6K1	984
DNMT3L	DNMT3B	Q9UBC3	984
DNMT3L	HDAC1	Q13547	980
DNMT3L	ATRX	P46100	978
DNMT3L	DNMT1	P26358	920
DNMT3L	TRDMT1	O14717	907
DNMT3L	TET2	Q6N021	880
DNMT3L	EZH2	Q15910	829
DNMT3L	UHRF1	Q96T88	784

IntAct

21 interactions, top by confidence:

A	B	Type	Score
RSL24D1	DNMT3L	psi-mi:“MI:0915”(physical association)	0.780
DNMT3L	RSL24D1	psi-mi:“MI:0915”(physical association)	0.780
PDZD4	DNMT3L	psi-mi:“MI:0915”(physical association)	0.560
DNMT3L	HDAC1	psi-mi:“MI:0407”(direct interaction)	0.540
DNMT3L	HDAC1	psi-mi:“MI:0915”(physical association)	0.540
DNMT3L	H3-3A	psi-mi:“MI:0407”(direct interaction)	0.440
Dnmt3a	DNMT3L	psi-mi:“MI:0213”(methylation reaction)	0.440
DNMT3A	DNMT3L	psi-mi:“MI:0915”(physical association)	0.370
DNMT3L	GSK3B	psi-mi:“MI:0915”(physical association)	0.370
NUDT21	DNMT3L	psi-mi:“MI:0915”(physical association)	0.370
PHPT1	DNMT3L	psi-mi:“MI:0915”(physical association)	0.370
PDZD4	DNMT3L	psi-mi:“MI:0915”(physical association)	0.000
RSL24D1	DNMT3L	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (118): RSL24D1 (Two-hybrid), DNMT3L (Two-hybrid), RSL24D1 (Two-hybrid), ETS1 (Reconstituted Complex), RELA (Reconstituted Complex), PAX6 (Reconstituted Complex), ESR1 (Reconstituted Complex), ESR2 (Reconstituted Complex), EGR4 (Reconstituted Complex), EGR2 (Reconstituted Complex), EGR1 (Reconstituted Complex), E2F6 (Reconstituted Complex), E2F4 (Reconstituted Complex), E2F3 (Reconstituted Complex), NFKB1 (Reconstituted Complex)

ESM2 similar proteins: A0A0R4IMY7, A0A0R4IY06, A0JPF9, A2AP18, A5PJN5, C0IN03, D2KX21, E1BVR9, E9PYK3, F1ND48, O00534, O75038, O94952, O95237, P0C1Q3, P53817, Q1LWG4, Q1LZ50, Q32PY6, Q4R3W5, Q4R6L3, Q5M7X9, Q5R5S1, Q5RJG7, Q5S6T3, Q5T8I9, Q6DC39, Q75WE7, Q7Z5M8, Q7ZU92, Q8BYI6, Q8C0L6, Q8CAE2, Q8CAS9, Q8K3R3, Q8NHH9, Q8SPR7, Q8VDH1, Q90678, Q93V51

Diamond homologs: A0A1L8GR68, E9Q9M8, F7AQ22, O88508, O88509, P00476, P09915, P0DOY1, P34906, Q10SU5, Q1LZ50, Q1LZ53, Q2RBJ4, Q4W5Z4, Q69Z61, Q6NUJ5, Q96N64, Q9CWR8, Q9LXE5, Q9M548, Q9UBC3, Q9UJW3, Q9Y6K1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	66
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
145468	GRCh38/hg38 21p11.2-q22.3(chr21:7749532-46664250)x3	Pathogenic

SpliceAI

2170 predictions. Top by Δscore:

Variant	Effect	Δscore
21:44249027:T:TA	donor_gain	1.0000
21:44250805:CGCA:C	donor_loss	1.0000
21:44250806:GCAC:G	donor_loss	1.0000
21:44250808:ACCT:A	donor_gain	1.0000
21:44250809:C:CT	donor_loss	1.0000
21:44250809:CCTC:C	donor_gain	1.0000
21:44250811:T:TA	donor_gain	1.0000
21:44250841:T:TA	donor_gain	1.0000
21:44250945:CCAGC:C	acceptor_gain	1.0000
21:44250946:CAGCC:C	acceptor_gain	1.0000
21:44251621:A:AC	donor_gain	1.0000
21:44251622:C:CA	donor_gain	1.0000
21:44251622:C:CC	donor_gain	1.0000
21:44251698:CCTG:C	acceptor_loss	1.0000
21:44251699:C:CA	acceptor_loss	1.0000
21:44251700:T:C	acceptor_loss	1.0000
21:44254615:ACAT:A	donor_gain	1.0000
21:44254616:CATC:C	donor_gain	1.0000
21:44256063:TCAC:T	donor_loss	1.0000
21:44256064:CAC:C	donor_loss	1.0000
21:44256065:ACC:A	donor_loss	1.0000
21:44256066:C:T	donor_loss	1.0000
21:44256152:CTC:C	acceptor_gain	1.0000
21:44256154:CCT:C	acceptor_loss	1.0000
21:44256162:T:TC	acceptor_gain	1.0000
21:44258517:CCTTA:C	donor_loss	1.0000
21:44258518:CTTA:C	donor_loss	1.0000
21:44258519:TTA:T	donor_loss	1.0000
21:44258520:T:TG	donor_loss	1.0000
21:44258521:A:AC	donor_gain	1.0000

AlphaMissense

2520 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:44249046:G:C	S325R	0.996
21:44249046:G:T	S325R	0.996
21:44249048:T:G	S325R	0.996
21:44258615:A:G	C142R	0.992
21:44259660:A:G	F68S	0.992
21:44259704:G:C	C53W	0.992
21:44259493:G:C	C96W	0.991
21:44259669:T:C	H65R	0.991
21:44258613:G:C	C142W	0.990
21:44258685:G:C	C118W	0.990
21:44254687:A:G	F208S	0.989
21:44258619:C:A	W140C	0.989
21:44258619:C:G	W140C	0.989
21:44259659:A:C	F68L	0.989
21:44259659:A:T	F68L	0.989
21:44259661:A:G	F68L	0.989
21:44259668:G:C	H65Q	0.989
21:44259668:G:T	H65Q	0.989
21:44259706:A:G	C53R	0.989
21:44258690:A:C	Y117D	0.988
21:44258614:C:G	C142S	0.987
21:44258614:C:T	C142Y	0.987
21:44258615:A:T	C142S	0.987
21:44259442:G:C	C113W	0.987
21:44259458:C:T	C108Y	0.987
21:44259495:A:G	C96R	0.987
21:44258621:A:G	W140R	0.986
21:44258621:A:T	W140R	0.986
21:44259459:A:G	C108R	0.986
21:44259654:C:T	G70E	0.986

dbSNP variants (sampled 300 via entrez): RS1000011395 (21:44263295 C>A,T), RS1000443273 (21:44262977 G>A,C,T), RS1001415641 (21:44261206 A>T), RS1001473371 (21:44263704 G>A,T), RS1001957353 (21:44247870 C>T), RS1002113451 (21:44256066 C>G,T), RS1002253502 (21:44255767 G>A), RS1002487702 (21:44261651 C>T), RS1002750588 (21:44256361 A>G), RS1002781753 (21:44253981 G>A,T), RS1002929450 (21:44253776 G>A), RS1003242866 (21:44254191 C>T), RS1003583597 (21:44259453 T>G), RS1003858063 (21:44261903 G>T), RS1003980934 (21:44263171 A>G)

Disease associations

OMIM: gene MIM:606588 | disease phenotypes: MIM:240300

GenCC curated gene-disease

Mondo (1): autoimmune polyendocrine syndrome type 1 (MONDO:0009411)

Orphanet (1): Autoimmune polyendocrinopathy type 1 (Orphanet:3453)

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3137291 (PROTEIN COMPLEX), CHEMBL3885560 (PROTEIN COMPLEX)

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

ChEMBL bioactivities

12 potent at pChembl≥5 of 19 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.41	IC50	390	nM	CHEMBL5425605
6.30	IC50	500	nM	Dichlon
6.16	IC50	700	nM	CHEMBL5415008
6.12	IC50	750	nM	CHEMBL5414585
6.03	IC50	930	nM	CHEMBL5575739
5.89	IC50	1300	nM	CHEMBL5428173
5.88	IC50	1320	nM	CHEMBL5575739
5.85	IC50	1400	nM	CHEMBL115145
5.75	IC50	1800	nM	CHEMBL5404240
5.72	IC50	1900	nM	CHEMBL2336409
5.55	IC50	2800	nM	CHEMBL3126646
5.00	IC50	1e+04	nM	CHEMBL2336409

PubChem BioAssay actives

12 with measured affinity, of 142 total; 10 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
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
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
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
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
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-[4-[(2-amino-6-methylpyrimidin-4-yl)amino]phenyl]-4-(quinolin-4-ylamino)benzamide	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	1.9000	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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	2
Valproic Acid	affects expression, increases methylation	2
ethyl-p-hydroxybenzoate	decreases expression	1
dimethylselenide	increases expression, increases oxidation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
4-nonylphenol	affects cotreatment, decreases expression, decreases reaction	1
tebuconazole	decreases expression	1
4-tert-octylphenol	affects cotreatment, decreases expression, decreases reaction	1
Wortmannin	affects cotreatment, decreases expression, decreases reaction	1
Arsenic Trioxide	decreases reaction, affects binding	1
Troglitazone	decreases expression	1
Acetaminophen	increases expression	1
Cadmium	decreases expression, increases abundance	1
Endosulfan	increases expression	1
Hydrogen Peroxide	affects expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Ozone	increases expression, increases oxidation	1
Smoke	affects binding, increases reaction, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
Aflatoxin B1	decreases expression	1
Hydroxyl Radical	increases expression, increases oxidation	1
Cadmium Chloride	decreases expression, increases abundance	1
Copper Sulfate	affects expression	1

ChEMBL screening assays

59 unique, capped per target: 59 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3129168	Binding	Inhibition of human DNMT3A2/3L using unmethylated DNA as substrate in presence of [methyl-3H]-AdoMet	Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1A6	SEES3-1V human DNMT3L, clone1	Embryonic stem cell	Male
CVCL_A1A7	SEES3-1V human DNMT3L, clone2	Embryonic stem cell	Male
CVCL_A1A8	SEES3-1V human DNMT3L, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00743782	PHASE2	COMPLETED	Comparing Pump With Subcutaneous Injection Delivery of PTH 1-34 in the Management of Chronic Hypoparathyroidism
NCT05398809	PHASE2	RECRUITING	Evaluate the Efficacy and Safety of Ruxolitinib on Hair Regrowth in Patients With Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED)-Associated Alopecia Areata