NSD1

Summary

NSD1 (nuclear receptor binding SET domain protein 1, HGNC:14234) is a protein-coding gene on chromosome 5q35.3, encoding Histone-lysine N-methyltransferase, H3 lysine-36 specific (Q96L73). Histone methyltransferase that dimethylates Lys-36 of histone H3 (H3K36me2). It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein containing a SET domain, 2 LXXLL motifs, 3 nuclear translocation signals (NLSs), 4 plant homeodomain (PHD) finger regions, and a proline-rich region. The encoded protein enhances androgen receptor (AR) transactivation, and this enhancement can be increased further in the presence of other androgen receptor associated coregulators. This protein may act as a nucleus-localized, basic transcriptional factor and also as a bifunctional transcriptional regulator. Mutations of this gene have been associated with Sotos syndrome and Weaver syndrome. One version of childhood acute myeloid leukemia is the result of a cryptic translocation with the breakpoints occurring within nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1 on chromosome 5 and nucleoporin, 98-kd on chromosome 11. Multiple transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 64324 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Sotos syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 43
• Clinical variants (ClinVar): 2,636 total — 463 pathogenic, 178 likely-pathogenic
• Phenotypes (HPO): 194
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 11 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_022455

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14234
Approved symbol	NSD1
Name	nuclear receptor binding SET domain protein 1
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	ARA267, FLJ22263, KMT3B
Ensembl gene	ENSG00000165671
Ensembl biotype	protein_coding
OMIM	606681
Entrez	64324

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 14 protein_coding, 7 protein_coding_CDS_not_defined, 5 retained_intron, 2 nonsense_mediated_decay

ENST00000347982, ENST00000354179, ENST00000375350, ENST00000439151, ENST00000503056, ENST00000504457, ENST00000505395, ENST00000508029, ENST00000508896, ENST00000510954, ENST00000511258, ENST00000513736, ENST00000515735, ENST00000602285, ENST00000638627, ENST00000644863, ENST00000685206, ENST00000686385, ENST00000686993, ENST00000687095, ENST00000687453, ENST00000688613, ENST00000689326, ENST00000689345, ENST00000689549, ENST00000692024, ENST00000936190, ENST00000936191

RefSeq mRNA: 12 — MANE Select: NM_022455 NM_001365684, NM_001409301, NM_001409302, NM_001409303, NM_001409304, NM_001409305, NM_001409306, NM_001409307, NM_001409308, NM_001409309, NM_022455, NM_172349

CCDS: CCDS4412

Canonical transcript exons

ENST00000439151 — 23 exons

Exon	Start	End
ENSE00001378782	177135087	177136030
ENSE00001516123	177133773	177133952
ENSE00001547915	177191884	177192019
ENSE00001549090	177204120	177204292
ENSE00003808375	177209636	177212195
ENSE00004014201	177256951	177257151
ENSE00004014202	177251730	177251853
ENSE00004014203	177283787	177283928
ENSE00004014204	177246678	177246796
ENSE00004014205	177273672	177273784
ENSE00004014206	177248181	177248324
ENSE00004014208	177239756	177239865
ENSE00004014209	177238237	177238507
ENSE00004014210	177291954	177292158
ENSE00004014211	177282465	177282581
ENSE00004014212	177269602	177269807
ENSE00004014213	177235821	177235945
ENSE00004014214	177259989	177260168
ENSE00004014215	177244195	177244270
ENSE00004014216	177280565	177280834
ENSE00004014217	177293832	177300213
ENSE00004014218	177267562	177267718
ENSE00004014219	177288819	177288925

Expression profiles

Bgee: expression breadth ubiquitous, 235 present calls, max score 96.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.4492 / max 352.3882, expressed in 1796 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60460	14.3604	1773
60458	1.3001	865
60462	0.9439	601
60459	0.9164	619
60461	0.7893	365
60457	0.6365	332
203809	0.4902	264
60467	0.0123	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	96.55	gold quality
colonic epithelium	UBERON:0000397	95.88	gold quality
calcaneal tendon	UBERON:0003701	95.00	gold quality
adrenal tissue	UBERON:0018303	94.42	gold quality
ventricular zone	UBERON:0003053	91.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.29	gold quality
ganglionic eminence	UBERON:0004023	90.08	gold quality
cortical plate	UBERON:0005343	89.94	gold quality
tendon	UBERON:0000043	89.44	gold quality
monocyte	CL:0000576	87.31	gold quality
leukocyte	CL:0000738	86.85	gold quality
mononuclear cell	CL:0000842	86.79	gold quality
sperm	CL:0000019	86.60	silver quality
tonsil	UBERON:0002372	86.16	gold quality
corpus callosum	UBERON:0002336	85.97	gold quality
stromal cell of endometrium	CL:0002255	85.54	gold quality
cervix squamous epithelium	UBERON:0006922	85.50	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.19	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.48	gold quality
cerebellar vermis	UBERON:0004720	84.44	gold quality
muscle of leg	UBERON:0001383	84.32	gold quality
male germ cell	CL:0000015	84.28	silver quality
granulocyte	CL:0000094	84.27	gold quality
islet of Langerhans	UBERON:0000006	84.08	gold quality
gastrocnemius	UBERON:0001388	84.03	gold quality
left testis	UBERON:0004533	83.84	gold quality
bone marrow cell	CL:0002092	83.76	gold quality
right testis	UBERON:0004534	83.76	gold quality
blood	UBERON:0000178	83.74	gold quality
testis	UBERON:0000473	83.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.08

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
PRB4	Activation

miRNA regulators (miRDB)

215 targeting NSD1, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• The genomic structure of NSD1 consists of at least 23 exons, the cDNA is 8552 bp long, contains at least six functional domains (SET, PWWP-I, PWWP-II, PHD-I, PHD-II, and PHD-III) and ten putative nuclear localization signals. (PMID:11733144)
• Haploinsufficiency of NSD1 causes Sotos syndrome (PMID:11896389)
• NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes (PMID:12464997)
• A novel 1 base pair mutation in the NSD1 gene is the cause of familial Sotos syndrome in a Sotos syndrome family. (PMID:12525543)
• In 26 patients with Soto’s syndrome 18 of the 20 microdeletions occurred prezygotically in the paternally derived chromosome 5, whereas those in the maternally derived chromosome were found in only two cases (PMID:12687502)
• In Sotos and Weaver syndromes mental retardation was consistently more severe in patients with NSD1 deletions. (PMID:12807965)
• fused to NUP98 and frequently transcribed in childhool AML (PMID:12931227)
• genetic susceptibility in Beckwith-Wiedemann syndrome; NSD1 could be involved in imprinting of the chromosome 11p15 region (PMID:14997421)
• NSD1(+/-) patients show endocrine and paracrine changes in the IGF system (PMID:15362962)
• Mutation or microdeletion of NSD1 is diagnostic of Sotos syndrome. (PMID:15365454)
• Haploinsufficiency of NSD1 is the major cause of Sotos syndrome, and NSD1 plays a role in growth and brain development in humans. (PMID:15539801)
• androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between ARA267-alpha and DR6 (PMID:15623156)
• Deletion of Low-copy repeats that are centromeric and telomeric to NSD1 is associated with Sotos syndrome (PMID:15640245)
• analysis of 266 Sotos syndrome patients with NSD1 aberrations (PMID:15942875)
• REVIEW: mutational analysis in Sotos syndrome (PMID:16010675)
• NSD1 mutation patients showed less severe behavior problems and an easier temperament than NSD1 non-mutation patients, and ADHD was not a consistent finding in these patients. (PMID:16780628)
• The SET domain of NSD1 is involved in NIH3T3 cell growth by modulating serum dependence. (PMID:17437319)
• investigated the NSD1 cDNA sequence in genetically confirmed Sos patients harbouring truncating and missense mutations (PMID:17561922)
• confirms the heterogeneity of NSD1 alterations in Sotos syndrome and therefore the need to complete sequencing analysis by screening for partial deletions and duplications to ensure an accurate molecular diagnosis (PMID:17565729)
• study shows that NUP98-NSD1 induces acute myeloid leukemia in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes (PMID:17589499)
• Screening for NSD1 mutations and deletions in patients with autism and macrocephaly is not warranted in the absence of other features of Sotos syndrome. (PMID:18001468)
• Mutation analysis was performed in 4 patients with Sotos syndrome with typical phenotypic characteristics. In each of the 4 patients a NSD1 mutation was found (2 frame shifts, 1 nonsense and 1 missense mutation). (PMID:19039236)
• Familial Sotos syndrome caused by a novel missense mutation in NSD1 is reported. (PMID:19545651)
• MLPA analysis in 30 Sotos syndrome patients revealed one total NSD1 deletion and two partial deletions not previously reported. (PMID:19596467)
• The severity of the hypodontia seemed to increase with the severity of aberration of the NSD1. (PMID:19876911)
• Data describe a NF-kappaB regulatory pathway that is driven by reversible lysine methylation of p65, carried out by nuclear receptor-binding SET domain-containing protein 1 (NSD1) and F-box and leucine-rich repeat protein 11 (FBXL11). (PMID:20080798)
• study describes two boys with Sotos syndrome in whom PCR amplification & direct sequencing of the NSD1 gene identified 2 novel mutations not previously described: c.4736dupG in exon 12 and c.3938_3939insT in exon (PMID:20420030)
• NSD1 regulates RNAP II recruitment to BMP4, and failure to do so leads to reduced gene expression and abrogated levels of H3K36Me and CTD phosphorylation. (PMID:20837538)
• The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation. (PMID:21196496)
• Our cases suggest a contiguous gene deletion syndrome including NSD1 and SLC34A1 and provide a potential genetic basis for idiopathic infantile hypercalcemia. (PMID:21597970)
• these finding exposes a key regulatory and recognition mechanism driven by the flexibility of a loop at the interface of the SET and postSET region in NSD1 protein. (PMID:21806967)
• NUP98/NSD1 identifies a previously unrecognized group of young AML patients, with distinct characteristics and dismal prognosis, for whom new treatment strategies are urgently needed. (PMID:21813447)
• data suggest that Sotos point mutations in NSD1 PHD domains disrupt its transcriptional regulation by interfering with its ability to bind epigenetic marks and recruit cofactors. (PMID:21972110)
• NSD1 abnormalities were identified in 15 (83%) patients. Among them, eight patients (53%) had 5q35 microdeletions and the other seven patients (47%) had seven different NSD1 intragenic mutations including four novel mutations (PMID:23190751)
• We performed a genetic analysis for Sotos syndrome which revealed a heterozygous mutation on the exon 23 of NSD1. (PMID:23333153)
• NSD1 mutations that cause Sotos syndrome are loss-of-function, primarily truncating mutations or missense mutations at key residues in functional domains. EZH2 mutations that cause Weaver syndrome are primarily missense variants (PMID:23592277)
• NSD1 interaction with liganded NRs including ERa, AR, RARa, RXRa, TRb, PPARg and VDR is mediated by an LXXLL motif. Interaction with the NR2E/F subfamily including COUP-TFI, COUP-TFII, EAR2 and TLX requires an overlapping F/YSXXLXXL/Y motif. (PMID:23975195)
• support to the adoption of screening for NUP98-NSD1 in pediatric AML without otherwise favorable genetic markers (PMID:23999921)
• 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)
• NSD1 prefers aromatic, hydrophobic, and basic residues at the -2, -1 and +2, and +1 sites of its substrate peptide in histone H3. (PMID:24412544)

Cross-species orthologs

22 orthologs

Organism	Symbol	Gene ID
danio_rerio	nsd1a	ENSDARG00000060016
danio_rerio	nsd1b	ENSDARG00000060705
mus_musculus	Nsd1	ENSMUSG00000021488
rattus_norvegicus	Nsd1	ENSRNOG00000016680
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), NSD2 (ENSG00000109685), ASH1L (ENSG00000116539), KMT2A (ENSG00000118058), SETDB2 (ENSG00000136169), SETD1B (ENSG00000139718), SETDB1 (ENSG00000143379), NSD3 (ENSG00000147548), SETBP1 (ENSG00000152217), SUV39H2 (ENSG00000152455), KMT2D (ENSG00000167548), EHMT1 (ENSG00000181090), SETD2 (ENSG00000181555), EHMT2 (ENSG00000204371), KMT2B (ENSG00000272333)

Protein

Protein identifiers

Histone-lysine N-methyltransferase, H3 lysine-36 specific — Q96L73 (reviewed: Q96L73)

Alternative names: Androgen receptor coactivator 267 kDa protein, Androgen receptor-associated protein of 267 kDa, H3-K36-HMTase, Lysine N-methyltransferase 3B, Nuclear receptor-binding SET domain-containing protein 1

All UniProt accessions (8): A0A1W2PS55, A0A2R8Y7J4, A0A8I5KV31, A0A8I5QJP2, Q96L73, D6RBP3, D6RG26, H7BYB0

UniProt curated annotations — full annotation on UniProt →

Function. Histone methyltransferase that dimethylates Lys-36 of histone H3 (H3K36me2). Transcriptional intermediary factor capable of both negatively or positively influencing transcription, depending on the cellular context.

Subunit / interactions. Interacts with the ligand-binding domains of RARA and THRA in the absence of ligand; in the presence of ligand the interaction is severely disrupted but some binding still occurs. Interacts with the ligand-binding domains of RXRA and ESRRA only in the presence of ligand. Interacts with ZNF496. Interacts with AR DNA- and ligand-binding domains.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Expressed in the fetal/adult brain, kidney, skeletal muscle, spleen, and the thymus, and faintly in the lung.

Disease relevance. Sotos syndrome (SOTOS) [MIM:117550] An autosomal dominant, childhood overgrowth syndrome characterized by pre- and postnatal overgrowth, developmental delay, intellectual disability, advanced bone age, and abnormal craniofacial morphology including macrodolichocephaly with frontal bossing, frontoparietal sparseness of hair, apparent hypertelorism, downslanting palpebral fissures, and facial flushing. Common oral findings include: premature eruption of teeth; high, arched palate; pointed chin and, more rarely, prognathism. The disease is caused by variants affecting the gene represented in this entry. Beckwith-Wiedemann syndrome (BWS) [MIM:130650] A disorder characterized by anterior abdominal wall defects including exomphalos (omphalocele), pre- and postnatal overgrowth, and macroglossia. Additional less frequent complications include specific developmental defects and a predisposition to embryonal tumors. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving NSD1 is found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NUP98. A chromosomal aberration involving NSD1 is found in an adult form of myelodysplastic syndrome (MDS). Insertion of NUP98 into NSD1 generates a NUP98-NSD1 fusion product.

Similarity. Belongs to the class V-like SAM-binding methyltransferase superfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96L73-1	1, ARA267-beta	yes
Q96L73-2	2, ARA267-alpha
Q96L73-3	3

RefSeq proteins (12): NP_001352613, NP_001396230, NP_001396231, NP_001396232, NP_001396233, NP_001396234, NP_001396235, NP_001396236, NP_001396237, NP_001396238, NP_071900, NP_758859 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000313	PWWP_dom	Domain
IPR001214	SET_dom	Domain
IPR001965	Znf_PHD	Domain
IPR003616	Post-SET_dom	Domain
IPR006560	AWS_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
IPR041306	C5HCH	Domain
IPR046341	SET_dom_sf	Homologous_superfamily
IPR047423	PWWP_NSD1_rpt2	Domain
IPR047426	PHD1_NSD1_2	Domain
IPR047428	PHD2_NSD1	Domain
IPR047429	PHD3_NSD1	Domain
IPR047430	PHD4_NSD1	Domain
IPR047432	PHD5_NSD1	Domain
IPR047433	SET_NSD1	Domain
IPR050777	SET2_Histone-Lys_MeTrsfase	Family
IPR055197	PHDvar_NSD	Domain
IPR055198	NSD_PHD	Domain
IPR059153	NSD_PHD-1st	Domain

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

Enzyme classification (BRENDA):

• EC 2.1.1.357 — [histone H3]-lysine36 N-dimethyltransferase (BRENDA: 4 organisms, 14 substrates, 5 inhibitors, 4 Km, 2 kcat entries)
• EC 2.1.1.362 — [histone H4]-N-methyl-L-lysine20 N-methyltransferase (BRENDA: 4 organisms, 9 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
S-ADENOSYL-L-METHIONINE	0.0028–0.0038	2
CHICKEN NUCLEOSOME	0.0003	1
RECOMBINANT NUCLEOSOME	—	1

Catalyzed reactions (Rhea), 1 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)

UniProt features (136 total): sequence conflict 26, sequence variant 21, compositionally biased region 19, region of interest 18, strand 11, helix 9, modified residue 8, domain 5, binding site 5, zinc finger region 4, cross-link 3, splice variant 3, mutagenesis site 2, chain 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3OOI	X-RAY DIFFRACTION	1.75
6KQQ	X-RAY DIFFRACTION	1.8
6KQP	X-RAY DIFFRACTION	2.4
8C5L	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96L73-F1	45.26	0.13

Functional residue map

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

Ligand- & substrate-binding residues (5): 1952–1954; 1994–1997; 2020–2021; 2065; 2071

Post-translational modifications (11): 117, 483, 486, 766, 1510, 2369, 2462, 2471, 906, 1339, 2616

Mutagenesis-validated functional residues (2):

Position	Phenotype
1914	reduced enzyme activity.
1952	nearly abolished enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3214841	PKMTs methylate histone lysines

MSigDB gene sets: 652 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, MYAATNNNNNNNGGC_UNKNOWN, GOBP_REGULATION_OF_PHOSPHORYLATION, NKX25_02, AAGTCCA_MIR422B_MIR422A, GOBP_PEPTIDYL_SERINE_MODIFICATION, GGCNKCCATNK_UNKNOWN, SHEPARD_BMYB_MORPHOLINO_DN, NFKB_Q6, NKX61_01, GOBP_REGULATION_OF_PEPTIDYL_SERINE_PHOSPHORYLATION, TGCTGAY_UNKNOWN, GRE_C, OCT1_06, KEGG_LYSINE_DEGRADATION

GO Biological Process (8): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), methylation (GO:0032259), regulation of peptidyl-serine phosphorylation (GO:0033135), positive regulation of DNA-templated transcription (GO:0045893), regulation of RNA polymerase II regulatory region sequence-specific DNA binding (GO:1903025), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338)

GO Molecular Function (20): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), chromatin binding (GO:0003682), transcription coregulator activity (GO:0003712), transcription corepressor activity (GO:0003714), zinc ion binding (GO:0008270), nuclear estrogen receptor binding (GO:0030331), histone H4K20 methyltransferase activity (GO:0042799), nuclear retinoic acid receptor binding (GO:0042974), nuclear retinoid X receptor binding (GO:0046965), nuclear thyroid hormone receptor binding (GO:0046966), histone H3K36 methyltransferase activity (GO:0046975), nuclear androgen receptor binding (GO:0050681), histone H3 methyltransferase activity (GO:0140938), histone H3K36 dimethyltransferase activity (GO:0140954), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), nuclear receptor binding (GO:0016922), histone methyltransferase activity (GO:0042054), metal ion binding (GO:0046872)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Chromatin modifying enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear receptor binding	4
negative regulation of DNA-templated transcription	2
DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
binding	2
protein-lysine N-methyltransferase activity	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
metabolic process	1
regulation of protein phosphorylation	1
peptidyl-serine phosphorylation	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription regulatory region DNA binding	1
cellular component organization	1
chromatin organization	1
cis-regulatory region sequence-specific DNA binding	1
transcription regulator activity	1
transcription coregulator activity	1
transition metal ion binding	1
histone H4 methyltransferase activity	1
nuclear retinoic acid receptor binding	1
histone H3 methyltransferase activity	1
histone methyltransferase activity	1
histone H3K36 methyltransferase activity	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
protein methyltransferase activity	1
histone modifying activity	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2774 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NSD1	NUP98	P52948	931
NSD1	DDX10	Q13206	731
NSD1	PHF23	Q9BUL5	725
NSD1	PSIP1	O75475	717
NSD1	ZNF496	Q96IT1	671
NSD1	SETBP1	Q9Y6X0	663
NSD1	MLLT10	P55197	656
NSD1	MLLT3	P42568	624
NSD1	RAP1GDS1	P52306	620
NSD1	HOXA9	P31269	614
NSD1	DOT1L	Q8TEK3	612
NSD1	SMYD2	Q9NRG4	604
NSD1	SETD3	Q86TU7	602
NSD1	KMT5B	Q4FZB7	597
NSD1	H4C7	Q99525	592

IntAct

47 interactions, top by confidence:

A	B	Type	Score
NSD1	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
NSD1	HMGA1	psi-mi:“MI:0915”(physical association)	0.560
G3BP1	NSD1	psi-mi:“MI:0407”(direct interaction)	0.560
MECP2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
ZBTB48	ZBTB24	psi-mi:“MI:0914”(association)	0.530
NSD1	G3BP2	psi-mi:“MI:0407”(direct interaction)	0.440
RELA	NSD1	psi-mi:“MI:0915”(physical association)	0.400
NSD1	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
NSD1	H1-2	psi-mi:“MI:0915”(physical association)	0.400
NSD1	PABPC1	psi-mi:“MI:0915”(physical association)	0.400
NSD1	YTHDC1	psi-mi:“MI:0915”(physical association)	0.400
NSD1	H1-4	psi-mi:“MI:0915”(physical association)	0.400
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
H2AZ1	SUPT5H	psi-mi:“MI:0914”(association)	0.350
H2BC21	SMCHD1	psi-mi:“MI:0914”(association)	0.350
NPM1	RPS3A	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
ZNF467	ZNF320	psi-mi:“MI:0914”(association)	0.350
CEACAM16	SBNO1	psi-mi:“MI:0914”(association)	0.350
RPL36	GTPBP10	psi-mi:“MI:0914”(association)	0.350
ILF3	GTPBP10	psi-mi:“MI:0914”(association)	0.350
ANOS1	ZNF724	psi-mi:“MI:0914”(association)	0.350
RPL4	POLRMT	psi-mi:“MI:0914”(association)	0.350
RPL23A	MPHOSPH10	psi-mi:“MI:0914”(association)	0.350
RSL1D1	MPHOSPH10	psi-mi:“MI:0914”(association)	0.350
LARP7	U2SURP	psi-mi:“MI:0914”(association)	0.350

BioGRID (158): HIST3H3 (Biochemical Activity), HIST1H1B (Biochemical Activity), ATRX (Biochemical Activity), HIST4H4 (Biochemical Activity), SNORD3A (Biochemical Activity), HIST1H1D (Biochemical Activity), HIST1H1C (Biochemical Activity), NSD1 (Affinity Capture-MS), NSD1 (Affinity Capture-MS), HIST1H3A (Biochemical Activity), HIST1H4A (Biochemical Activity), NSD1 (Affinity Capture-Western), NSD1 (Reconstituted Complex), NSD1 (Affinity Capture-MS), NSD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A087WXM9, A0A2K1JJ00, A0JM83, A4IGL8, E1BC15, E9Q5F9, O14513, O35923, O60673, O88491, P46013, P97929, Q14B71, Q28DZ0, Q29RT4, Q3MHH3, Q3TNU4, Q3ZBP0, Q4QY64, Q4V7J0, Q5DTT3, Q5E9A0, Q5F2C3, Q5RD08, Q5VWN6, Q5VYV7, Q61493, Q69YH5, Q6NS59, Q703I1, Q80U59, Q86XD8, Q8IXS0, Q8IYL3, Q8L7I1, Q8N7Z5, Q8NFU7, Q8TEP8, Q92628, Q96BU1

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

4 interactions.

A	Effect	B	Mechanism
NSD1	up-regulates	RELA	methylation
NSD1	up-regulates	NfKb-p65/p50	methylation
NSD1	“up-regulates quantity by expression”	PRB4	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 56 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
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	7	21.7×	8e-06
Peptide chain elongation	6	20.0×	2e-05
Viral mRNA Translation	6	20.0×	2e-05
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	6	19.8×	2e-05
Selenocysteine synthesis	6	19.0×	2e-05
Eukaryotic Translation Termination	6	19.0×	2e-05
L13a-mediated translational silencing of Ceruloplasmin expression	7	18.6×	1e-05
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	6	18.6×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	6	21.0×	1e-04
nucleosome assembly	5	13.2×	3e-03
translation	5	9.7×	9e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 11 cancer types — BLCA, CEAD, ESCA, HNSC, LUSC, MEL, MLYM, NPC, PAST, STOMACH, UCEC.

Clinical variants and AI predictions

ClinVar

2636 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	463
Likely pathogenic	178
Uncertain significance	935
Likely benign	565
Benign	122

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028263	NM_022455.5(NSD1):c.4378+1G>T	Pathogenic
1038714	NM_022455.5(NSD1):c.6475T>A (p.Cys2159Ser)	Pathogenic
1065474	NM_022455.5(NSD1):c.3364dup (p.Ile1122fs)	Pathogenic
1068588	NM_022455.5(NSD1):c.4655T>A (p.Leu1552Ter)	Pathogenic
1069132	NM_022455.5(NSD1):c.5753_5754del (p.Leu1917_Tyr1918insTer)	Pathogenic
1069920	NM_022455.5(NSD1):c.6294del (p.Lys2098fs)	Pathogenic
1071923	NM_022455.5(NSD1):c.4514dup (p.His1505fs)	Pathogenic
1073231	NM_022455.5(NSD1):c.4672dup (p.Cys1558fs)	Pathogenic
1073800	NM_022455.5(NSD1):c.2674del (p.Ser892fs)	Pathogenic
1074877	NM_022455.5(NSD1):c.5190T>G (p.His1730Gln)	Pathogenic
1074998	NM_022455.5(NSD1):c.3145_3146dup (p.Thr1050fs)	Pathogenic
1076373	NM_022455.5(NSD1):c.3254del (p.Pro1085fs)	Pathogenic
1076793	NM_022455.5(NSD1):c.1828C>T (p.Gln610Ter)	Pathogenic
1172670	NM_022455.5(NSD1):c.3109C>T (p.Gln1037Ter)	Pathogenic
1176497	NM_022455.5(NSD1):c.858del (p.Ser287fs)	Pathogenic
1191918	NM_022455.5(NSD1):c.5855G>A (p.Arg1952Gln)	Pathogenic
1202491	NM_022455.5(NSD1):c.1318C>T (p.Arg440Ter)	Pathogenic
1210027	NM_022455.5(NSD1):c.5741G>T (p.Arg1914Leu)	Pathogenic
1214278	NM_022455.5(NSD1):c.1216_1219del (p.Glu406fs)	Pathogenic
1283908	NM_022455.5(NSD1):c.4220_4221del (p.Lys1407fs)	Pathogenic
1299651	NM_022455.5(NSD1):c.5824_5828del (p.Pro1942fs)	Pathogenic
1320149	NM_022455.5(NSD1):c.1727dup (p.Asn576fs)	Pathogenic
1321321	NM_022455.5(NSD1):c.4361C>G (p.Ser1454Ter)	Pathogenic
1323377	NM_022455.5(NSD1):c.6258+1G>T	Pathogenic
1331627	NM_022455.5(NSD1):c.911C>A (p.Ser304Ter)	Pathogenic
1338369	NM_022455.5(NSD1):c.6488del (p.Gln2163fs)	Pathogenic
1338653	NM_022455.5(NSD1):c.2808C>A (p.Tyr936Ter)	Pathogenic
1339482	NM_022455.5(NSD1):c.3017del (p.Pro1006fs)	Pathogenic
1365499	NM_022455.5(NSD1):c.3701T>G (p.Leu1234Ter)	Pathogenic
1366561	NM_022455.5(NSD1):c.2163_2181del (p.Gly722fs)	Pathogenic

SpliceAI

4415 predictions. Top by Δscore:

Variant	Effect	Δscore
5:177134527:G:GT	donor_gain	1.0000
5:177136019:G:GT	donor_gain	1.0000
5:177136020:A:T	donor_gain	1.0000
5:177136028:TTT:T	donor_gain	1.0000
5:177136031:G:GG	donor_gain	1.0000
5:177169365:A:AG	acceptor_gain	1.0000
5:177169366:A:G	acceptor_gain	1.0000
5:177169369:T:TA	acceptor_gain	1.0000
5:177191856:T:A	acceptor_gain	1.0000
5:177191875:T:TA	acceptor_gain	1.0000
5:177191880:A:AG	acceptor_gain	1.0000
5:177191880:AAAGT:A	acceptor_gain	1.0000
5:177191881:A:G	acceptor_gain	1.0000
5:177191882:A:AG	acceptor_gain	1.0000
5:177191883:G:GG	acceptor_gain	1.0000
5:177191883:GT:G	acceptor_gain	1.0000
5:177192016:AAAGG:A	donor_loss	1.0000
5:177192017:AAGGT:A	donor_loss	1.0000
5:177192020:G:GA	donor_loss	1.0000
5:177192021:T:A	donor_loss	1.0000
5:177204117:TA:T	acceptor_loss	1.0000
5:177204118:A:AG	acceptor_gain	1.0000
5:177204118:AG:A	acceptor_loss	1.0000
5:177204119:G:GA	acceptor_gain	1.0000
5:177204119:GT:G	acceptor_gain	1.0000
5:177204119:GTTT:G	acceptor_gain	1.0000
5:177204279:GATA:G	donor_gain	1.0000
5:177204289:TAAG:T	donor_loss	1.0000
5:177204290:AAG:A	donor_loss	1.0000
5:177204292:GGTAG:G	donor_loss	1.0000

AlphaMissense

17693 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:177191938:T:A	W328R	1.000
5:177191938:T:C	W328R	1.000
5:177191939:G:C	W328S	1.000
5:177191940:G:C	W328C	1.000
5:177191940:G:T	W328C	1.000
5:177191962:T:A	W336R	1.000
5:177191962:T:C	W336R	1.000
5:177191964:G:C	W336C	1.000
5:177191964:G:T	W336C	1.000
5:177191965:T:A	W337R	1.000
5:177191965:T:C	W337R	1.000
5:177191969:C:A	P338H	1.000
5:177204185:T:A	W377R	1.000
5:177204185:T:C	W377R	1.000
5:177204240:T:C	L395P	1.000
5:177209660:T:A	W421R	1.000
5:177209660:T:C	W421R	1.000
5:177209661:G:C	W421S	1.000
5:177209662:G:C	W421C	1.000
5:177209662:G:T	W421C	1.000
5:177248319:T:A	C1546S	1.000
5:177248319:T:C	C1546R	1.000
5:177248320:G:A	C1546Y	1.000
5:177248320:G:C	C1546S	1.000
5:177248321:T:G	C1546W	1.000
5:177251752:T:C	L1555P	1.000
5:177251755:T:C	L1556P	1.000
5:177251760:T:A	C1558S	1.000
5:177251760:T:C	C1558R	1.000
5:177251761:G:A	C1558Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000005820 (5:177268819 A>G), RS1000009801 (5:177289440 T>A), RS1000036439 (5:177139978 G>A), RS1000067308 (5:177150427 G>C), RS1000072133 (5:177146699 C>G), RS1000077764 (5:177241372 G>C,T), RS1000088425 (5:177140334 T>C), RS1000114112 (5:177159681 C>G,T), RS1000116471 (5:177162287 G>A), RS1000170661 (5:177162570 G>A), RS1000198684 (5:177281931 C>T), RS1000207383 (5:177241159 C>T), RS1000239371 (5:177227469 T>A,G), RS1000242235 (5:177244447 C>T), RS1000253837 (5:177144640 G>A,C)

Disease associations

OMIM: gene MIM:606681 | disease phenotypes: MIM:117550, MIM:236750, MIM:157170, MIM:130650, MIM:601626, MIM:189800, MIM:603563

GenCC curated gene-disease

Disease	Classification	Inheritance
Sotos syndrome 1	Definitive	Autosomal dominant
Sotos syndrome	Definitive	Autosomal dominant
Beckwith-Wiedemann syndrome due to NSD1 mutation	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Sotos syndrome	Definitive	AD

Mondo (14): Sotos syndrome (MONDO:0019349), neurodevelopmental disorder (MONDO:0700092), non-immune hydrops fetalis (MONDO:0009369), holoprosencephaly 2 (MONDO:0007999), intellectual disability (MONDO:0001071), Beckwith-Wiedemann syndrome (MONDO:0007534), acute myeloid leukemia (MONDO:0018874), preeclampsia (MONDO:0005081), scoliosis (MONDO:0005392), choroid plexus carcinoma (MONDO:0016718), hereditary spastic paraplegia 8 (MONDO:0011339), microcephaly (MONDO:0001149), (MONDO:0007299), Beckwith-Wiedemann syndrome due to NSD1 mutation (MONDO:0016547)

Orphanet (9): Sotos syndrome (Orphanet:821), Non-immune hydrops fetalis (Orphanet:363999), Holoprosencephaly (Orphanet:2162), Beckwith-Wiedemann syndrome (Orphanet:116), Acute myeloid leukemia (Orphanet:519), Preeclampsia (Orphanet:275555), Choroid plexus carcinoma (Orphanet:251899), Autosomal dominant spastic paraplegia type 8 (Orphanet:100989), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

194 total (30 of 194 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000034	Hydrocele testis
HP:0000047	Hypospadias
HP:0000073	Ureteral duplication
HP:0000074	Ureteropelvic junction obstruction
HP:0000076	Vesicoureteral reflux
HP:0000077	Abnormality of the kidney
HP:0000083	Renal insufficiency
HP:0000098	Tall stature
HP:0000104	Renal agenesis
HP:0000126	Hydronephrosis
HP:0000144	Decreased fertility
HP:0000164	Abnormality of the dentition
HP:0000189	Narrow palate
HP:0000218	High palate
HP:0000239	Large fontanelles
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000311	Round face
HP:0000316	Hypertelorism

GWAS associations

43 associations (top):

Study	Trait	p-value
GCST001574_7	Activated partial thromboplastin time	6.000000e-88
GCST002647_130	Height	5.000000e-11
GCST002830_5	Urate levels in lean individuals	4.000000e-06
GCST004562_100	Waist circumference adjusted for body mass index	5.000000e-11
GCST004562_126	Waist circumference adjusted for body mass index	1.000000e-12
GCST004562_167	Waist circumference adjusted for body mass index	6.000000e-13
GCST004562_223	Waist circumference adjusted for body mass index	5.000000e-11
GCST004562_23	Waist circumference adjusted for body mass index	3.000000e-10
GCST004563_103	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	6.000000e-12
GCST004563_186	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	1.000000e-10
GCST004563_240	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	6.000000e-12
GCST004563_6	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	1.000000e-09
GCST004563_87	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	3.000000e-10
GCST004564_35	Waist circumference adjusted for BMI in active individuals	2.000000e-07
GCST004564_36	Waist circumference adjusted for BMI in active individuals	3.000000e-10
GCST004564_37	Waist circumference adjusted for BMI in active individuals	5.000000e-07
GCST004564_38	Waist circumference adjusted for BMI in active individuals	9.000000e-08
GCST004564_39	Waist circumference adjusted for BMI in active individuals	3.000000e-10
GCST005956_15	Waist-to-hip ratio adjusted for BMI	1.000000e-07
GCST005957_13	Waist-to-hip ratio adjusted for BMI (age <50)	3.000000e-07
GCST005962_42	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-08
GCST006491_7	Circulating fibroblast growth factor 23 levels	1.000000e-07
GCST007293_138	Body fat distribution (arm fat ratio)	1.000000e-08
GCST007293_79	Body fat distribution (arm fat ratio)	2.000000e-11
GCST007293_97	Body fat distribution (arm fat ratio)	2.000000e-10
GCST007294_102	Body fat distribution (trunk fat ratio)	2.000000e-10
GCST007294_155	Body fat distribution (trunk fat ratio)	4.000000e-09
GCST007640_1	Narrowest width of the femoral neck	2.000000e-08
GCST008839_461	Height	7.000000e-10
GCST008971_108	Urate levels	3.000000e-08

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008002	physical activity measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004341	body fat distribution
EFO:0004511	femoral neck bone geometry
EFO:0003959	cleft lip
EFO:0008039	BMI-adjusted hip circumference
EFO:0004587	lymphocyte count
EFO:0004833	neutrophil count

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D001506	Beckwith-Wiedemann Syndrome	C16.131.077.133; C16.131.260.080; C16.320.180.080; C16.320.447.375
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D015470	Leukemia, Myeloid, Acute	C04.557.337.539.275; C15.378.508.539.275
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
D011225	Pre-Eclampsia	C12.050.703.395.249
D012600	Scoliosis	C05.116.900.800.875
D058495	Sotos Syndrome	C16.131.077.889; C16.131.260.905; C16.320.180.905
C562943	Choroid Plexus Carcinoma (supp.)
C563579	Holoprosencephaly 2 (supp.)
C580458	Spastic Paraplegia Type 8 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3588738 (SINGLE PROTEIN), CHEMBL6066040 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 70,511 (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
CHEMBL506	PRIMAQUINE	4	10,279
CHEMBL58510	CHLOROQUINE PHOSPHATE	4	5,477
CHEMBL265502	SURAMIN	3	36,848
CHEMBL1214186	SINEFUNGIN	2	2,165
CHEMBL1215331	PF-03882845	1	59
CHEMBL295316	PLUMBAGIN	1	6,294

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	6.16	pIC50

ChEMBL bioactivities

28 potent at pChembl≥5 of 40 total, top 25 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.96	IC50	110	nM	CHEMBL337173
6.82	IC50	150	nM	CHEMBL337173
6.80	IC50	160	nM	CHEMBL5408212
6.67	IC50	214	nM	CHEMBL5438312
6.65	IC50	225	nM	CHEMBL5419719
6.61	IC50	248	nM	CHEMBL5396709
6.57	IC50	270	nM	CHEMBL5432302
6.47	IC50	340	nM	CHEMBL2028187
6.16	IC50	690	nM	CHEMBL5422549
5.92	Kd	1200	nM	CHEMBL5438496
5.85	Kd	1400	nM	QUINACRINE DIHYDROCHLORIDE
5.85	IC50	1400	nM	TANSHINONE IIA
5.82	IC50	1500	nM	CHEMBL6170408
5.75	IC50	1800	nM	PRIMAQUINE
5.70	IC50	2000	nM	NAPHTHOQUINONE
5.62	IC50	2400	nM	VENETOCLAX
5.58	IC50	2600	nM	CHEMBL1572280
5.58	IC50	2600	nM	CHEMBL337173
5.51	IC50	3100	nM	TANSHINONE I
5.46	IC50	3500	nM	CRYPTOTANSHINONE
5.33	Kd	4700	nM	CHLOROQUINE PHOSPHATE
5.31	IC50	4900	nM	CHEMBL1361596
5.24	IC50	5800	nM	CHEMBL5270736
5.24	IC50	5700	nM	PLUMBAGIN
5.23	IC50	5900	nM	CHEMBL6149804

PubChem BioAssay actives

18 with measured affinity, of 115 total; 12 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-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione	2017799: Inhibition of N-terminal polyhistidine-tagged recombinant human NSD1 (1538 to 2696 residues) expressed in baculovirus infected insect cell using SAM as substrate preincubated for 20 mins followed by substrate addition measured after 1 hrs by hotspot assay	ic50	0.1100	uM
9-[[5-[(3R)-3-amino-3-(methoxymethyl)piperidin-1-yl]-2-(3,4-difluorophenyl)-4-pyridinyl]methyl]purin-6-amine	2011299: Inhibition of human recombinant NSD1 incubated for 2 hrs by AlphaLISA method	ic50	0.1600	uM
9-[[5-[(3R)-3-amino-3-(cyclopropyloxymethyl)piperidin-1-yl]-2-(3,4-difluorophenyl)-4-pyridinyl]methyl]purin-6-amine	2011299: Inhibition of human recombinant NSD1 incubated for 2 hrs by AlphaLISA method	ic50	0.2140	uM
9-[[5-[(3R)-3-amino-3-(methoxymethyl)piperidin-1-yl]-2-(2,4-difluorophenyl)-4-pyridinyl]methyl]purin-6-amine	2011299: Inhibition of human recombinant NSD1 incubated for 2 hrs by AlphaLISA method	ic50	0.2250	uM
9-[[5-[(3R)-3-amino-3-(methoxymethyl)piperidin-1-yl]-2-(5-chloro-2-fluorophenyl)-4-pyridinyl]methyl]purin-6-amine	2011299: Inhibition of human recombinant NSD1 incubated for 2 hrs by AlphaLISA method	ic50	0.2480	uM
9-[[5-[(3R)-3-amino-3-(cyclobutyloxymethyl)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4-pyridinyl]methyl]purin-6-amine	2011299: Inhibition of human recombinant NSD1 incubated for 2 hrs by AlphaLISA method	ic50	0.2700	uM
N-[3-[(7-chloro-5,8-dioxoquinolin-6-yl)amino]-1-bicyclo[1.1.1]pentanyl]but-2-ynamide	1966592: Inhibition of NSD1 (unknown origin)	ic50	0.6900	uM
5,8-dihydroxy-1,4-bis[2-(2-hydroxyethylamino)ethylamino]-4a,9a-dihydroanthracene-9,10-dione;dihydrochloride	2011305: Binding affinity to NSD1 (unknown origin) assessed as dissociation constant by ITC assay	kd	1.2000	uM
2-amino-6-(2-methylaziridin-1-yl)-1,3-benzothiazol-4-ol	1980351: Inhibition of NSD1 (unknown origin) measured after 16 hrs by MS assay	ic50	1.4000	uM
4-N-(6-chloro-2-methoxyacridin-9-yl)-1-N,1-N-diethylpentane-1,4-diamine;dihydrochloride	2011305: Binding affinity to NSD1 (unknown origin) assessed as dissociation constant by ITC assay	kd	1.4000	uM
Venetoclax	2017799: Inhibition of N-terminal polyhistidine-tagged recombinant human NSD1 (1538 to 2696 residues) expressed in baculovirus infected insect cell using SAM as substrate preincubated for 20 mins followed by substrate addition measured after 1 hrs by hotspot assay	ic50	2.4000	uM
Chloroquine Phosphate	2011305: Binding affinity to NSD1 (unknown origin) assessed as dissociation constant by ITC assay	kd	4.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	5
bisphenol A	affects binding, affects folding, decreases reaction, decreases expression	3
bisphenol AF	decreases reaction, affects binding, affects folding	2
Estradiol	affects binding, increases reaction	2
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
afimoxifene	affects response to substance	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
coumarin	increases phosphorylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
CGP 52608	increases reaction, affects binding	1
abrine	decreases expression	1
Acrolein	increases abundance, affects cotreatment, decreases expression	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	decreases expression	1
Diethylstilbestrol	decreases expression	1
Formaldehyde	increases expression	1
Lead	affects expression	1
Ozone	decreases expression, increases abundance, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Asbestos, Crocidolite	affects expression	1
Cadmium Chloride	decreases expression	1
Volatile Organic Compounds	affects cotreatment, decreases expression	1

ChEMBL screening assays

90 unique, capped per target: 90 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3592411	Binding	Inhibition of NSD1 (unknown origin) at 1 uM after 1 hr by filter-based assay	Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2. — ACS Med Chem Lett

Cellosaurus cell lines

11 cell lines: 5 cancer cell line, 3 transformed cell line, 3 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B3CT	Abcam HEK293T NSD1 KO	Transformed cell line	Female
CVCL_C7FT	IGGi001-A	Induced pluripotent stem cell	Female
CVCL_C7FU	IGGi001-B	Induced pluripotent stem cell	Female
CVCL_D6MP	IGGi003-A	Induced pluripotent stem cell	Female
CVCL_E3GB	HCI-EC-23	Cancer cell line	Female
CVCL_F102	GM19977	Transformed cell line	Male
CVCL_F103	GM19978	Transformed cell line	Male
CVCL_TB11	HAP1 NSD1 (-) 1	Cancer cell line	Male
CVCL_TB12	HAP1 NSD1 (-) 2	Cancer cell line	Male
CVCL_TB13	HAP1 NSD1 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

298 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,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
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
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT04993235	Not specified	UNKNOWN	Body Perception and Representation in Overgrowth Syndromes, Behavioral Assessment and Neuropsychological Development
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders