NSD2

Summary

NSD2 (nuclear receptor binding SET domain protein 2, HGNC:12766) is a protein-coding gene on chromosome 4p16.3, encoding Histone-lysine N-methyltransferase NSD2 (O96028). Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at ‘Lys-36’ (H3K36me2). It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein that contains four domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain, and a PHD-type zinc finger. It is expressed ubiquitously in early development. Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4. This gene maps to the 165 kb WHS critical region and has also been involved in the chromosomal translocation t(4;14)(p16.3;q32.3) in multiple myelomas. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. Some transcript variants are nonsense-mediated mRNA (NMD) decay candidates, hence not represented as reference sequences.

Source: NCBI Gene 7468 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 730 total — 44 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 170
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 4 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001042424

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12766
Approved symbol	NSD2
Name	nuclear receptor binding SET domain protein 2
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	MMSET, KMT3G
Ensembl gene	ENSG00000109685
Ensembl biotype	protein_coding
OMIM	602952
Entrez	7468

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 29 protein_coding, 6 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay, 5 retained_intron

ENST00000312087, ENST00000353275, ENST00000382888, ENST00000382891, ENST00000382892, ENST00000382895, ENST00000398261, ENST00000420906, ENST00000482415, ENST00000502425, ENST00000503128, ENST00000503207, ENST00000505643, ENST00000507094, ENST00000507820, ENST00000508299, ENST00000508355, ENST00000508803, ENST00000509115, ENST00000511904, ENST00000512700, ENST00000513726, ENST00000514045, ENST00000514329, ENST00000515695, ENST00000515806, ENST00000677559, ENST00000677895, ENST00000678128, ENST00000678714, ENST00000679039, ENST00000899091, ENST00000899092, ENST00000922144, ENST00000922145, ENST00000922146, ENST00000922147, ENST00000922148, ENST00000922149, ENST00000922150, ENST00000922151, ENST00000922152, ENST00000922153, ENST00000922154, ENST00000922155

RefSeq mRNA: 6 — MANE Select: NM_001042424 NM_001042424, NM_007331, NM_133330, NM_133331, NM_133334, NM_133335

CCDS: CCDS3356, CCDS33940, CCDS46999

Canonical transcript exons

ENST00000508803 — 22 exons

Exon	Start	End
ENSE00001410632	1871393	1871542
ENSE00001604875	1938451	1938532
ENSE00001625929	1978638	1982192
ENSE00001749370	1930626	1930770
ENSE00001784217	1918141	1918623
ENSE00003526278	1961035	1961151
ENSE00003535738	1974863	1975004
ENSE00003567918	1939654	1939778
ENSE00003580543	1976475	1976679
ENSE00003591856	1953324	1953524
ENSE00003596471	1951072	1951203
ENSE00003613086	1955161	1955340
ENSE00003617202	1975294	1975400
ENSE00003622823	1935144	1935262
ENSE00003636220	1959471	1959740
ENSE00003640217	1952108	1952231
ENSE00003665684	1955693	1955849
ENSE00003673879	1957933	1958036
ENSE00003676418	1916871	1917037
ENSE00003676685	1904216	1904378
ENSE00003787179	1955983	1956188
ENSE00003801156	1900626	1901251

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 97.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.4588 / max 379.9191, expressed in 1755 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46576	8.2020	1636
46575	2.9547	1333
46577	2.5091	1139
46581	1.8483	592
46578	0.7641	417
46580	0.1805	59

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.99	gold quality
ganglionic eminence	UBERON:0004023	97.28	gold quality
cortical plate	UBERON:0005343	95.84	gold quality
sural nerve	UBERON:0015488	94.81	gold quality
embryo	UBERON:0000922	94.74	gold quality
left testis	UBERON:0004533	93.52	gold quality
right testis	UBERON:0004534	93.52	gold quality
secondary oocyte	CL:0000655	93.51	gold quality
bone marrow cell	CL:0002092	93.42	gold quality
testis	UBERON:0000473	92.60	gold quality
male germ cell	CL:0000015	92.57	gold quality
stromal cell of endometrium	CL:0002255	92.52	gold quality
sperm	CL:0000019	92.50	gold quality
colonic epithelium	UBERON:0000397	92.16	gold quality
mucosa of transverse colon	UBERON:0004991	91.96	gold quality
rectum	UBERON:0001052	91.64	gold quality
transverse colon	UBERON:0001157	90.18	gold quality
type B pancreatic cell	CL:0000169	90.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.07	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.60	gold quality
adrenal tissue	UBERON:0018303	89.59	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.57	gold quality
prefrontal cortex	UBERON:0000451	89.43	gold quality
thymus	UBERON:0002370	89.39	gold quality
tonsil	UBERON:0002372	89.24	gold quality
bone marrow	UBERON:0002371	88.96	gold quality
cerebellar hemisphere	UBERON:0002245	88.80	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.75	gold quality
calcaneal tendon	UBERON:0003701	88.73	gold quality
cerebellar cortex	UBERON:0002129	88.72	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	694.94
E-MTAB-6678	yes	8.09
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
AR	Unknown
CDKN2A
FGFR1
ID1	Unknown
MIR126
NCAM1
NSD3
SLAMF7
TRIM28

miRNA regulators (miRDB)

120 targeting NSD2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-548AC	99.84	70.77	4351

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• data indicate that t(4;14)(p16;q32) and loss of fibroblast growth factor receptor 3 occurred at a very early stage of multiple myeloma and suggest that activation of multiple myeloma SET domain protein may be transforming event of this translocation (PMID:12433679)
• connection between the syndrome phenotype and cytogenetic abnormalities, through gradual shortening of the length of the critical region WHSCR (finally up to 165 kb), and sequencing it, at least 2 genes (WHSC1 and WHSC2) were identified. (PMID:12715353)
• different transcripts detected, multiple myeloma SET domain containing protein (MMSET I), MMSET II, Exon 4a/MMSET III, and response element II binding protein (RE-IIBP), are produced by alternative splicing (PMID:15677557)
• Overexpression of WHISTLE repressed transcription of the SV40 promoter. Our results suggest that WHISTLE is a novel SET domain containing a protein with specific H3K4 and H3K27 HMTase activity. (PMID:16682010)
• Our results suggest that HMTase WHISTLE induces apoptosis in an HMTase activity-dependent manner and represses transcription of target genes through HDAC1 recruitment. (PMID:17239852)
• that MMSET plays a significant role in t(4;14) MM and suggest that therapies targeting this gene could impact this particular subset of poor-prognosis patients. (PMID:17942756)
• MM Patients showing the t(4;14) chromosomal translocation at FGFR3 and MMSET genes had a significant elevation of serum crosslaps, reported to be the marker most reliably correlated with the extent of bone resorption (PMID:18036184)
• MMSET influences gene expression and potentially acts as a pathogenic agent in multiple myeloma (PMID:18156491)
• RE-IIBP is upregulated in leukemia. SET domain Cys483 & Arg477 are needed for histone methyltransferase activity. Overexpression causes histone H3-K27 methylation, HDAC recruitment, & histone H3 hypoacetylation on the IL-5 promoter repressing expression. (PMID:18172012)
• WHSC1 expression increases with ascending tumor proliferation activity. (PMID:18182627)
• dysregulation of MMSET affects the expression of several genes involved in the regulation of cell cycle progression, cell adhesion and survival (PMID:19059936)
• These data suggest that MMSET potentially acts as a pathogenic agent in many cancers. (PMID:19121287)
• NSD2 protein is recruited to the enhancer region of the PSA gene by AR in an agonist-enhanced manner. (PMID:19481544)
• overexpression of multiple myeloma SET domain protein is associated with the translocation t(4;14)in multiple myeloma. (PMID:20974671)
• a pathway involving gammaH2AX-MDC1-MMSET regulates the induction of H4K20 methylation on histones around DSBs, which, in turn, facilitates 53BP1 recruitment (PMID:21293379)
• The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors. (PMID:21385930)
• MMSET is implicated in neuroblastomagenesis possibly by supporting proliferation of progenitor cells and negatively regulating their differentiation. (PMID:21527557)
• WHSC1 regulates the methylation status of the histone H4 K20 residue and is required for the recruitment of 53BP1 to sites of DNA damage. (PMID:21788515)
• Data show significant up-regulation of WHSC1 expression in bladder and lung cancer cells at both transcriptional and the protein levels. (PMID:22028615)
• NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. (PMID:22099308)
• NSD2 is a key chromatin regulator of NF-kappaB and mediator of the cytokine autocrine loop for constitutive NF-kappaB activation and emphasize the important roles played by NSD2 in cancer cell proliferation and survival and tumor growth. (PMID:22645312)
• ACA11, an orphan box H/ACA class small nucleolar RNA (snoRNA) encoded within an intron of WHSC1, was highly expressed in t(4;14)-positive multiple myeloma and other cancers (PMID:22751105)
• Depletion of TWIST1 in MMSET-overexpressing cells blocked cell invasion and epithelial-mesenchymal transition, indicating that TWIST1 is a critical target of MMSET, responsible for the acquisition of an invasive phenotype. (PMID:22797064)
• Overexpression of the histone methyltransferase MMSET is associated with myeloma. (PMID:22972034)
• The EZH2-MMSET-histone methylase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis. (PMID:23159737)
• Overexpression of MMSET was significantly associated with Edmondson stage. (PMID:23225158)
• MMSET, a gene often deleted in Wolf-Hirschhorn syndrome, regulates class switch recombination provides one possible mechanism for Ab deficiency observed in these patients. (PMID:23241889)
• High MMSET expression correlated with the advanced extent of serous ovarian carcinoma and poor outcome. (PMID:23566000)
• it will be of interest to determine whether inhibition of MMSET activity can be beneficial not only for t(4;14)thorn MM patients but also for patients who express a mutant allele of this protein. (PMID:23823660)
• In this study it was found MMSET knockdown could reduce SLAMF7 levels in t(4;14) MM cells. Furthermore, we found MMSET proteins were enriched in the SLAMF7 promoter region and regulated the transcription level of SLAMF7. (PMID:23900284)
• Haploinsufficiency of WHSC1 and/or LETM1 contributes to Wolf-Hirschhorn Syndrome, but that loss of distinct and/or additional genes in 4p16.3 is necessary for the expression of the core Wolf-Hirschhorn Syndrome phenotype. (PMID:23963300)
• all of the H3K36-specific methyltransferases, including ASH1L, HYPB, NSD1, and NSD2 were inhibited by ubH2A, whereas the other histone methyltransferases, including PRC2, G9a, and Pr-Set7 were not affected by ubH2A. (PMID:24019522)
• Gastric cancer patients with high MMSET and BRCA1 attain a longer median survival compared with those with high BRCA1 and low MMSET. (PMID:24809779)
• The role of the shorter isoform (REIIBP) in myeloma cells was characterized and identified a clear and novel interaction of REIIBP with members of the SMN complex. (PMID:24923560)
• Results show that WHSC1 is overexpressed in Squamous cell carcinoma of the head and neck (SCCHN) and that it promotes cell-cycle progression through activation of NEK7, indicating its potential role as an oncogenic force in SCCHN. (PMID:25280969)
• The results describe the binding of NSD1, 2 and 3 catalytic domains (CD) on histone tails through recognition of histone-lysine and methylation properties. (PMID:25494638)
• Studies indicate that the NSD methyltransferases NSD1, NSD2/WHSC1/MMSET and NSD3/WHSC1L1 were overexpressed, amplified or somatically mutated in multiple types of cancer, suggesting their critical role in cancer. (PMID:25942451)
• It was observed that RE-IIBP induces MEIS1-mediated apoptosis, which was dependent on H2BK120 ubiquitination by RNF20. (PMID:26206755)
• Results showed that high levels of MMSET in the myeloma-like cells drove the formation of hypermethyled proteoforms containing H3K36me2 co-existent with the repressive marks H3K9me2/3 and H3K27me2/3. (PMID:26272979)
• In MMSET-depleted cells there are defects in DNA replication and a decreased association with chromatin. (PMID:26771714)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	nsd2	ENSDARG00000026225
mus_musculus	Nsd2	ENSMUSG00000057406
rattus_norvegicus	Nsd2	ENSRNOG00000038140
drosophila_melanogaster	ash1	FBGN0005386
drosophila_melanogaster	trr	FBGN0023518
drosophila_melanogaster	Set2	FBGN0030486
drosophila_melanogaster	CG4565	FBGN0037841
drosophila_melanogaster	G9a	FBGN0040372
drosophila_melanogaster	egg	FBGN0086908
caenorhabditis_elegans	set-32	WBGENE00008062
caenorhabditis_elegans		WBGENE00008206
caenorhabditis_elegans		WBGENE00008527
caenorhabditis_elegans		WBGENE00011729
caenorhabditis_elegans	met-1	WBGENE00016603
caenorhabditis_elegans		WBGENE00018023
caenorhabditis_elegans		WBGENE00019584
caenorhabditis_elegans		WBGENE00019690
caenorhabditis_elegans		WBGENE00019883
caenorhabditis_elegans		WBGENE00020006
caenorhabditis_elegans		WBGENE00020919
caenorhabditis_elegans		WBGENE00021282

Paralogs (19): KMT2C (ENSG00000055609), SETD1A (ENSG00000099381), SUV39H1 (ENSG00000101945), EZH2 (ENSG00000106462), EZH1 (ENSG00000108799), ASH1L (ENSG00000116539), KMT2A (ENSG00000118058), SETDB2 (ENSG00000136169), SETD1B (ENSG00000139718), SETDB1 (ENSG00000143379), NSD3 (ENSG00000147548), SETBP1 (ENSG00000152217), SUV39H2 (ENSG00000152455), NSD1 (ENSG00000165671), KMT2D (ENSG00000167548), EHMT1 (ENSG00000181090), SETD2 (ENSG00000181555), EHMT2 (ENSG00000204371), KMT2B (ENSG00000272333)

Protein

Protein identifiers

Histone-lysine N-methyltransferase NSD2 — O96028 (reviewed: O96028)

Alternative names: Multiple myeloma SET domain-containing protein, Nuclear SET domain-containing protein 2, Protein trithorax-5, Wolf-Hirschhorn syndrome candidate 1 protein

All UniProt accessions (9): O96028, A0A7I2V2S2, A0A7I2YQS5, A0A7P0P278, D6R9V2, D6RFE7, D6RIS1, H0Y9L4, H0Y9U6

UniProt curated annotations — full annotation on UniProt →

Function. Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at ‘Lys-36’ (H3K36me2). Also monomethylates nucleosomal histone H3 at ‘Lys-36’ (H3K36me) in vitro. Does not trimethylate nucleosomal histone H3 at ‘Lys-36’ (H3K36me3). However, specifically trimethylates histone H3 at ‘Lys-36’ (H3K36me3) at euchromatic regions in embryonic stem (ES) cells. By methylating histone H3 at ‘Lys-36’, involved in the regulation of gene transcription during various biological processes. In ES cells, associates with developmental transcription factors such as SALL1 and represses inappropriate gene transcription mediated by histone deacetylation. During heart development, associates with transcription factor NKX2-5 to repress transcription of NKX2-5 target genes. Plays an essential role in adipogenesis, by regulating expression of genes involved in pre-adipocyte differentiation. During T-cell receptor (TCR) and CD28-mediated T-cell activation, promotes the transcription of transcription factor BCL6 which is required for follicular helper T (Tfh) cell differentiation. During B-cell development, required for the generation of the B1 lineage. During B2 cell activation, may contribute to the control of isotype class switch recombination (CRS), splenic germinal center formation, and the humoral immune response. Plays a role in class switch recombination of the immunoglobulin heavy chain (IgH) locus during B-cell activation. By regulating the methylation of histone H3 at ‘Lys-36’ and histone H4 at ‘Lys-20’ at the IgH locus, involved in TP53BP1 recruitment to the IgH switch region and promotes the transcription of IgA. Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at ‘Lys-36’ (H3K36me2). Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at ‘Lys-36’ (H3K36me2). Methylation of histone H3 at ‘Lys-27’ is controversial. Mono-, di- or tri-methylates histone H3 at ‘Lys-27’ (H3K27me, H3K27me2 and H3K27me3). Does not methylate histone H3 at ‘Lys-27’. May act as a transcription regulator that binds DNA and suppresses IL5 transcription through HDAC recruitment.

Subunit / interactions. Interacts with HDAC1. Interacts (via PHD-type zinc fingers 1, 2 and 3) with SALL1. Interacts (via PHD-type 1, 2 and 3) with SALL4. Interacts with NANOG. Interacts with OGT. Interacts (via HMG box) with NKX2-5.

Subcellular location. Nucleus. Chromosome Nucleus. Chromosome Nucleus Cytoplasm. Nucleolus.

Tissue specificity. Widely expressed. Predominantly expressed in thymus and testis.

Disease relevance. Rauch-Steindl syndrome (RAUST) [MIM:619695] An autosomal dominant disorder characterized by poor pre- and postnatal growth, facial dysmorphism, and variable developmental delay with delayed motor and speech acquisition and impaired intellectual. Other features may include hypotonia and behavioral abnormalities. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving NSD2 is a cause of multiple myeloma tumors. Translocation t(4;14)(p16.3;q32.3) with IgH. NSD2 is located in the Wolf-Hirschhorn syndrome (WHS) critical region. WHS results from by sub-telomeric deletions in the short arm of chromosome 4. NSD2 is deleted in every case, however deletion of linked genes contributes to both the severity of the core characteristics and the presence of the additional syndromic problems.

Similarity. Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. SET2 subfamily.

Isoforms (7)

UniProt ID	Names	Canonical?
O96028-1	1, MMSET type II	yes
O96028-2	2
O96028-3	3, MMSET type I
O96028-4	4, RE-IIBP, IL-5 promoter REII-region-binding protein
O96028-5	5
O96028-6	6
O96028-7	7

RefSeq proteins (6): NP_001035889, NP_015627, NP_579877, NP_579878, NP_579889, NP_579890 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000313	PWWP_dom	Domain
IPR001214	SET_dom	Domain
IPR001841	Znf_RING	Domain
IPR001965	Znf_PHD	Domain
IPR003616	Post-SET_dom	Domain
IPR006560	AWS_dom	Domain
IPR009071	HMG_box_dom	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR019786	Zinc_finger_PHD-type_CS	Conserved_site
IPR019787	Znf_PHD-finger	Domain
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR041306	C5HCH	Domain
IPR046341	SET_dom_sf	Homologous_superfamily
IPR047426	PHD1_NSD1_2	Domain
IPR047434	PWWP_NSD2_rpt1	Domain
IPR047435	PWWP_NSD2_rpt2	Domain
IPR047437	SET_NSD2	Domain
IPR047439	PHD2_NSD2	Domain
IPR047441	PHD3_NSD2	Domain
IPR047442	PHD5_NSD2	Domain
IPR047443	HMG-box_NSD2	Domain
IPR050777	SET2_Histone-Lys_MeTrsfase	Family
IPR055197	PHDvar_NSD	Domain
IPR055198	NSD_PHD	Domain
IPR059153	NSD_PHD-1st	Domain

Pfam: PF00505, PF00628, PF00855, PF00856, PF17907, PF17982, PF22908, PF23004, PF23011

Enzyme classification (BRENDA):

• EC 2.1.1.356 — [histone H3]-lysine27 N-trimethyltransferase (BRENDA: 12 organisms, 23 substrates, 3 inhibitors, 14 Km, 13 kcat entries)
• EC 2.1.1.357 — [histone H3]-lysine36 N-dimethyltransferase (BRENDA: 4 organisms, 14 substrates, 5 inhibitors, 4 Km, 2 kcat entries)
• EC 2.1.1.359 — [histone H3]-lysine36 N-trimethyltransferase (BRENDA: 13 organisms, 30 substrates, 2 inhibitors, 12 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
S-ADENOSYL-L-METHIONINE	0.0033–0.13	6
(+/-)-2’,3’-DIBENZYL-S-ADENOSYL-L-METHIONINE	0.072–0.917	3
(+/-)-3’-BENZYL-S-ADENOSYL-L-METHIONINE	0.086–2.8	3
HISTONE H3(K27)	0.2762–3.9	3
S-ADENOSYL-L-METHIONINE	0.06–0.126	3
(+/-)-2’-BENZYL-S-ADENOSYL-L-METHIONINE	0.086–0.128	2
S-ADENOSYL-L-METHIONINE	0.0028–0.0038	2
CHICKEN NUCLEOSOME	0.0003	1
RECOMBINANT NUCLEOSOME	—	1
CHICKEN NUCLEOSOME	0.0089	1
HISTONE H3(PEPTIDE 21-44)	0.0005	1
RECOMBINANT NUCLEOSOME	0.0081	1
[HISTONE H3]-L-LYSINE36	0.0015	1
[HISTONE H3]-N6,N6-DIMETHYL-L-LYSINE36	0.0025	1
[HISTONE H3]-N6-METHYL-L-LYSINE36	0.0024	1

Catalyzed reactions (Rhea), 2 shown:

• L-lysyl(36)-[histone H3] + 2 S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl(36)-[histone H3] + 2 S-adenosyl-L-homocysteine + 2 H(+) (RHEA:60308)
• L-lysyl(36)-[histone H3] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl(36)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (RHEA:60312)

UniProt features (119 total): strand 21, helix 19, binding site 17, splice variant 11, sequence variant 10, modified residue 8, turn 6, compositionally biased region 6, domain 5, region of interest 5, zinc finger region 4, mutagenesis site 3, sequence conflict 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
9FOC	X-RAY DIFFRACTION	1.62
6XCG	X-RAY DIFFRACTION	1.64
9EXY	X-RAY DIFFRACTION	1.7
9GBF	X-RAY DIFFRACTION	1.76
5VC8	X-RAY DIFFRACTION	1.8
9KNB	X-RAY DIFFRACTION	1.84
9EXX	X-RAY DIFFRACTION	1.94
9FOE	X-RAY DIFFRACTION	1.96
9KN9	X-RAY DIFFRACTION	2
5LSU	X-RAY DIFFRACTION	2.14
7LMT	X-RAY DIFFRACTION	2.27
6UE6	X-RAY DIFFRACTION	2.4
7MDN	X-RAY DIFFRACTION	2.42
9EXW	X-RAY DIFFRACTION	2.43
7E8D	ELECTRON MICROSCOPY	2.8
9KNA	X-RAY DIFFRACTION	2.92
7VLN	X-RAY DIFFRACTION	3.09
7CRO	ELECTRON MICROSCOPY	3.75
29HG	ELECTRON MICROSCOPY	4
29HH	ELECTRON MICROSCOPY	4.2
29HI	ELECTRON MICROSCOPY	5.9
9CVD	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O96028-F1	66.22	0.29

Functional residue map

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

Ligand- & substrate-binding residues (17): 1016; 1018; 1026; 1026; 1032; 1041; 1046; 1052; 1075; 1115–1118; 1141–1142; 1144 …

Post-translational modifications (8): 110, 114, 121, 172, 376, 422, 544, 614

Mutagenesis-validated functional residues (3):

Position	Phenotype
1092	loss of methyltransferase activity. reduces levels of h3k36me2 in preadipocytes; when associated with a-1179.
1142	reduces levels of h3k36me2 in preadipocytes; when associated with a-1179.
1179	loss of methyltransferase activity. reduces levels of h3k36me2 in preadipocytes; when associated with a-1092 or g-1142.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-69473	G2/M DNA damage checkpoint

MSigDB gene sets: 789 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_REGULATION_OF_CELL_ACTIVATION, MORF_DNMT1, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, KANG_DOXORUBICIN_RESISTANCE_UP, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, MORF_ESPL1, GNF2_CENPF, GOBP_VENTRICULAR_SEPTUM_MORPHOGENESIS, MORF_BUB1, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS

GO Biological Process (13): negative regulation of transcription by RNA polymerase II (GO:0000122), membranous septum morphogenesis (GO:0003149), atrial septum primum morphogenesis (GO:0003289), atrial septum secundum morphogenesis (GO:0003290), double-strand break repair (GO:0006302), regulation of DNA-templated transcription (GO:0006355), methylation (GO:0032259), positive regulation of isotype switching to IgA isotypes (GO:0048298), bone development (GO:0060348), regulation of establishment of protein localization (GO:0070201), regulation of double-strand break repair via nonhomologous end joining (GO:2001032), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338)

GO Molecular Function (14): chromatin binding (GO:0003682), zinc ion binding (GO:0008270), histone H4K20 methyltransferase activity (GO:0042799), sequence-specific DNA binding (GO:0043565), histone H3K36 methyltransferase activity (GO:0046975), histone H3 methyltransferase activity (GO:0140938), histone H3K36 dimethyltransferase activity (GO:0140954), histone H3K36 trimethyltransferase activity (GO:0140955), DNA binding (GO:0003677), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), histone methyltransferase activity (GO:0042054), metal ion binding (GO:0046872)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Chromatin modifying enzymes	1
DNA Double Strand Break Response	1
DNA Double-Strand Break Repair	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
G2/M Checkpoints	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
atrial septum morphogenesis	2
binding	2
protein-lysine N-methyltransferase activity	2
histone H3K36 methyltransferase activity	2
nuclear lumen	2
intracellular membraneless organelle	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
anatomical structure morphogenesis	1
ventricular septum morphogenesis	1
septum primum development	1
septum secundum development	1
DNA repair	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
metabolic process	1
positive regulation of isotype switching	1
isotype switching to IgA isotypes	1
regulation of isotype switching to IgA isotypes	1
skeletal system development	1
animal organ development	1
regulation of protein localization	1
establishment of protein localization	1
double-strand break repair via nonhomologous end joining	1
regulation of double-strand break repair	1
cellular component organization	1
chromatin organization	1
transition metal ion binding	1
histone H4 methyltransferase activity	1
DNA binding	1
histone H3 methyltransferase activity	1
histone methyltransferase activity	1
nucleic acid binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
protein methyltransferase activity	1
histone modifying activity	1

Protein interactions and networks

STRING

2980 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NSD2	NKX2-5	P52952	941
NSD2	IGHV4-38-2	P0DP08	875
NSD2	SALL4	Q9UJQ4	874
NSD2	SALL1	Q9NSC2	870
NSD2	LETM1	O95202	854
NSD2	FGFR3	P22607	839
NSD2	H3-3A	P06351	796
NSD2	H3C1	P02295	796
NSD2	H3C14	Q71DI3	795
NSD2	H3-4	Q16695	795
NSD2	H3-7	Q5TEC6	795
NSD2	H3-5	Q6NXT2	794
NSD2	BRD3	Q15059	789
NSD2	NANOG	Q9H9S0	750
NSD2	DOT1L	Q8TEK3	737

IntAct

176 interactions, top by confidence:

A	B	Type	Score
rep	MPHOSPH10	psi-mi:“MI:0914”(association)	0.660
RPL14	RRP8	psi-mi:“MI:0914”(association)	0.640
NOP53	RRP8	psi-mi:“MI:0914”(association)	0.640
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
RPL10A	RRP8	psi-mi:“MI:0914”(association)	0.640
NPM1	MPHOSPH10	psi-mi:“MI:0914”(association)	0.610
NSD2	AR	psi-mi:“MI:0914”(association)	0.600
NSD2	AR	psi-mi:“MI:0915”(physical association)	0.600
AR	NSD2	psi-mi:“MI:0407”(direct interaction)	0.600
AR	NSD2	psi-mi:“MI:0403”(colocalization)	0.600
MDC1	NSD2	psi-mi:“MI:0915”(physical association)	0.590
NSD2	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.560
NSD2	HORMAD2	psi-mi:“MI:0915”(physical association)	0.560
RRP8	NVL	psi-mi:“MI:0914”(association)	0.530
H1-4	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
RPL37A	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
ZNF2	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
PRR11	NVL	psi-mi:“MI:0914”(association)	0.530
KNOP1	DHX15	psi-mi:“MI:0914”(association)	0.530
RPL30	RRP8	psi-mi:“MI:0914”(association)	0.530
RPL8	RRP8	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
ZC3HAV1	KHNYN	psi-mi:“MI:0914”(association)	0.530

BioGRID (374): WHSC1 (Affinity Capture-Western), HIST1H3A (Biochemical Activity), ESR1 (Biochemical Activity), WHSC1 (Biochemical Activity), WHSC1 (Protein-peptide), WHSC1 (Affinity Capture-MS), WHSC1 (Affinity Capture-MS), WHSC1 (Affinity Capture-MS), WHSC1 (Affinity Capture-MS), WHSC1 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN5 (Affinity Capture-MS), DDX20 (Affinity Capture-MS), GOLGA3 (Affinity Capture-MS), MYBBP1A (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GR68, A2CG63, E6ZGB4, F7AQ22, F8VPQ2, G3V8T1, O75151, O75376, O75475, O88974, O96028, P29374, Q0VEE6, Q0VGB7, Q15047, Q2TB10, Q3TYA6, Q4KKX4, Q4LE39, Q5F363, Q5HYC2, Q5JSH3, Q5R9U6, Q5XJV7, Q5XXA9, Q5ZMU6, Q60974, Q62315, Q66T72, Q6DCQ0, Q6INA9, Q6NVE8, Q6P7W0, Q6P949, Q6P964, Q812D1, Q8BVE8, Q8MJG1, Q8QG78, Q8VBW5

Diamond homologs: A0A1L7TZE5, A4IGY9, A7E2Z2, A8XI75, J9VWH9, O43463, O54864, O60016, O65312, O82175, O88491, O88974, O96028, P20659, P42124, P45975, P46995, P55200, P70351, P93831, Q03164, Q06ZW3, Q08BR4, Q08BS4, Q0VD24, Q15047, Q15910, Q24742, Q28CQ7, Q28D84, Q294B9, Q2NL30, Q32PH7, Q4PB36, Q4R381, Q4R3E0, Q4V863, Q53H47, Q5DW34, Q5F3W5

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NSD2	up-regulates	AR	binding
BRCA1	“down-regulates quantity by destabilization”	NSD2	ubiquitination
AURKA	“up-regulates quantity by stabilization”	NSD2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 165 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
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	5	32.3×	3e-06
Peptide chain elongation	24	29.3×	2e-27
Viral mRNA Translation	24	29.3×	2e-27
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	24	29.0×	2e-27
Selenocysteine synthesis	24	27.7×	5e-27
Eukaryotic Translation Termination	24	27.7×	5e-27
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	24	27.2×	7e-27
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	24	27.2×	7e-27

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription by RNA polymerase III	5	31.4×	5e-05
cytoplasmic translation	25	31.1×	4e-28
positive regulation of transcription by RNA polymerase I	5	21.8×	2e-04
ribosomal large subunit biogenesis	7	20.8×	6e-06
ribosomal small subunit biogenesis	12	18.3×	4e-10
translation	24	16.6×	4e-20
rRNA processing	15	14.3×	4e-11
negative regulation of translation	8	10.5×	1e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 4 cancer types — ALL, BL, PCM, UTUC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	36
Uncertain significance	300
Likely benign	233
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1029069	NM_001042424.3(NSD2):c.2887C>T (p.Gln963Ter)	Pathogenic
1220533	NM_001042424.3(NSD2):c.1363_1364dup (p.Asp455fs)	Pathogenic
1308650	NM_001042424.3(NSD2):c.3223_3226dup (p.Gly1076fs)	Pathogenic
1333173	NM_001042424.3(NSD2):c.3412C>T (p.Arg1138Ter)	Pathogenic
1333175	NM_001042424.3(NSD2):c.2803C>T (p.Arg935Ter)	Pathogenic
1333176	NM_001042424.3(NSD2):c.1577dup (p.Asn527fs)	Pathogenic
1333179	NM_001042424.3(NSD2):c.3056A>G (p.Lys1019Arg)	Pathogenic
1678116	NM_001042424.3(NSD2):c.2498G>A (p.Trp833Ter)	Pathogenic
1680168	NM_001042424.3(NSD2):c.1169_1170del (p.Val390fs)	Pathogenic
1697318	NM_001042424.3(NSD2):c.1947_1948del (p.Glu650fs)	Pathogenic
1709695	NM_001042424.3(NSD2):c.1103_1104del (p.Glu368fs)	Pathogenic
1710711	NM_001042424.3(NSD2):c.2827dup (p.Asp943fs)	Pathogenic
1804473	NM_001042424.3(NSD2):c.3530_3531del (p.Thr1176_Phe1177insTer)	Pathogenic
2025192	NM_001042424.3(NSD2):c.2263C>T (p.Arg755Ter)	Pathogenic
2446542	NM_001042424.3(NSD2):c.3295GAG[2] (p.Glu1101del)	Pathogenic
2506516	NM_001042424.3(NSD2):c.28dup (p.Leu10fs)	Pathogenic
2584449	NM_001042424.3(NSD2):c.1641_1642del (p.Arg548fs)	Pathogenic
2584531	NM_001042424.3(NSD2):c.367G>T (p.Glu123Ter)	Pathogenic
2772967	NM_001042424.3(NSD2):c.3458G>A (p.Trp1153Ter)	Pathogenic
3064105	NM_001042424.3(NSD2):c.2518+1G>A	Pathogenic
3069179	NM_001042424.3(NSD2):c.2277C>A (p.Cys759Ter)	Pathogenic
3248645	NM_001042424.3(NSD2):c.2714C>T (p.Pro905Leu)	Pathogenic
3391883	GRCh37/hg19 4p16.3(chr4:1918373-1953592)x1	Pathogenic
3708536	NM_001042424.3(NSD2):c.2684C>T (p.Pro895Leu)	Pathogenic
3897864	NM_001042424.3(NSD2):c.1798C>T (p.Arg600Ter)	Pathogenic
3922022	NM_001042424.3(NSD2):c.394dup (p.Tyr132fs)	Pathogenic
4087730	NM_001042424.3(NSD2):c.1466C>G (p.Ser489Ter)	Pathogenic
4291083	NM_001042424.3(NSD2):c.2137G>C (p.Gly713Arg)	Pathogenic
4538234	NM_001042424.3(NSD2):c.3298del (p.Glu1100fs)	Pathogenic
4538251	NM_001042424.3(NSD2):c.643del (p.Asp215fs)	Pathogenic

SpliceAI

5024 predictions. Top by Δscore:

Variant	Effect	Δscore
4:1900616:A:AG	acceptor_gain	1.0000
4:1900624:A:AG	acceptor_gain	1.0000
4:1900625:G:GG	acceptor_gain	1.0000
4:1900625:GT:G	acceptor_gain	1.0000
4:1901161:G:GT	donor_gain	1.0000
4:1904212:TCA:T	acceptor_loss	1.0000
4:1904214:A:AG	acceptor_gain	1.0000
4:1904214:AG:A	acceptor_loss	1.0000
4:1904215:G:C	acceptor_loss	1.0000
4:1904215:G:GG	acceptor_gain	1.0000
4:1916869:A:T	acceptor_loss	1.0000
4:1916996:G:GT	donor_gain	1.0000
4:1916997:A:T	donor_gain	1.0000
4:1917024:C:G	donor_gain	1.0000
4:1917033:T:G	donor_gain	1.0000
4:1918139:A:AG	acceptor_gain	1.0000
4:1918140:G:GG	acceptor_gain	1.0000
4:1918140:G:GT	acceptor_loss	1.0000
4:1918140:GC:G	acceptor_gain	1.0000
4:1918140:GCT:G	acceptor_gain	1.0000
4:1918140:GCTA:G	acceptor_gain	1.0000
4:1918140:GCTAT:G	acceptor_gain	1.0000
4:1918569:G:GT	donor_gain	1.0000
4:1930624:A:T	acceptor_loss	1.0000
4:1930625:G:GC	acceptor_loss	1.0000
4:1930767:TCTGG:T	donor_loss	1.0000
4:1930768:CTGGT:C	donor_loss	1.0000
4:1930769:TGGT:T	donor_loss	1.0000
4:1930770:GG:G	donor_loss	1.0000
4:1930771:G:GA	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000032680 (4:1896471 C>T), RS1000047857 (4:1960787 T>C), RS1000048675 (4:1879461 C>A,T), RS10000617 (4:1881361 T>C), RS1000068503 (4:1945068 C>A,T), RS1000099937 (4:1960439 C>T), RS1000143658 (4:1952731 G>A), RS1000157443 (4:1879288 A>G), RS1000171999 (4:1882459 C>G,T), RS1000180233 (4:1962894 G>T), RS1000223443 (4:1976257 C>T), RS1000227275 (4:1910314 C>T), RS1000239460 (4:1934532 A>C), RS1000253665 (4:1962501 A>G), RS10002574 (4:1922023 T>A,C)

Disease associations

OMIM: gene MIM:602952 | disease phenotypes: MIM:194190, MIM:619695, MIM:614429, MIM:119800

GenCC curated gene-disease

Disease	Classification	Inheritance
Rauch-Steindl syndrome	Definitive	Autosomal dominant
Wolf-Hirschhorn syndrome	Definitive	Autosomal dominant
neurodevelopmental disorder	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Mondo (13): Wolf-Hirschhorn syndrome (MONDO:0008684), syndromic intellectual disability (MONDO:0000508), Rauch-Steindl syndrome (MONDO:0859219), neurodevelopmental disorder (MONDO:0700092), thrombocytopenia (MONDO:0002049), ventricular septal defect (MONDO:0002070), anemia (MONDO:0002280), hypoglycemia (MONDO:0004946), hypertrophic cardiomyopathy (MONDO:0005045), lymphoma (MONDO:0005062), clubfoot (MONDO:0007342), macroglossia (MONDO:0015496), microcephaly (MONDO:0001149)

Orphanet (8): Wolf-Hirschhorn syndrome (Orphanet:280), Rare genetic syndromic intellectual disability (Orphanet:183763), Rauch-Steindl syndrome (Orphanet:659642), Macroglossia (Orphanet:156207), Familial clubfoot with or without associated lower limb anomalies (Orphanet:199315), Rare hypertrophic cardiomyopathy (Orphanet:217569), Lymphoma (Orphanet:223735), NON RARE IN EUROPE: Ventricular septal defect (Orphanet:1480)

HPO phenotypes

170 total (30 of 170 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000077	Abnormality of the kidney
HP:0000078	Abnormality of the genital system
HP:0000079	Abnormality of the urinary system
HP:0000119	Abnormality of the genitourinary system
HP:0000151	Aplasia of the uterus
HP:0000153	Abnormality of the mouth
HP:0000159	Abnormal lip morphology
HP:0000175	Cleft palate
HP:0000188	Short upper lip
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000233	Thin vermilion border
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000288	Abnormality of the philtrum
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000331	Short chin
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000384	Preauricular skin tag

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008476_6	Emphysema annual change measurement in smokers (percent low attenuation area)	2.000000e-06
GCST009356_12	Nonsyndromic cleft palate	5.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007626	emphysema imaging measurement

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D000740	Anemia	C15.378.050
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D003025	Clubfoot	C05.330.488.655.063; C05.330.495.681.063; C05.660.585.512.380.813.063; C16.131.621.585.512.500.681.063
D006345	Heart Septal Defects, Ventricular	C14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540
D007003	Hypoglycemia	C18.452.394.984
D008223	Lymphoma	C04.557.386; C15.604.515.569; C20.683.515.761
D008260	Macroglossia	C07.465.910.460
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
D054877	Wolf-Hirschhorn Syndrome	C16.131.077.944; C16.131.260.985; C16.320.180.985

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3108645 (SINGLE PROTEIN), CHEMBL5169064 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066047 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 364,720 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3137309	VENETOCLAX	4	9,389
CHEMBL58	MITOXANTRONE	4	166,878
CHEMBL265502	SURAMIN	3	36,848
CHEMBL1214186	SINEFUNGIN	2	2,165
CHEMBL1232461	MOLIBRESIB	2	1,538
CHEMBL284328	HOMIDIUM BROMIDE	2	147,818
CHEMBL1215331	PF-03882845	1	59
CHEMBL5095235	EZM-0414	1	25

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 2.1.1.43 Histone methyltransferases (HMTs)

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 15a [PMID: 36642961]	Inhibition	6.64	pIC50

Binding affinities (BindingDB)

8 measured of 39 human assays (59 total across all organisms); most potent 8 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
9-[[5-[(3R)-3-amino-3-[(S)-fluoro(pyridin-2-yl)methyl]piperidin-1-yl]-2-(3,4-difluorophenyl)-4-pyridinyl]methyl]purin-6-amine	IC50	5.5 nM	US-11420970: Piperidinyl-methyl-purineamines as NSD2 inhibitors and anti-cancer agents
3-[(3S)-3-amino-1-[4-[(6-aminopurin-9-yl)methyl]-6-(3,4-difluorophenyl)-3-pyridinyl]piperidin-3-yl]piperidin-2-one	IC50	5.5 nM	US-11420970: Piperidinyl-methyl-purineamines as NSD2 inhibitors and anti-cancer agents
(1S)-1-[(3R)-3-amino-1-[2-[(6-aminopurin-9-yl)methyl]-4-(2,5-difluoro-4-methoxyphenyl)phenyl]piperidin-3-yl]-2,2-difluoroethanol	IC50	5.5 nM	US-20250361235: PIPERIDINYL-METHYLPURINE BENZENES AND RELATED COMPOUNDS AND THEIR USE IN TREATING DISEASES AND CONDITIONS
US20250206740, Compound II-2	IC50	55 nM	US-20250206740: PIPERIDINYL-METHYLPURINE PYRIMIDINES AND RELATED COMPOUNDS AND THEIR USE IN TREATING DISEASES AND CONDITIONS
(1S)-1-[(3R)-3-amino-1-[3-[(6-aminopurin-9-yl)methyl]-5-(2,5-difluoro-4-methoxyphenyl)-2-pyridinyl]piperidin-3-yl]-2,2-difluoroethanol	IC50	505 nM	US-20250361235: PIPERIDINYL-METHYLPURINE BENZENES AND RELATED COMPOUNDS AND THEIR USE IN TREATING DISEASES AND CONDITIONS
(1S)-1-[(3R)-3-amino-1-[4-[(6-aminopurin-9-yl)methyl]-2-(2,5-difluoro-4-methoxyphenyl)pyrimidin-5-yl]piperidin-3-yl]-2,2-difluoroethanol	IC50	550 nM	US-20250206740: PIPERIDINYL-METHYLPURINE PYRIMIDINES AND RELATED COMPOUNDS AND THEIR USE IN TREATING DISEASES AND CONDITIONS
(1S)-1-[(3R)-3-amino-1-[4-[(6-aminopurin-9-yl)methyl]-6-(2,5-difluoro-4-methoxyphenyl)pyridazin-3-yl]piperidin-3-yl]-2,2-difluoroethanol	IC50	550 nM	US-20250206740: PIPERIDINYL-METHYLPURINE PYRIMIDINES AND RELATED COMPOUNDS AND THEIR USE IN TREATING DISEASES AND CONDITIONS
CHEMBL4876215	IC50	890 nM

ChEMBL bioactivities

833 potent at pChembl≥5 of 1029 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL5557662
8.91	IC50	1.23	nM	CHEMBL5200945
8.60	Kd	2.512	nM	CHEMBL5559507
8.40	IC50	3.981	nM	CHEMBL5559507
8.26	IC50	5.5	nM	CHEMBL5751773
8.26	IC50	5.5	nM	CHEMBL5408212
8.26	IC50	5.5	nM	CHEMBL5968753
8.26	IC50	5.5	nM	CHEMBL6060827
8.26	IC50	5.5	nM	CHEMBL5396709
8.26	IC50	5.5	nM	CHEMBL5783629
8.26	IC50	5.5	nM	CHEMBL5955963
8.26	IC50	5.5	nM	CHEMBL5419719
8.26	IC50	5.5	nM	CHEMBL6063007
8.26	IC50	5.5	nM	CHEMBL5786123
8.26	IC50	5.5	nM	CHEMBL5432302
8.26	IC50	5.5	nM	CHEMBL5947924
8.26	IC50	5.5	nM	CHEMBL5739719
8.26	IC50	5.5	nM	CHEMBL5783068
8.26	IC50	5.5	nM	CHEMBL5857132
8.26	IC50	5.5	nM	CHEMBL5954725
8.26	IC50	5.5	nM	CHEMBL5904536
8.26	IC50	5.5	nM	CHEMBL5810084
8.26	IC50	5.5	nM	CHEMBL5995187
8.26	IC50	5.5	nM	CHEMBL5839336
8.26	IC50	5.5	nM	CHEMBL5861904
8.26	IC50	5.5	nM	CHEMBL5757623
8.26	IC50	5.5	nM	CHEMBL5982206
8.26	IC50	5.5	nM	CHEMBL5838209
8.26	IC50	5.5	nM	CHEMBL5997942
8.26	IC50	5.5	nM	CHEMBL5438639
8.26	IC50	5.5	nM	CHEMBL5965445
8.26	IC50	5.5	nM	CHEMBL6018611
8.26	IC50	5.5	nM	CHEMBL5957146
8.26	IC50	5.5	nM	CHEMBL5746181
8.26	IC50	5.5	nM	CHEMBL5909782
8.26	IC50	5.5	nM	CHEMBL5762902
8.26	IC50	5.5	nM	CHEMBL5791245
8.26	IC50	5.5	nM	CHEMBL5437594
8.26	IC50	5.5	nM	CHEMBL5780199
8.26	IC50	5.5	nM	CHEMBL6044474
8.26	IC50	5.5	nM	CHEMBL5956697
8.26	IC50	5.5	nM	CHEMBL5872987
8.26	IC50	5.5	nM	CHEMBL5955746
8.26	IC50	5.5	nM	CHEMBL5947764
8.26	IC50	5.5	nM	CHEMBL6053828
8.26	IC50	5.5	nM	CHEMBL5749148
8.26	IC50	5.5	nM	CHEMBL5819117
8.26	IC50	5.5	nM	CHEMBL5946316
8.26	IC50	5.5	nM	CHEMBL5771947
8.26	IC50	5.5	nM	CHEMBL5877276

PubChem BioAssay actives

272 with measured affinity, of 636 total; 50 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
methyl 1-[[3,5-dimethyl-4-[1-methyl-5-(3-oxo-4H-1,4-benzoxazin-7-yl)imidazol-4-yl]phenyl]methyl]piperidine-4-carboxylate	2072126: Inhibition of human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells incubated for 45 mins by biochemical assay	ic50	0.0010	uM
N-cyclopropyl-3-oxo-N-[[4-(pyrimidin-4-ylcarbamoyl)phenyl]methyl]-4H-1,4-benzoxazine-7-carboxamide	2072144: Inhibition of NSD2 PWWP1 domain (unknown origin) by NanoBRET target engagement assay	ic50	0.0012	uM
7-[5-methyl-3-[2-methyl-5-(piperidin-1-ylmethyl)phenyl]-1,2-oxazol-4-yl]-4H-1,4-benzoxazin-3-one	2072127: Binding affinity to human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells assessed as dissociation constant measured upto 180 secs by SPR analysis	kd	0.0025	uM
N-[3-[3-[acetyl(methyl)amino]pyrrolidin-1-yl]-5-fluorophenyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	2115820: Inhibition of MMSET (953 to 1240 residues) (unknown origin) by Alpha Screen assay	ic50	0.0070	uM
4-fluoro-7-methyl-N-[(1R,3S)-3-[(3S)-3-[methyl(methylsulfonyl)amino]pyrrolidin-1-yl]cyclohexyl]-1H-indole-2-carboxamide	2115820: Inhibition of MMSET (953 to 1240 residues) (unknown origin) by Alpha Screen assay	ic50	0.0080	uM
N-[3-[4-(dimethylamino)piperidin-1-yl]phenyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	2115820: Inhibition of MMSET (953 to 1240 residues) (unknown origin) by Alpha Screen assay	ic50	0.0100	uM
(3R)-3-amino-1-[4-[(6-aminopurin-9-yl)methyl]-6-(3-fluorophenyl)-3-pyridinyl]-N-methylpiperidine-3-carboxamide	2034034: Inhibition of NSD2 in human CGTH-W-1 cells assessed as reduction in H3K36me2 level incubated for 72 hrs by ELISA	ic50	0.0120	uM
6-methoxy-7-(3-piperidin-1-ylpropoxy)-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazoline-2-carbonitrile	2117163: Inhibition of NSD2 (unknown origin) by AlphaLISA assay	ic50	0.0120	uM
7-[3-methyl-5-[2-methyl-5-(piperidin-1-ylmethyl)phenyl]imidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072127: Binding affinity to human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells assessed as dissociation constant measured upto 180 secs by SPR analysis	kd	0.0126	uM
7-[3-(dimethylamino)propoxy]-6-methoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazoline-2-carbonitrile	2117163: Inhibition of NSD2 (unknown origin) by AlphaLISA assay	ic50	0.0130	uM
N-[[4-[[4-[6-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]hexylcarbamoyl]phenyl]carbamoyl]phenyl]methyl]-N-cyclopropyl-3-oxo-4H-1,4-benzoxazine-7-carboxamide	2011314: Binding affinity to NSD2 PWWP1 domain (unknown origin) assessed as dissociation constant by SPR assay	kd	0.0140	uM
6-methoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]-7-(3-pyrrolidin-1-ylpropoxy)quinoline-2-carbonitrile	2117163: Inhibition of NSD2 (unknown origin) by AlphaLISA assay	ic50	0.0140	uM
6-methoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]-7-(3-pyrrolidin-1-ylpropoxy)quinazoline-2-carbonitrile	2117163: Inhibition of NSD2 (unknown origin) by AlphaLISA assay	ic50	0.0170	uM
6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazoline-2-carbonitrile	2117163: Inhibition of NSD2 (unknown origin) by AlphaLISA assay	ic50	0.0170	uM
N-[(1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	2115820: Inhibition of MMSET (953 to 1240 residues) (unknown origin) by Alpha Screen assay	ic50	0.0180	uM
9-[[5-[(3R)-3-amino-3-pyridin-2-ylpiperidin-1-yl]-2-(3,4-difluorophenyl)-4-pyridinyl]methyl]purin-6-amine	2034034: Inhibition of NSD2 in human CGTH-W-1 cells assessed as reduction in H3K36me2 level incubated for 72 hrs by ELISA	ic50	0.0180	uM
6,7-dimethoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazoline-2-carbonitrile	2117163: Inhibition of NSD2 (unknown origin) by AlphaLISA assay	ic50	0.0220	uM
N-[[4-[[4-(6-aminohexylcarbamoyl)phenyl]carbamoyl]phenyl]methyl]-N-cyclopropyl-3-oxo-4H-1,4-benzoxazine-7-carboxamide	2115829: Binding affinity to NSD2 (unknown origin) assessed as dissociation constant by SPR analysis	kd	0.0240	uM
7-[5-methyl-3-[2-methyl-5-(piperidin-1-ylmethyl)phenyl]-1,2-thiazol-4-yl]-4H-1,4-benzoxazin-3-one	2072126: Inhibition of human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells incubated for 45 mins by biochemical assay	ic50	0.0251	uM
4-[(1-cyclopropylpiperidin-4-yl)amino]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline-2-carbonitrile	2117163: Inhibition of NSD2 (unknown origin) by AlphaLISA assay	ic50	0.0270	uM
4-[(1-cyclopropylpiperidin-4-yl)amino]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline-2-carbonitrile	2117163: Inhibition of NSD2 (unknown origin) by AlphaLISA assay	ic50	0.0280	uM
6-methoxy-7-(2-methoxyethoxy)-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazoline-2-carbonitrile	2130264: Inhibition of recombinant human NSD2 (941 to 1240 residues) using unmethylated histone H3 as substrate incubated for 40 mins in the presence of SAM and nucleosomes by AlphaLISA method	ic50	0.0290	uM
7-[3-methyl-5-[2-methyl-4-[[[(2R)-6-oxopiperidin-2-yl]methylamino]methyl]phenyl]imidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072126: Inhibition of human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells incubated for 45 mins by biochemical assay	ic50	0.0316	uM
7-[3-methyl-5-[2-methyl-4-[[[(2R)-5-oxopyrrolidin-2-yl]methylamino]methyl]phenyl]imidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072126: Inhibition of human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells incubated for 45 mins by biochemical assay	ic50	0.0316	uM
7-[3-(4,4-difluoropiperidin-1-yl)propoxy]-6-methoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazoline-2-carbonitrile	2130264: Inhibition of recombinant human NSD2 (941 to 1240 residues) using unmethylated histone H3 as substrate incubated for 40 mins in the presence of SAM and nucleosomes by AlphaLISA method	ic50	0.0320	uM
(2S)-1-[(3R)-3-amino-1-[4-[(6-aminopurin-9-yl)methyl]-6-(3,4-difluorophenyl)-3-pyridinyl]piperidin-3-yl]-2-methylbutan-1-one	2034035: Inhibition of NSD2 in human KMS-11-Par cells assessed as reduction in H3K36me2 level incubated for 72 hrs by ELISA	ic50	0.0340	uM
7-[3-(3,3-difluoropyrrolidin-1-yl)propoxy]-6-methoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazoline-2-carbonitrile	2130264: Inhibition of recombinant human NSD2 (941 to 1240 residues) using unmethylated histone H3 as substrate incubated for 40 mins in the presence of SAM and nucleosomes by AlphaLISA method	ic50	0.0380	uM
7-[5-[5-(aminomethyl)-2-methylphenyl]-3-methylimidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072127: Binding affinity to human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells assessed as dissociation constant measured upto 180 secs by SPR analysis	kd	0.0398	uM
7-[3-methyl-5-[2-methyl-5-(piperidin-1-ylmethyl)phenyl]-1,2-oxazol-4-yl]-4H-1,4-benzoxazin-3-one	2072126: Inhibition of human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells incubated for 45 mins by biochemical assay	ic50	0.0398	uM
7-[5-[4-(aminomethyl)-2,6-dimethylphenyl]-3-methylimidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072127: Binding affinity to human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells assessed as dissociation constant measured upto 180 secs by SPR analysis	kd	0.0398	uM
6-methoxy-7-(2-morpholin-4-ylethoxy)-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazoline-2-carbonitrile	2130264: Inhibition of recombinant human NSD2 (941 to 1240 residues) using unmethylated histone H3 as substrate incubated for 40 mins in the presence of SAM and nucleosomes by AlphaLISA method	ic50	0.0440	uM
4-[(1-cyclopropylpiperidin-4-yl)amino]-6,7-dimethoxyquinazoline-2-carbonitrile	2130264: Inhibition of recombinant human NSD2 (941 to 1240 residues) using unmethylated histone H3 as substrate incubated for 40 mins in the presence of SAM and nucleosomes by AlphaLISA method	ic50	0.0450	uM
N-[[4-[[4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]carbamoyl]phenyl]methyl]-N-cyclopropyl-3-oxo-4H-1,4-benzoxazine-7-carboxamide	2011277: Binding affinity to NSD2 PWWP1 domain (unknown origin) assessed as dissociation constant	kd	0.0460	uM
6-methoxy-7-phenylmethoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazoline-2-carbonitrile	2130264: Inhibition of recombinant human NSD2 (941 to 1240 residues) using unmethylated histone H3 as substrate incubated for 40 mins in the presence of SAM and nucleosomes by AlphaLISA method	ic50	0.0490	uM
7-[3-methyl-5-[2-methyl-5-[[[(2S)-oxetan-2-yl]methylamino]methyl]phenyl]imidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072126: Inhibition of human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells incubated for 45 mins by biochemical assay	ic50	0.0501	uM
7-[3-methyl-5-[2-methyl-4-[[[(3R)-5-oxopyrrolidin-3-yl]methylamino]methyl]phenyl]imidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072126: Inhibition of human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells incubated for 45 mins by biochemical assay	ic50	0.0501	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179236: Binding affinity against WHSC1 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0510	uM
7-hydroxy-6-methoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazoline-2-carbonitrile	2130264: Inhibition of recombinant human NSD2 (941 to 1240 residues) using unmethylated histone H3 as substrate incubated for 40 mins in the presence of SAM and nucleosomes by AlphaLISA method	ic50	0.0600	uM
7-[3-methyl-5-[2-methyl-5-[(pyridin-3-ylamino)methyl]phenyl]imidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072126: Inhibition of human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells incubated for 45 mins by biochemical assay	ic50	0.0631	uM
7-[3-methyl-5-[2-methyl-4-[[[(4R)-2-oxopiperidin-4-yl]methylamino]methyl]phenyl]imidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072126: Inhibition of human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells incubated for 45 mins by biochemical assay	ic50	0.0631	uM
6-methoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazoline-2-carbonitrile	2130264: Inhibition of recombinant human NSD2 (941 to 1240 residues) using unmethylated histone H3 as substrate incubated for 40 mins in the presence of SAM and nucleosomes by AlphaLISA method	ic50	0.0850	uM
(1S)-1-[(3R)-3-amino-1-[4-[(6-aminopurin-9-yl)methyl]-6-(2,5-difluoro-4-methoxyphenyl)-3-pyridinyl]piperidin-3-yl]-2,2-difluoroethanol	2130307: Inhibition of NSD2-SET domain (unknown origin)	ic50	0.1000	uM
(1S)-1-[(3R)-3-amino-1-[4-[(6-aminopurin-9-yl)methyl]-6-(2,5-difluoro-4-methoxyphenyl)-3-pyridinyl]piperidin-3-yl]-2-fluoroethanol	2117163: Inhibition of NSD2 (unknown origin) by AlphaLISA assay	ic50	0.1000	uM
7-[3-methyl-5-[2-methyl-5-[[[(2R)-oxetan-2-yl]methylamino]methyl]phenyl]imidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072126: Inhibition of human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells incubated for 45 mins by biochemical assay	ic50	0.1000	uM
4-[5-[4-[(4-aminopiperidin-1-yl)methyl]-2,6-dimethylphenyl]-3-methylimidazol-4-yl]naphthalene-1-carbonitrile	1869406: Binding affinity to N-terminal His6/Sumo-tagged NSD2 PWWP1 domain (211 to 350 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) using ATKAARKSAPATGGV-Lys (me)2-KPHRYRPG polypeptide as substrate incubated for 3 hrs by HTRF assay	ic50	0.1100	uM
6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione	2011302: Inhibition of NSD2 E1099K mutant (unknown origin)	ic50	0.1100	uM
7-[5-[2,6-dimethyl-4-(morpholin-4-ylmethyl)phenyl]-3-methylimidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072127: Binding affinity to human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells assessed as dissociation constant measured upto 180 secs by SPR analysis	kd	0.1259	uM
7-[3-methyl-5-[2-methyl-4-(piperidin-1-ylmethyl)phenyl]imidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072126: Inhibition of human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells incubated for 45 mins by biochemical assay	ic50	0.1259	uM
7-[5-[2,6-dimethyl-4-(piperidin-1-ylmethyl)phenyl]-3-methylimidazol-4-yl]-4H-1,4-benzoxazin-3-one	2072127: Binding affinity to human C-terminal his tagged NSD2 PWWP1 domain (208 to 358 residues) expressed in Escherichia coli Bl21 (DE3) gold cells assessed as dissociation constant measured upto 180 secs by SPR analysis	kd	0.1259	uM
2-[[4-[(3R)-1-oxo-3,4-dihydroisochromene-3-carbonyl]piperazin-1-yl]methyl]-5,6,7,8-tetrahydro-3H-[1]benzothiolo[2,3-d]pyrimidin-4-one	2115828: Inhibition of NSD2 SET domain (unknown origin) extracted from Escherichia coli BL21	ic50	0.1320	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	7
trichostatin A	decreases expression, affects cotreatment	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
cobaltous chloride	decreases expression	2
entinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Arsenic	increases abundance, increases expression, affects methylation, affects cotreatment	2
Benzo(a)pyrene	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Silicon Dioxide	increases expression, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression, increases oxidation	1
bisphenol A	decreases expression	1
geraniol	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	decreases phosphorylation	1
beta-glycerophosphoric acid	affects cotreatment, decreases expression	1
methacrylaldehyde	decreases expression, increases oxidation, increases abundance, affects cotreatment	1
3-deazaneplanocin	increases degradation, decreases reaction	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, increases degradation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1

ChEMBL screening assays

264 unique, capped per target: 256 binding, 8 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3111725	Binding	Inhibition of WHSC1 (unknown origin)-mediated incorporation of methyl group from [3H]-SAM into peptide substrate up to 50 uM after 1 hr by scintillation proximity assay	Discovery and development of potent and selective inhibitors of histone methyltransferase g9a. — ACS Med Chem Lett
CHEMBL5510077	Functional	In vivo PROTAC activity at CRBN/NSD2 in SCID mouse xenografted with human SEM cells assessed as downregulation of NSD2 level at 60 mg/kg, iv for 5 days by Western blot analysis	Discovery of LLC0424 as a Potent and Selective in Vivo NSD2 PROTAC Degrader. — J Med Chem

Cellosaurus cell lines

37 cell lines: 33 cancer cell line, 4 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_0012	LP-1	Cancer cell line	Female
CVCL_0093	RS4;11	Cancer cell line	Female
CVCL_1851	RCH-ACV	Cancer cell line	Female
CVCL_3122	PALL-2	Cancer cell line	Male
CVCL_3943	KOPN-41	Cancer cell line	Male
CVCL_3993	KOCL-45	Cancer cell line	Male
CVCL_4687	THP-8	Cancer cell line	Female
CVCL_7125	SCMC-L1	Cancer cell line	Female
CVCL_7128	SCMC-L2	Cancer cell line	Male
CVCL_7972	KOPB-26	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE