SETD1B

Summary

SETD1B (SET domain containing 1B, histone lysine methyltransferase, HGNC:29187) is a protein-coding gene on chromosome 12q24.31, encoding Histone-lysine N-methyltransferase SETD1B (Q9UPS6). Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4) via a non-processive mechanism. It is a selective cancer dependency (DepMap: 14.9% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

SET1B is a component of a histone methyltransferase complex that produces trimethylated histone H3 at Lys4 (Lee et al., 2007 [PubMed 17355966]).

Source: NCBI Gene 23067 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 795 total — 57 pathogenic, 33 likely-pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 8 cancer types
• Cancer dependency (DepMap): dependent in 14.9% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001353345

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29187
Approved symbol	SETD1B
Name	SET domain containing 1B, histone lysine methyltransferase
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1076, Set1B, KMT2G
Ensembl gene	ENSG00000139718
Ensembl biotype	protein_coding
OMIM	611055
Entrez	23067

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000542440, ENST00000604567, ENST00000619791

RefSeq mRNA: 1 — MANE Select: NM_001353345 NM_001353345

CCDS: CCDS86338

Canonical transcript exons

ENST00000604567 — 17 exons

Exon	Start	End
ENSE00000939838	121825200	121825366
ENSE00001123014	121827933	121828070
ENSE00001123019	121827735	121827854
ENSE00001123024	121827519	121827650
ENSE00001189919	121822490	121823749
ENSE00001322154	121819404	121819895
ENSE00001625414	121809603	121810835
ENSE00001670989	121817033	121817294
ENSE00001673307	121814106	121814930
ENSE00001691720	121805835	121806105
ENSE00001749776	121808208	121808320
ENSE00001755962	121817799	121817904
ENSE00001771972	121805118	121805216
ENSE00002304612	121804724	121804911
ENSE00003463311	121817370	121817704
ENSE00003905207	121830066	121832656
ENSE00003907027	121804009	121804233

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 96.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.1119 / max 252.8718, expressed in 1807 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128467	13.7897	1790
128466	5.8604	1714
128468	0.1870	68
128469	0.1696	69
206937	0.1052	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood vessel layer	UBERON:0004797	96.56	gold quality
cervix squamous epithelium	UBERON:0006922	96.33	gold quality
hair follicle	UBERON:0002073	96.18	gold quality
parietal pleura	UBERON:0002400	96.18	gold quality
cardia of stomach	UBERON:0001162	96.16	gold quality
visceral pleura	UBERON:0002401	96.05	gold quality
urethra	UBERON:0000057	95.95	gold quality
nipple	UBERON:0002030	95.73	gold quality
pleura	UBERON:0000977	95.66	gold quality
saphenous vein	UBERON:0007318	95.64	gold quality
germinal epithelium of ovary	UBERON:0001304	95.52	gold quality
seminal vesicle	UBERON:0000998	95.39	gold quality
pylorus	UBERON:0001166	95.36	gold quality
mucosa of stomach	UBERON:0001199	95.15	gold quality
tibia	UBERON:0000979	94.84	gold quality
squamous epithelium	UBERON:0006914	94.73	gold quality
gingival epithelium	UBERON:0001949	94.63	gold quality
mucosa of urinary bladder	UBERON:0001259	94.52	gold quality
esophagus squamous epithelium	UBERON:0006920	94.48	gold quality
epithelium of esophagus	UBERON:0001976	94.46	gold quality
superficial temporal artery	UBERON:0001614	94.36	gold quality
trabecular bone tissue	UBERON:0002483	94.22	gold quality
epithelium of nasopharynx	UBERON:0001951	94.10	gold quality
gingiva	UBERON:0001828	94.06	gold quality
renal medulla	UBERON:0000362	93.98	gold quality
oviduct epithelium	UBERON:0004804	93.97	gold quality
superior surface of tongue	UBERON:0007371	93.73	gold quality
pharyngeal mucosa	UBERON:0000355	93.64	gold quality
penis	UBERON:0000989	93.55	gold quality
caput epididymis	UBERON:0004358	93.39	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.32

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 14.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 15)

• both Rbm15 and the leukemogenic Rbm15-Mkl1 fusion protein interact with the Setd1b histone H3-Lys4 methyltransferase (PMID:22927943)
• We analyzed SETD1B expression in gastric and colorectal cancer. Loss of SETD1B was identified in 15% to 55% of the GC and CRC with respect to the microsatellite instability status. Loss of expression was more common in those with SETD1B mutations. (PMID:24925220)
• we propose histone demethylase KDM2B and histone methyltransferase SETD1B as the two most plausible candidate genes involved in intellectual disability, autism, epilepsy, and craniofacial anomalies (PMID:27106595)
• report the existence of a cytoplasmic form of SET1B/COMPASS, which is essential for maintaining breast tumor cell viability and promotes cell growth. (PMID:29138278)
• SETD1B aberration is likely to be the core defect in 12q24.3 deletion syndrome. (PMID:29322246)
• KMT2G levels were higher in metastatic clear cell renal cell carcinomas and may be a good marker for discriminating metastatic tumors from non-metastatic tumors. (PMID:29944950)
• the results demonstrated that SETD1B is essential in the progression of hepatocellular carcinoma and may be used as a potential prognostic marker and therapeutic target in hepatocellular carcinoma. (PMID:30628696)
• Results show that SETD1B is the most frequently mutated gene along with TP53 in primary hepatic neuroendocrine tumors (PHNETs). A biological analysis suggests that one of the three SETD1B mutants, A1054del, promotes cell proliferation, migration and invasion compared to wild-type SETD1B. Our work unveils that SETD1B A1054del mutant is functional in PHNET and implicates this gene on PHNET pathogenesis. (PMID:30977120)
• we report a first epilepsy patient with a frameshift variant in SETD1B, emphasizing a possible pathomechanistic association of SETD1B abnormality with neurodevelopmental delay with epilepsy. (PMID:31110234)
• Study identify a specific hypermethylation signature associated with loss of function mutations in the SETD1B gene which may be used as an epigenetic marker supporting the diagnosis of syndromic SETD1B-related diseases. (PMID:31685013)
• SETD1B-associated neurodevelopmental disorder. (PMID:32546566)
• Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome. (PMID:34345025)
• Molecular insight into the SETD1A/B N-terminal region and its interaction with WDR82. (PMID:37030068)
• Phenotypic spectrum of SETD1B-related disorder: Myoclonic absence seizures and concurrent intellectual disability - Insights from two cases. (PMID:38048716)
• SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma. (PMID:39235528)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	setd1ba	ENSDARG00000060847
mus_musculus	Setd1b	ENSMUSG00000038384
rattus_norvegicus	Setd1b	ENSRNOG00000001337
drosophila_melanogaster	Set2	FBGN0030486
drosophila_melanogaster	CG4565	FBGN0037841
drosophila_melanogaster	G9a	FBGN0040372
caenorhabditis_elegans	set-32	WBGENE00008062
caenorhabditis_elegans		WBGENE00008206
caenorhabditis_elegans		WBGENE00008527
caenorhabditis_elegans	met-1	WBGENE00016603
caenorhabditis_elegans		WBGENE00018023
caenorhabditis_elegans		WBGENE00019584
caenorhabditis_elegans		WBGENE00019690
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), 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 SETD1B — Q9UPS6 (reviewed: Q9UPS6)

Alternative names: Lysine N-methyltransferase 2G, SET domain-containing protein 1B

All UniProt accessions (1): Q9UPS6

UniProt curated annotations — full annotation on UniProt →

Function. Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4) via a non-processive mechanism. Part of chromatin remodeling machinery, forms H3K4me1, H3K4me2 and H3K4me3 methylation marks at active chromatin sites where transcription and DNA repair take place. Plays an essential role in regulating the transcriptional programming of multipotent hematopoietic progenitor cells and lymphoid lineage specification during hematopoiesis.

Subunit / interactions. Component of the SET1B/COMPASS complex composed of the catalytic subunit SETD1B, WDR5, WDR82, RBBP5, ASH2L/ASH2, CXXC1/CFP1, HCFC1, DPY30 homotrimer and BOD1. Forms a core complex with the evolutionary conserved subcomplex WRAD composed of WDR5, RBBP5, ASH2L/ASH2 and DPY30 subunits; WRAD differentially stimulates the methyltransferase activity. Interacts with HCFC1 and ASH2L/ASH2. Interacts (via N-terminal region) with WDR82. Interacts (via the RRM domain) with hyperphosphorylated C-terminal domain (CTD) of RNA polymerase II large subunit (POLR2A) only in the presence of WDR82. Binds specifically to CTD heptad repeats phosphorylated on ‘Ser-5’ of each heptad. Interacts with RBM15. Interacts (via WIN motif) with WDR5.

Subcellular location. Nucleus. Nucleus speckle. Chromosome. Cytoplasm.

Disease relevance. Intellectual developmental disorder with seizures and language delay (IDDSELD) [MIM:619000] An autosomal dominant neurodevelopmental disorder characterized by mild to profound intellectual development impairment, speech and language delay, and seizures. Autism and anxiety are common features. Facial dysmorphism, tapering fingers, and pigmentary skin changes may also be observed. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UPS6-1	1	yes
Q9UPS6-2	2

RefSeq proteins (1): NP_001340274* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR001214	SET_dom	Domain
IPR003616	Post-SET_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR024657	COMPASS_Set1_N-SET	Domain
IPR034468	Set1B_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR037841	SET_SETD1A/B	Domain
IPR044570	Set1-like	Family
IPR046341	SET_dom_sf	Homologous_superfamily

Pfam: PF00076, PF00856, PF11764

Catalyzed reactions (Rhea), 3 shown:

• L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (RHEA:60264)
• N(6)-methyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (RHEA:60268)
• N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (RHEA:60272)

UniProt features (70 total): compositionally biased region 23, region of interest 10, modified residue 8, sequence variant 6, strand 4, helix 4, domain 3, mutagenesis site 3, short sequence motif 2, splice variant 2, turn 2, chain 1, coiled-coil region 1, binding site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8ILZ	X-RAY DIFFRACTION	1.77
4ES0	X-RAY DIFFRACTION	1.82
3UVO	X-RAY DIFFRACTION	2.2
8WXV	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UPS6-F1	46.43	0.09

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 (1): 1943

Post-translational modifications (8): 986, 994, 1031, 1265, 1283, 1335, 1659, 1663

Mutagenesis-validated functional residues (3):

Position	Phenotype
577	abolishes interaction with rbm15.
579	abolishes interaction with rbm15.
1905	abolishes interaction with s-adenosyl-l-methionine.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-8936459	RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function
R-HSA-9772755	Formation of WDR5-containing histone-modifying complexes
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-212436	Generic Transcription Pathway
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878171	Transcriptional regulation by RUNX1
R-HSA-9917777	Epigenetic regulation by WDR5-containing histone modifying complexes

MSigDB gene sets: 185 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN, KEGG_LYSINE_DEGRADATION, MORF_IKBKG, GOBP_CHROMATIN_REMODELING, GOBP_METHYLATION, GOCC_NUCLEAR_SPECK, GOCC_TRANSFERASE_COMPLEX, GOCC_NUCLEAR_BODY, GOCC_SET1C_COMPASS_COMPLEX, GOCC_RIBONUCLEOPROTEIN_GRANULE, GOCC_HISTONE_METHYLTRANSFERASE_COMPLEX, GOCC_METHYLTRANSFERASE_COMPLEX, GOMF_N_METHYLTRANSFERASE_ACTIVITY, chr12q24

GO Biological Process (3): methylation (GO:0032259), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338)

GO Molecular Function (9): RNA binding (GO:0003723), histone H3 methyltransferase activity (GO:0140938), histone H3K4 monomethyltransferase activity (GO:0140945), nucleic acid binding (GO:0003676), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), histone H3K4 methyltransferase activity (GO:0042800), histone H3K4 trimethyltransferase activity (GO:0140999)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), cytoplasm (GO:0005737), nuclear speck (GO:0016607), histone methyltransferase complex (GO:0035097), Set1C/COMPASS complex (GO:0048188)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Gene expression (Transcription)	2
Chromatin modifying enzymes	1
Transcriptional regulation by RUNX1	1
Epigenetic regulation by WDR5-containing histone modifying complexes	1
RNA Polymerase II Transcription	1
Chromatin organization	1
Generic Transcription Pathway	1
Epigenetic regulation of gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
histone H3K4 methyltransferase activity	2
binding	2
cellular anatomical structure	2
metabolic process	1
cellular component organization	1
chromatin organization	1
nucleic acid binding	1
histone methyltransferase activity	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
protein-lysine N-methyltransferase activity	1
histone H3 methyltransferase activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
nuclear ribonucleoprotein granule	1
nucleoplasm	1
methyltransferase complex	1
nuclear protein-containing complex	1
histone methyltransferase complex	1

Protein interactions and networks

STRING

2111 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SETD1B	WDR82	Q6UXN9	997
SETD1B	RBBP5	Q15291	994
SETD1B	ASH2L	Q9UBL3	985
SETD1B	CXXC1	Q9P0U4	984
SETD1B	WDR5	P61964	979
SETD1B	DPY30	Q9C005	978
SETD1B	SETD1A	O15047	956
SETD1B	KMT2C	Q8NEZ4	940
SETD1B	KMT2B	Q9UMN6	842
SETD1B	H3-5	Q6NXT2	789
SETD1B	H3-7	Q5TEC6	789
SETD1B	H3C14	Q71DI3	788
SETD1B	H3-4	Q16695	788
SETD1B	H3-3A	P06351	783
SETD1B	H3C1	P02295	783

IntAct

45 interactions, top by confidence:

A	B	Type	Score
WDR5	KMT2D	psi-mi:“MI:0914”(association)	0.910
ASH2L	KMT2D	psi-mi:“MI:0914”(association)	0.890
RBBP5	KMT2D	psi-mi:“MI:0914”(association)	0.840
CXXC1	SETD1A	psi-mi:“MI:0914”(association)	0.760
WDR5	MEN1	psi-mi:“MI:0914”(association)	0.710
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
PIP4K2A	AP3B1	psi-mi:“MI:0914”(association)	0.530
DAXX	TNRC18	psi-mi:“MI:0914”(association)	0.530
EDA	AP3B1	psi-mi:“MI:0914”(association)	0.530
EPB41L1	AP3B1	psi-mi:“MI:0914”(association)	0.530
SETD1B	H1-2	psi-mi:“MI:0915”(physical association)	0.400
SETD1B	H1-1	psi-mi:“MI:0915”(physical association)	0.400
CXXC1	HCFC1	psi-mi:“MI:0914”(association)	0.350
Bod1	SPTBN2	psi-mi:“MI:0914”(association)	0.350
Cxxc1	HCFC1	psi-mi:“MI:0914”(association)	0.350
SETD1B	WBP4	psi-mi:“MI:0914”(association)	0.350
Kif18b	EIF2AK2	psi-mi:“MI:0914”(association)	0.350
SYNCRIP	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
PRMT2	KRBA1	psi-mi:“MI:0914”(association)	0.350
WDR5	KDM6A	psi-mi:“MI:0914”(association)	0.350
CXXC1	SETD1A	psi-mi:“MI:0914”(association)	0.350
ASH2L	MEN1	psi-mi:“MI:0914”(association)	0.350
WDR5	PHF20L1	psi-mi:“MI:0914”(association)	0.350
DYRK2	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
DCAF4	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (151): SETD1B (Affinity Capture-Western), SETD1B (Affinity Capture-Western), HIST1H3A (Biochemical Activity), SETD1B (Affinity Capture-MS), SETD1B (Affinity Capture-MS), SETD1B (Affinity Capture-Western), SETD1A (Affinity Capture-MS), SETD1A (Affinity Capture-Western), MVD (Affinity Capture-MS), RBBP5 (Affinity Capture-MS), ASH2L (Affinity Capture-MS), WDR5 (Affinity Capture-MS), WBP4 (Affinity Capture-MS), SETD1B (Affinity Capture-MS), SETD1B (Affinity Capture-MS)

ESM2 similar proteins: A0JLT2, A4QNZ7, A5PK23, B1AZP2, F5HSE3, O60293, O75420, O95402, P61129, P78312, P97839, Q03111, Q07FY3, Q08C81, Q08DM1, Q174D3, Q1LVC2, Q32NP7, Q3T044, Q4G0F8, Q5EAY2, Q5F368, Q5R8Q8, Q5U2R6, Q6DD45, Q6DRL8, Q6PEI3, Q7TN02, Q80Z38, Q8C1B1, Q8C1S0, Q8CFT2, Q8CGI1, Q8IVL1, Q8K4J6, Q90YL3, Q90YY5, Q969V6, Q96A73, Q99MR1

Diamond homologs: A4IGY9, A8XI75, C6KTD2, E9Q5F9, F4K1J4, J9VWH9, O08550, O22781, O43463, O54864, O60016, O64827, O82175, O88974, P20659, P38827, P45975, P55200, Q03164, Q06ZW3, Q08BR4, Q08D57, Q0VD24, Q18221, Q1DR06, Q1DU03, Q1L8U8, Q1LY77, Q24742, Q28CQ7, Q28Z18, Q294B9, Q2GWF3, Q2H988, Q2LAE1, Q2NL30, Q2UMH3, Q2UTN6, Q32KD2, Q32PH7

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
SETD1B	“down-regulates activity”	H3C1	methylation
SETD1B	“down-regulates activity”	H3-4	methylation
SETD1B	“down-regulates activity”	H3-3A	methylation
SETD1B	“form complex”	“MLL/SET subcomplex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 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 WDR5-containing histone-modifying complexes	10	73.8×	1e-14
Deactivation of the beta-catenin transactivating complex	5	32.4×	3e-05
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	5	27.4×	6e-05
PKMTs methylate histone lysines	5	22.3×	1e-04
Epigenetic regulation by WDR5-containing histone modifying complexes	5	21.4×	1e-04
Formation of the beta-catenin:TCF transactivating complex	5	16.7×	3e-04
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	5	16.7×	3e-04
Activation of anterior HOX genes in hindbrain development during early embryogenesis	5	12.7×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
chromatin remodeling	6	9.7×	6e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 8 cancer types — ESCA, HNSC, LUAD, NSCLC, OVT, PAAD, STAD, UTUC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	57
Likely pathogenic	33
Uncertain significance	472
Likely benign	172
Benign	22

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070120	NM_001353345.2(SETD1B):c.3985C>T (p.Arg1329Ter)	Pathogenic
1073989	NM_001353345.2(SETD1B):c.4567del (p.Arg1523fs)	Pathogenic
1213699	NM_001353345.2(SETD1B):c.1579C>T (p.Gln527Ter)	Pathogenic
1321921	NM_001353345.2(SETD1B):c.1371dup (p.Asp458fs)	Pathogenic
1332879	NM_001353345.2(SETD1B):c.5619T>G (p.Tyr1873Ter)	Pathogenic
1344988	NM_001353345.2(SETD1B):c.4612C>T (p.Arg1538Ter)	Pathogenic
1679142	NM_001353345.2(SETD1B):c.293_294insAACGTGGG (p.Pro99fs)	Pathogenic
1703503	NM_001353345.2(SETD1B):c.1044_1056del (p.Ser349fs)	Pathogenic
1708376	NM_001353345.2(SETD1B):c.480_481insT (p.Val161fs)	Pathogenic
1801351	NM_001353345.2(SETD1B):c.598dup (p.Gln200fs)	Pathogenic
1802554	NM_001353345.2(SETD1B):c.598del (p.Gln200fs)	Pathogenic
1992426	NM_001353345.2(SETD1B):c.214del (p.Arg72fs)	Pathogenic
2236999	NM_001353345.2(SETD1B):c.22dup (p.His8fs)	Pathogenic
2303158	NM_001353345.2(SETD1B):c.773del (p.Tyr258fs)	Pathogenic
2384616	NM_001353345.2(SETD1B):c.3367del (p.Asp1123fs)	Pathogenic
2438172	NM_001353345.2(SETD1B):c.62C>A (p.Ser21Ter)	Pathogenic
2498277	NM_001353345.2(SETD1B):c.5702C>A (p.Ala1901Glu)	Pathogenic
2498278	NM_001353345.2(SETD1B):c.284_286delinsA (p.Phe95_Tyr96delinsTer)	Pathogenic
2498279	NM_001353345.2(SETD1B):c.337_363inv (p.Asn113_Asp121delinsValProGlnGluValPheThrAspVal)	Pathogenic
2498280	NM_001353345.2(SETD1B):c.3386C>T (p.Ala1129Val)	Pathogenic
2503269	NM_001353345.2(SETD1B):c.5551G>A (p.Glu1851Lys)	Pathogenic
2505247	NM_001353345.2(SETD1B):c.5384C>T (p.Ser1795Leu)	Pathogenic
2572639	NM_001353345.2(SETD1B):c.5325dup (p.Ala1776fs)	Pathogenic
2631674	NM_001353345.2(SETD1B):c.3100del (p.Glu1034fs)	Pathogenic
3027140	NM_001353345.2(SETD1B):c.3961dup (p.Leu1321fs)	Pathogenic
3251206	NM_001353345.2(SETD1B):c.2983G>T (p.Glu995Ter)	Pathogenic
3317717	NM_001353345.2(SETD1B):c.4005_4010delinsAT (p.Ser1335fs)	Pathogenic
3342612	NM_001353345.2(SETD1B):c.4570C>T (p.Arg1524Ter)	Pathogenic
3343935	NM_001353345.2(SETD1B):c.2986C>T (p.Arg996Ter)	Pathogenic
3358978	NM_001353345.2(SETD1B):c.2338C>T (p.Gln780Ter)	Pathogenic

SpliceAI

2347 predictions. Top by Δscore:

Variant	Effect	Δscore
12:121804909:GCG:G	donor_gain	1.0000
12:121804909:GCGGT:G	donor_loss	1.0000
12:121804910:CGG:C	donor_loss	1.0000
12:121804912:G:C	donor_loss	1.0000
12:121804913:T:A	donor_loss	1.0000
12:121805114:ACAG:A	acceptor_loss	1.0000
12:121805115:C:G	acceptor_gain	1.0000
12:121805115:CAG:C	acceptor_loss	1.0000
12:121805116:A:AG	acceptor_gain	1.0000
12:121805116:AGAT:A	acceptor_gain	1.0000
12:121805117:G:GC	acceptor_gain	1.0000
12:121805117:GA:G	acceptor_gain	1.0000
12:121805117:GAT:G	acceptor_gain	1.0000
12:121805117:GATG:G	acceptor_gain	1.0000
12:121805117:GATGT:G	acceptor_gain	1.0000
12:121805214:AAGG:A	donor_loss	1.0000
12:121805215:AG:A	donor_gain	1.0000
12:121805215:AGGT:A	donor_loss	1.0000
12:121805216:GG:G	donor_gain	1.0000
12:121805217:G:GG	donor_gain	1.0000
12:121805217:GT:G	donor_loss	1.0000
12:121805218:T:A	donor_loss	1.0000
12:121805822:C:CA	acceptor_gain	1.0000
12:121805823:G:A	acceptor_gain	1.0000
12:121805829:T:TA	acceptor_gain	1.0000
12:121805832:CAG:C	acceptor_loss	1.0000
12:121805833:A:AG	acceptor_gain	1.0000
12:121805833:AGA:A	acceptor_loss	1.0000
12:121805833:AGATC:A	acceptor_gain	1.0000
12:121805834:G:A	acceptor_loss	1.0000

AlphaMissense

12717 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:121804831:T:G	Y32D	1.000
12:121804834:A:G	K33E	1.000
12:121804836:G:C	K33N	1.000
12:121804836:G:T	K33N	1.000
12:121804838:T:C	L34S	1.000
12:121804838:T:G	L34W	1.000
12:121804847:A:G	D37G	1.000
12:121804856:T:C	L40P	1.000
12:121804879:T:G	Y48D	1.000
12:121804882:C:A	R49S	1.000
12:121804883:G:C	R49P	1.000
12:121804885:T:G	Y50D	1.000
12:121804891:G:T	G52W	1.000
12:121805146:T:A	V68D	1.000
12:121805212:T:C	F90S	1.000
12:121805847:T:G	Y96D	1.000
12:121805853:G:C	G98R	1.000
12:121805854:G:A	G98D	1.000
12:121805854:G:T	G98V	1.000
12:121805875:T:A	V105E	1.000
12:121805878:C:A	T106K	1.000
12:121805878:C:G	T106R	1.000
12:121805880:T:C	F107L	1.000
12:121805881:T:C	F107S	1.000
12:121805881:T:G	F107C	1.000
12:121805882:T:A	F107L	1.000
12:121805882:T:G	F107L	1.000
12:121805883:G:C	A108P	1.000
12:121805884:C:A	A108D	1.000
12:121805890:T:A	L110Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000022042 (12:121803127 C>T), RS1000033021 (12:121797487 G>A), RS1000034067 (12:121823277 C>T), RS1000136481 (12:121802911 T>C), RS1000148507 (12:121795445 G>A), RS1000250301 (12:121823670 G>A), RS1000363191 (12:121793293 T>C), RS1000372640 (12:121791770 G>C), RS1000398805 (12:121824339 A>C,G), RS1000533723 (12:121815876 G>A), RS1000564729 (12:121819633 G>A,C), RS1000581451 (12:121824679 A>G), RS1000727647 (12:121788782 G>A), RS1000741266 (12:121824376 A>G), RS1000796187 (12:121805942 G>A,C)

Disease associations

OMIM: gene MIM:611055 | disease phenotypes: MIM:619000

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder with seizures and language delay	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (3): intellectual developmental disorder with seizures and language delay (MONDO:0033559), neurodevelopmental disorder (MONDO:0700092), epilepsy (MONDO:0005027)

Orphanet (0):

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000179	Thick lower lip vermilion
HP:0000293	Full cheeks
HP:0000321	Square face
HP:0000494	Downslanted palpebral fissures
HP:0000574	Thick eyebrow
HP:0000729	Autistic behavior
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0001182	Tapered finger
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0002069	Bilateral tonic-clonic seizure
HP:0002187	Profound intellectual disability
HP:0002392	EEG with polyspike wave complexes
HP:0005469	Flat occiput
HP:0010848	EEG with spike-wave complexes (2.5-3.5 Hz)
HP:0011150	Myoclonic absence seizure
HP:0031535	Increased theta frequency activity in EEG
HP:0032794	Myoclonic seizure

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002184_10	Mean platelet volume	6.000000e-38
GCST006666_6	Lipid traits (pleiotropy) (HIPO component 1)	3.000000e-10
GCST007545_1	Coronary artery disease and triglyceride levels (multivariate analysis)	2.000000e-09
GCST007547_1	Coronary artery disease and HDL cholesterol levels (multivariate analysis)	9.000000e-08
GCST90002390_176	Mean corpuscular hemoglobin	1.000000e-12
GCST90002395_146	Mean platelet volume	5.000000e-25
GCST90002397_220	Mean spheric corpuscular volume	2.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105837 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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)

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.35	Kd	45	nM	MOLIBRESIB
7.22	IC50	60	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 19 total; 1 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179232: Binding affinity against SETD1B (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0450	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
trichostatin A	affects expression, decreases expression	2
sodium arsenite	decreases expression, increases abundance, increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Cisplatin	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
FR900359	affects phosphorylation	1
bisphenol F	decreases expression, affects cotreatment	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
1-aminomethylphosphonic acid	increases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
Bortezomib	increases expression	1
Irinotecan	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Glyphosate	increases expression	1
Ethanol	decreases expression	1
Berberine	increases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Demecolcine	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Estradiol	increases expression	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1

ChEMBL screening assays

18 unique, capped per target: 18 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4017389	Binding	Inhibition of SETb (unknown origin) H3K4 methyltransferase activity using biotinyl-H3 peptide (1 to 21 residues) and using [3H]-S adenosylmethionine as methyl donor up to 100 uM after 1 hr by scintillation counting	Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)-Mixed Lineage Leukemia (MLL) Protein-Protein Interaction. — J Med Chem

Clinical trials (associated diseases)

202 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,
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
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
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
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
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice