SETD2

Summary

SETD2 (SET domain containing 2, histone lysine methyltransferase, HGNC:18420) is a protein-coding gene on chromosome 3p21.31, encoding Histone-lysine N-methyltransferase SETD2 (Q9BYW2). Histone methyltransferase that specifically trimethylates ‘Lys-36’ of histone H3 (H3K36me3) using dimethylated ‘Lys-36’ (H3K36me2) as substrate. It is a selective cancer dependency (DepMap: 33.4% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

Huntington’s disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein belonging to a class of huntingtin interacting proteins characterized by WW motifs. This protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II.

Source: NCBI Gene 29072 — RefSeq curated summary.

At a glance

• Gene–disease (curated): SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 30
• Clinical variants (ClinVar): 1,504 total — 42 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 67
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 23 cancer types
• Cancer dependency (DepMap): dependent in 33.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_014159

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18420
Approved symbol	SETD2
Name	SET domain containing 2, histone lysine methyltransferase
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	HYPB, HIF-1, KIAA1732, FLJ23184, KMT3A
Ensembl gene	ENSG00000181555
Ensembl biotype	protein_coding
OMIM	612778
Entrez	29072

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 13 protein_coding, 9 nonsense_mediated_decay, 7 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000330022, ENST00000409792, ENST00000412450, ENST00000431180, ENST00000445387, ENST00000479832, ENST00000484689, ENST00000492397, ENST00000638947, ENST00000685005, ENST00000685237, ENST00000685399, ENST00000685505, ENST00000686773, ENST00000686792, ENST00000686876, ENST00000687657, ENST00000688290, ENST00000690157, ENST00000690461, ENST00000691544, ENST00000691902, ENST00000692362, ENST00000692883, ENST00000693321, ENST00000693738, ENST00000893753, ENST00000952253, ENST00000952254, ENST00000952255

RefSeq mRNA: 2 — MANE Select: NM_014159 NM_001349370, NM_014159

CCDS: CCDS2749, CCDS93261

Canonical transcript exons

ENST00000409792 — 21 exons

Exon	Start	End
ENSE00001267623	47105997	47106120
ENSE00001576862	47163854	47164113
ENSE00001579695	47120182	47124548
ENSE00003472121	47017638	47017739
ENSE00003486885	47042561	47042700
ENSE00003500671	47037666	47037777
ENSE00003512693	47088113	47088247
ENSE00003513168	47046487	47046621
ENSE00003513481	47113876	47114004
ENSE00003515235	47062163	47062346
ENSE00003557711	47056821	47057490
ENSE00003576223	47067070	47067118
ENSE00003590850	47126648	47126663
ENSE00003598049	47016436	47017254
ENSE00003605282	47019760	47019840
ENSE00003628857	47101458	47101555
ENSE00003633676	47103346	47103423
ENSE00003650392	47116623	47116754
ENSE00003664957	47097955	47098081
ENSE00003667442	47083720	47084382
ENSE00003690981	47086195	47086314

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 96.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.8291 / max 728.8657, expressed in 1780 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42033	9.1157	1734
42030	1.8850	885
42031	1.1135	709
42032	0.9239	524
42028	0.6162	283
42029	0.1332	52
42027	0.0240	7
42022	0.0176	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	96.20	gold quality
endothelial cell	CL:0000115	95.03	gold quality
colonic epithelium	UBERON:0000397	94.73	gold quality
tendon	UBERON:0000043	94.69	gold quality
calcaneal tendon	UBERON:0003701	94.57	gold quality
cervix squamous epithelium	UBERON:0006922	93.84	gold quality
ventricular zone	UBERON:0003053	93.76	gold quality
cortical plate	UBERON:0005343	93.74	gold quality
sural nerve	UBERON:0015488	93.67	gold quality
pancreatic ductal cell	CL:0002079	93.43	gold quality
adrenal tissue	UBERON:0018303	92.95	gold quality
epithelial cell of pancreas	CL:0000083	92.44	gold quality
ganglionic eminence	UBERON:0004023	92.29	gold quality
medial globus pallidus	UBERON:0002477	91.82	gold quality
oviduct epithelium	UBERON:0004804	91.19	gold quality
tonsil	UBERON:0002372	90.92	gold quality
corpus callosum	UBERON:0002336	90.65	gold quality
tibia	UBERON:0000979	90.57	gold quality
gastrocnemius	UBERON:0001388	90.32	gold quality
parietal pleura	UBERON:0002400	89.68	gold quality
muscle of leg	UBERON:0001383	89.64	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.62	gold quality
pleura	UBERON:0000977	89.59	gold quality
globus pallidus	UBERON:0001875	89.35	gold quality
skin of hip	UBERON:0001554	89.34	gold quality
visceral pleura	UBERON:0002401	89.29	gold quality
epithelium of nasopharynx	UBERON:0001951	89.25	gold quality
hair follicle	UBERON:0002073	89.22	gold quality
epithelium of mammary gland	UBERON:0003244	89.20	gold quality
monocyte	CL:0000576	89.19	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.67
E-CURD-135	no	552.87
E-CURD-112	no	2.15

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
FOXO3	Activation

Upstream regulators (CollecTRI, top): HIF1A

miRNA regulators (miRDB)

101 targeting SETD2, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
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-548I	99.94	71.25	3481
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 33.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals (PMID:16118227)
• HYPB protein is a histone H3 lysine 36-specific methyltransferase that associates with hyperphosphorylated RNA polymerase II. (PMID:16118227)
• solution structure of the Set2-Rpb1 interacting domain in human Set2 (hSRI domain). (PMID:16314571)
• These findings suggest that the histone methyltransferase SETD2 could selectively regulate the transcription of subset genes via cooperation with the transcription factor p53. (PMID:18585004)
• Iws1 connects two distinct CTD-binding proteins, Spt6 and HYPB/Setd2, in a megacomplex that affects mRNA export as well as the histone modification state of active genes (PMID:19141475)
• Transcription analysis and genome-wide histone modification studies on these mutants suggested that K36me2 is sufficient to target Rpd3S in vivo, thereby maintaining a functional Set2-Rpd3S pathway. (PMID:19155214)
• The levels of SETD2 mRNA were significantly lower in malignant breast cancer. (PMID:19698110)
• identification of inactivating mutations in two genes–SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C, a histone H3 lysine 4 demethylase–as well as mutations in the histone H3 lysine 27 demethylase, UTX in clear cell renal cell carcinoma (PMID:20054297)
• Identification of missense mutations in 2 out of 10 primary cRCC tumor samples added support to the involvement of loss of SETD2 function in the development of cRCC tumors. (PMID:20501857)
• This study offers further evidence that SETD2 behaves like a tumour suppressor gene (PMID:20944102)
• SETD3 exhibits histone methyltransferases activity on nucleosomal histone 3 in a SET-domain dependent manner. We propose that this newly identified Setd3 gene may play an important role in carcinogenesis. (PMID:23065515)
• SETD2 activity modulates FACT recruitment and nucleosome dynamics, thereby repressing cryptic transcription initiation. (PMID:23325844)
• SETD2 mutations were found to be specific to high-grade gliomas affecting 15% of pediatric tumors(11/73) and 8% of adult high-grade gliomas (5/65), while no SETD2 mutations were identified in low-grade diffuse gliomas. (PMID:23417712)
• BAP1 and SETD2 mutations (6%-12%) are associated with worse cancer-specific survival , suggesting their roles in disease progression. (PMID:23620406)
• PBRM1, KDM6A, SETD2 and BAP1 were unmethylated in all tumor and normal specimens. (PMID:23644518)
• 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)
• Mutation frequencies among CT images of clear cell RCCs were as follows: SETD2, 7.3% (17 of 233). (PMID:24029645)
• These results directly link mutations in SETD2 to chromatin accessibility changes and RNA processing defects in cancer (PMID:24158655)
• HYPB interacts with the proline-rich region of HTT protein. (PMID:24412394)
• loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations (PMID:24509477)
• Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia. (PMID:24662245)
• Results implicate SETD2 as a tumor suppressor gene and demonstrate that loss-of-function SETD2 mutations can facilitate the initiation and maintenance of leukemias with chromosomal translocations through a global reduction of H3K36me3. (PMID:24706662)
• loss of SETD2 may afford an alternative mechanism for the inactivation of the p53-mediated checkpoint without the need for additional genetic mutations in TP53. (PMID:24843002)
• Identified two heterozygous mutations in the SETD2 gene in two patients with ‘Sotos-like’ syndrome. (PMID:24852293)
• Data establish a presynaptic role for SETD2 methyltransferase in HR; it facilitates the recruitment of C-terminal binding protein interacting protein and promotes DSB resection, allowing Replication Protein A (RPA) and RAD51 binding to DNA damage sites. (PMID:24931610)
• association of SETD2 mutations with multiple major chromosomal translocations implies a common mechanism in various subtypes of leukemia with SETD2 mutations (PMID:25077743)
• found that SETD2 mutation also mediated MMR via AKT-induced PMS2 decrease and co-loss of MLH1 loss in renal clear cell carcinoma (PMID:25528216)
• Findings extend the knowledge about the regulation of SETD2 at the posttranscriptional level by miRNA and regulatory mechanism downstream of SETD2 in ccRCC. (PMID:25714014)
• Data show that SETD2 mutations are not associated with microsatellite instability in renal cancer and suggest a role for SETD2 in maintaining genome integrity through nucleosome stabilization, DNA repair and suppression of replication stress. (PMID:25728682)
• Both ASH1L and SETD2 are H3K36 specific methyltransferases but only SETD2 can trimethylate this mark. (PMID:26002201)
• miRNA network regulates SETD2 in in colorectal metastasis tissues. (PMID:26069251)
• This study provides evidence for HOTAIR to promote tumorigenesis via downregulating SETD2 in liver cancer stem cells. (PMID:26172293)
• SETD2 is a novel GIST tumour suppressor gene associated with disease progression. (PMID:26338826)
• Use bioinformatic tools to predict the molecular effects of all mutations lying in SETD2 genes. (PMID:26452128)
• This study provide the evidence SETD2 mutation releate to Autism Spectrum Disorder. (PMID:26637798)
• Mutation in SETD2 gene is associated with renal cell carcinoma. (PMID:26646321)
• SETD2 gene deletion is associated with chordoma. (PMID:27072194)
• SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease (PMID:27282254)
• SETD2 is a potential prognostic biomarker for overall survival and progression-free survival prediction in patients with metastatic renal cell carcinoma receiving targeted therapy (PMID:27288695)
• functional loss of SETD2 enables renal primary tubular epithelial cells to bypass the senescence barrier by maintaining CDKN2A-E2F signaling, facilitating a malignant transformation toward Clear Cell Renal Cell Carcinoma. (PMID:27292023)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
mus_musculus	Setd2	ENSMUSG00000044791
rattus_norvegicus	Setd2	ENSRNOG00000020915
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), SETD1B (ENSG00000139718), SETDB1 (ENSG00000143379), NSD3 (ENSG00000147548), SETBP1 (ENSG00000152217), SUV39H2 (ENSG00000152455), NSD1 (ENSG00000165671), KMT2D (ENSG00000167548), EHMT1 (ENSG00000181090), EHMT2 (ENSG00000204371), KMT2B (ENSG00000272333)

Protein

Protein identifiers

Histone-lysine N-methyltransferase SETD2 — Q9BYW2 (reviewed: Q9BYW2)

Alternative names: HIF-1, Huntingtin yeast partner B, Huntingtin-interacting protein 1, Huntingtin-interacting protein B, Lysine N-methyltransferase 3A, Protein-lysine N-methyltransferase SETD2, SET domain-containing protein 2, p231HBP

All UniProt accessions (15): A0A1W2PPX9, A0A8I5KNR2, A0A8I5KPS6, A0A8I5KQS3, A0A8I5KSB8, A0A8I5KV15, A0A8I5KW81, A0A8I5KWD0, A0A8I5KYR1, A0A8I5QJW6, C9JG86, Q9BYW2, H7BXT4, H7BZ93, H7C3H4

UniProt curated annotations — full annotation on UniProt →

Function. Histone methyltransferase that specifically trimethylates ‘Lys-36’ of histone H3 (H3K36me3) using dimethylated ‘Lys-36’ (H3K36me2) as substrate. It is capable of trimethylating unmethylated H3K36 (H3K36me0) in vitro. Represents the main enzyme generating H3K36me3, a specific tag for epigenetic transcriptional activation. Plays a role in chromatin structure modulation during elongation by coordinating recruitment of the FACT complex and by interacting with hyperphosphorylated POLR2A. Acts as a key regulator of DNA mismatch repair in G1 and early S phase by generating H3K36me3, a mark required to recruit MSH6 subunit of the MutS alpha complex: early recruitment of the MutS alpha complex to chromatin to be replicated allows a quick identification of mismatch DNA to initiate the mismatch repair reaction. Required for DNA double-strand break repair in response to DNA damage: acts by mediating formation of H3K36me3, promoting recruitment of RAD51 and DNA repair via homologous recombination (HR). Acts as a tumor suppressor. H3K36me3 also plays an essential role in the maintenance of a heterochromatic state, by recruiting DNA methyltransferase DNMT3A. H3K36me3 is also enhanced in intron-containing genes, suggesting that SETD2 recruitment is enhanced by splicing and that splicing is coupled to recruitment of elongating RNA polymerase. Required during angiogenesis. Required for endoderm development by promoting embryonic stem cell differentiation toward endoderm: acts by mediating formation of H3K36me3 in distal promoter regions of FGFR3, leading to regulate transcription initiation of FGFR3. In addition to histones, also mediates methylation of other proteins, such as tubulins and STAT1. Trimethylates ‘Lys-40’ of alpha-tubulins such as TUBA1B (alpha-TubK40me3); alpha-TubK40me3 is required for normal mitosis and cytokinesis and may be a specific tag in cytoskeletal remodeling. Involved in interferon-alpha-induced antiviral defense by mediating both monomethylation of STAT1 at ‘Lys-525’ and catalyzing H3K36me3 on promoters of some interferon-stimulated genes (ISGs) to activate gene transcription. (Microbial infection) Recruited to the promoters of adenovirus 12 E1A gene in case of infection, possibly leading to regulate its expression.

Subunit / interactions. Specifically interacts with hyperphosphorylated C-terminal domain (CTD) of RNA polymerase II large subunit (POLR2A): binds to CTD heptad repeats doubly phosphorylated on ‘Ser-2’ and ‘Ser-5’ of each heptad. Interacts with HTT. Interacts with IWS1. Interacts with p53/TP53; leading to regulate p53/TP53 target genes. Component of a complex with HNRNPL. Interacts with TUBA1A; the interaction is independent on alpha-tubulin acetylation on ‘Lys-40’. Interacts with STAT1.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. May be automethylated.

Disease relevance. Renal cell carcinoma (RCC) [MIM:144700] Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Clear cell renal cell carcinoma is the most common subtype. The disease may be caused by variants affecting the gene represented in this entry. Defects of SETD2 are associated with loss of DNA methylation at non-promoter regions. SETD2 defects lead to aberrant and reduced nucleosome compaction and chromatin association of key replication proteins, such as MCM7 and DNA polymerase delta, leading to hinder replication fork progression and prevent loading of RAD51 homologous recombination repair factor at DNA breaks. Luscan-Lumish syndrome (LLS) [MIM:616831] An autosomal dominant syndrome with a variable phenotype. Clinical features include macrocephaly, distinctive facial appearance, postnatal overgrowth, various degrees of learning difficulties, autism spectrum disorder, and intellectual disability. The disease may be caused by variants affecting the gene represented in this entry. Leukemia, acute lymphoblastic (ALL) [MIM:613065] A subtype of acute leukemia, a cancer of the white blood cells. ALL is a malignant disease of bone marrow and the most common malignancy diagnosed in children. The malignant cells are lymphoid precursor cells (lymphoblasts) that are arrested in an early stage of development. The lymphoblasts replace the normal marrow elements, resulting in a marked decrease in the production of normal blood cells. Consequently, anemia, thrombocytopenia, and neutropenia occur to varying degrees. The lymphoblasts also proliferate in organs other than the marrow, particularly the liver, spleen, and lymphnodes. The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry. Leukemia, acute myelogenous (AML) [MIM:601626] A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry. Intellectual developmental disorder, autosomal dominant 70 (MRD70) [MIM:620157] An autosomal dominant disorder characterized by mild global developmental delay, moderately impaired intellectual disability with speech difficulties, and behavioral abnormalities. The disease is caused by variants affecting the gene represented in this entry. Rabin-Pappas syndrome (RAPAS) [MIM:620155] An autosomal dominant neurodevelopmental disorder characterized by severely impaired global development, intellectual disability, microcephaly, facial dysmorphism, and variable congenital anomalies affecting the skeletal, genitourinary, cardiac, and other organ systems. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Specifically inhibited by sinefungin derivatives. N-propyl sinefungin (Pr-SNF) interacts preferentially with SETD2.

Domain organisation. The low charge region mediates the transcriptional activation activity. The catalytic SET domain binds histone H3. It is also able to bind oncogenic histone H3 K36M/I found in a number of cancer types, in which histone H3 ‘Lys-36’ is replaced by a Met or an Ile residue. When binding the oncogenic variant histone H3 K36M/I, the SET domain undergoes dramatic conformational change to accommodate the histone H3 peptide, leading to sequester and inhibit SETD2 activity and block global H3K36 methylation.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BYW2-1	1	yes
Q9BYW2-2	2
Q9BYW2-3	3

RefSeq proteins (2): NP_001336299, NP_054878* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001202	WW_dom	Domain
IPR001214	SET_dom	Domain
IPR003616	Post-SET_dom	Domain
IPR006560	AWS_dom	Domain
IPR013257	SRI	Domain
IPR035441	TFIIS/LEDGF_dom_sf	Homologous_superfamily
IPR036020	WW_dom_sf	Homologous_superfamily
IPR038190	SRI_sf	Homologous_superfamily
IPR042294	SETD2_animal	Family
IPR044437	SETD2/Set2_SET	Domain
IPR046341	SET_dom_sf	Homologous_superfamily

Pfam: PF00397, PF00856, PF08236, PF17907

Enzyme classification (BRENDA):

• 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)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
S-ADENOSYL-L-METHIONINE	0.0033–0.13	6
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), 3 shown:

• L-lysyl-[protein] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:51736)
• L-lysyl-[protein] + 3 S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl-[protein] + 3 S-adenosyl-L-homocysteine + 3 H(+) (RHEA:54192)
• L-lysyl(36)-[histone H3] + 3 S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl(36)-[histone H3] + 3 S-adenosyl-L-homocysteine + 3 H(+) (RHEA:60324)

UniProt features (229 total): sequence variant 45, modified residue 30, compositionally biased region 28, strand 27, mutagenesis site 22, binding site 17, region of interest 15, helix 15, sequence conflict 12, turn 7, domain 4, cross-link 3, splice variant 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

43 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5JLB	X-RAY DIFFRACTION	1.5
5LT7	X-RAY DIFFRACTION	1.51
5LT8	X-RAY DIFFRACTION	1.57
7EVS	X-RAY DIFFRACTION	1.6
5LSY	X-RAY DIFFRACTION	1.62
5LSZ	X-RAY DIFFRACTION	1.62
9G4A	X-RAY DIFFRACTION	1.65
6J9J	X-RAY DIFFRACTION	1.78
5LSS	X-RAY DIFFRACTION	1.79
7EVR	X-RAY DIFFRACTION	1.8
7LZD	X-RAY DIFFRACTION	1.8
8Q5P	X-RAY DIFFRACTION	1.81
9HGG	X-RAY DIFFRACTION	1.9
5LT6	X-RAY DIFFRACTION	2.05
5JJY	X-RAY DIFFRACTION	2.05
4H12	X-RAY DIFFRACTION	2.06
4FMU	X-RAY DIFFRACTION	2.1
8RZU	X-RAY DIFFRACTION	2.19
7LZB	X-RAY DIFFRACTION	2.28
6VDB	X-RAY DIFFRACTION	2.3
7TY3	X-RAY DIFFRACTION	2.3
5JLE	X-RAY DIFFRACTION	2.4
5V22	X-RAY DIFFRACTION	2.4
5V21	X-RAY DIFFRACTION	2.42
7TY2	X-RAY DIFFRACTION	2.44
7LZF	X-RAY DIFFRACTION	2.47
5LSX	X-RAY DIFFRACTION	2.9
9EGZ	ELECTRON MICROSCOPY	2.9
7EA8	ELECTRON MICROSCOPY	3.1
9EH1	ELECTRON MICROSCOPY	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BYW2-F1	43.81	0.12

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): 1499; 1501; 1516; 1516; 1520; 1529; 1533; 1539; 1560–1562; 1603–1605; 1628–1629; 1631 …

Post-translational modifications (33): 131, 321, 323, 344, 422, 532, 614, 624, 626, 698, 708, 744, 754, 1098, 1228, 1413, 1415, 1417, 1696, 1844 …

Mutagenesis-validated functional residues (22):

Position	Phenotype
1589	strongly reduced methyltransferase activity.
1604	increased methyltransferase activity.
1625	loss of methyltransferase activity. abolishes ability to monomethylate stat1.
1631	does not affect methyltransferase activity.
1636	increased methyltransferase activity.
1637	increased methyltransferase activity.
1668	strongly reduced methyltransferase activity.
1669	loss of methyltransferase activity.
1670	impaired methyltransferase activity.
1670	loss of methyltransferase activity.
1671	strongly reduced methyltransferase activity.
2475	does not affect interaction with hyperphosphorylated polr2a.
2476	does not affect interaction with hyperphosphorylated polr2a.
2480	does not affect interaction with hyperphosphorylated polr2a.
2481	does not affect interaction with hyperphosphorylated polr2a.
2483	impairs interaction with hyperphosphorylated polr2a.
2506	impairs interaction with hyperphosphorylated polr2a.
2510	impairs interaction with hyperphosphorylated polr2a.
2514	impairs interaction with hyperphosphorylated polr2a.
2515	does not affect interaction with hyperphosphorylated polr2a.
2528	increases interaction with hyperphosphorylated polr2a; when associated with a-2531.
2531	increases interaction with hyperphosphorylated polr2a; when associated with a-2528.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization

MSigDB gene sets: 424 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_RESPONSE_TO_PEPTIDE, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, TATTATA_MIR374, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, BROWNE_HCMV_INFECTION_16HR_UP, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR_VIA_HOMOLOGOUS_RECOMBINATION, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_REGULATION_OF_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT, SRF_01, GOBP_NUCLEAR_TRANSPORT

GO Biological Process (31): mismatch repair (GO:0006298), regulation of DNA-templated transcription (GO:0006355), transcription elongation by RNA polymerase II (GO:0006368), response to metal ion (GO:0010038), regulation of gene expression (GO:0010468), positive regulation of autophagy (GO:0010508), regulation of double-strand break repair via homologous recombination (GO:0010569), regulation of mRNA export from nucleus (GO:0010793), peptidyl-lysine trimethylation (GO:0018023), regulation of cytokinesis (GO:0032465), positive regulation of interferon-alpha production (GO:0032727), response to type I interferon (GO:0034340), nucleosome organization (GO:0034728), endodermal cell differentiation (GO:0035987), response to alkaloid (GO:0043279), positive regulation of ossification (GO:0045778), stem cell differentiation (GO:0048863), defense response to virus (GO:0051607), microtubule cytoskeleton organization involved in mitosis (GO:1902850), regulation of protein localization to chromatin (GO:1905634), autophagosome assembly (GO:0000045), immune system process (GO:0002376), DNA repair (GO:0006281), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338), DNA damage response (GO:0006974), proteasomal protein catabolic process (GO:0010498), cell differentiation (GO:0030154), methylation (GO:0032259), innate immune response (GO:0045087), protein K48-linked ubiquitination (GO:0070936)

GO Molecular Function (10): protein-lysine N-methyltransferase activity (GO:0016279), alpha-tubulin binding (GO:0043014), metal ion binding (GO:0046872), histone H3K36 methyltransferase activity (GO:0046975), histone H3 methyltransferase activity (GO:0140938), histone H3K36 trimethyltransferase activity (GO:0140955), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), histone methyltransferase activity (GO:0042054)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Chromatin organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	2
protein methyltransferase activity	2
cellular anatomical structure	2
DNA repair	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
DNA-templated transcription elongation	1
transcription by RNA polymerase II	1
response to chemical	1
gene expression	1
regulation of macromolecule biosynthetic process	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
regulation of DNA recombination	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair	1
mRNA export from nucleus	1
regulation of RNA export from nucleus	1
regulation of ribonucleoprotein complex localization	1
peptidyl-lysine methylation	1
cytokinesis	1
regulation of cell cycle process	1
regulation of cell division	1
positive regulation of type I interferon production	1
interferon-alpha production	1
regulation of interferon-alpha production	1
response to cytokine	1
innate immune response	1
chromatin remodeling	1
protein-DNA complex organization	1
endoderm formation	1
response to nitrogen compound	1
ossification	1
regulation of ossification	1
positive regulation of multicellular organismal process	1
defense response	1
response to virus	1
microtubule cytoskeleton organization	1

Protein interactions and networks

STRING

4332 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SETD2	POLR2A	P24928	995
SETD2	WDR5	P61964	989
SETD2	HTT	P42858	893
SETD2	IWS1	Q96ST2	865
SETD2	KDM5C	P41229	857
SETD2	PBRM1	Q86U86	857
SETD2	SUPT6H	Q7KZ85	829
SETD2	PRPF40A	O75400	797
SETD2	SETD1A	O15047	789
SETD2	KDM6A	O15550	781
SETD2	RNF20	Q5VTR2	781
SETD2	MORF4L1	Q9UBU8	774
SETD2	DOT1L	Q8TEK3	769
SETD2	TP53	P04637	766
SETD2	H3-3A	P06351	753

IntAct

157 interactions, top by confidence:

A	B	Type	Score
rep	MTHFD1	psi-mi:“MI:0914”(association)	0.640
CSNK2B	RPS6KA4	psi-mi:“MI:0914”(association)	0.640
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
SETD2	rep	psi-mi:“MI:0915”(physical association)	0.550
WDR37	CLUH	psi-mi:“MI:0914”(association)	0.530
PIP4K2A	AP3B1	psi-mi:“MI:0914”(association)	0.530
RSBN1	SETD1A	psi-mi:“MI:0914”(association)	0.530
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
LRRTM4	AP3B1	psi-mi:“MI:0914”(association)	0.530
AURKA	WDR62	psi-mi:“MI:0914”(association)	0.530
SRPK2	RRP9	psi-mi:“MI:0914”(association)	0.530
SETD2	SMAD3	psi-mi:“MI:0915”(physical association)	0.510
SMAD3	SETD2	psi-mi:“MI:0915”(physical association)	0.510
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
SETD2		psi-mi:“MI:0407”(direct interaction)	0.440
SETD2	VP40	psi-mi:“MI:0407”(direct interaction)	0.440
SETD2	M	psi-mi:“MI:0407”(direct interaction)	0.440
SETD2	NP	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (179): HIST3H3 (Biochemical Activity), SETD2 (Affinity Capture-MS), SETD2 (Affinity Capture-MS), SETD2 (Affinity Capture-MS), SETD2 (Affinity Capture-MS), SETD2 (Affinity Capture-MS), EIF3I (Co-fractionation), SETD2 (Affinity Capture-MS), SETD2 (Affinity Capture-MS), SETD2 (Affinity Capture-MS), SETD2 (Affinity Capture-MS), SETD2 (Affinity Capture-MS), SETD2 (Negative Genetic), HIST1H3A (Protein-peptide), SETD2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTH6, A0A1D5RMD1, A1KXM5, A2AEY4, A6NCI8, A6QQS3, A7KBS4, C4P6S0, O94713, P0C9Z7, P53963, P53976, Q0P670, Q0VAV2, Q10668, Q196W1, Q2KHR3, Q2YDJ5, Q32MG2, Q3V0A6, Q3V3Q4, Q4V8E9, Q5JRM2, Q68FV4, Q6AXV6, Q6AYN3, Q6NS59, Q7TSG5, Q80VJ6, Q80Y39, Q80YD3, Q810T2, Q86XD8, Q8C5U4, Q8CH19, Q8IWI9, Q8K4E0, Q8NDH2, Q8NEV8, Q8NFU7

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

6 interactions.

A	Effect	B	Mechanism
SETD2	“up-regulates quantity by expression”	FOXO3	“transcriptional regulation”
SETD2	“up-regulates quantity by expression”	FOXO	“transcriptional regulation”
SETD2	“up-regulates activity”	H3C1	trimethylation
SETD2	“up-regulates activity”	TUBA1B	methylation
SETD2	“up-regulates activity”	STAT1	methylation
SETD2	“form complex”	“Iws1:Spt6:CTD complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 172 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
Transport of Mature Transcript to Cytoplasm	6	20.9×	2e-05
mRNA 3’-end processing	11	19.9×	4e-10
mRNA Splicing	19	19.1×	2e-17
RNA Polymerase II Transcription Termination	9	18.1×	8e-08
mRNA Polyadenylation	21	16.9×	3e-18
Processing of Capped Intron-Containing Pre-mRNA	22	16.6×	9e-19
mRNA Splicing - Minor Pathway	7	14.4×	2e-05
Transport of Mature mRNA derived from an Intron-Containing Transcript	10	14.0×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	8	41.1×	3e-09
U2-type prespliceosome assembly	5	20.9×	6e-04
regulation of alternative mRNA splicing, via spliceosome	9	14.8×	2e-06
mRNA splicing, via spliceosome	19	11.7×	3e-12
mRNA processing	17	9.0×	3e-09
RNA splicing	15	8.9×	4e-08

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 23 cancer types — ALL, CCRCC, CLLSLL, EGC, ES, GB, GIST, HCC, LGGNOS, LUAD, MEL, NSCLC…(+11 more).

Clinical variants and AI predictions

ClinVar

1504 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	42
Likely pathogenic	23
Uncertain significance	760
Likely benign	373
Benign	106

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1005470	NM_014159.7(SETD2):c.5635C>T (p.Arg1879Cys)	Pathogenic
1073170	NM_014159.7(SETD2):c.5236G>T (p.Glu1746Ter)	Pathogenic
1074219	NM_014159.7(SETD2):c.6069T>A (p.Tyr2023Ter)	Pathogenic
1076326	NM_014159.7(SETD2):c.5177del (p.Gly1726fs)	Pathogenic
1164031	NM_014159.7(SETD2):c.1748_1751del (p.Lys583fs)	Pathogenic
1172620	NM_014159.7(SETD2):c.4180G>T (p.Glu1394Ter)	Pathogenic
1197645	NM_014159.7(SETD2):c.5278-1G>C	Pathogenic
1213369	NM_014159.7(SETD2):c.4486C>T (p.Arg1496Ter)	Pathogenic
1320096	NM_014159.7(SETD2):c.6712_6718del (p.Ser2238fs)	Pathogenic
1338780	NM_014159.7(SETD2):c.5219G>A (p.Arg1740Gln)	Pathogenic
1434833	NM_014159.7(SETD2):c.4375C>T (p.Arg1459Ter)	Pathogenic
1451327	NM_014159.7(SETD2):c.4792C>T (p.Arg1598Ter)	Pathogenic
1710202	NM_014159.7(SETD2):c.5945dup (p.Asp1982fs)	Pathogenic
1804986	NM_014159.7(SETD2):c.6844_6845del (p.Val2282fs)	Pathogenic
222953	NM_014159.7(SETD2):c.6341del (p.Asn2114fs)	Pathogenic
222954	NM_014159.7(SETD2):c.5444T>G (p.Leu1815Trp)	Pathogenic
222955	NM_014159.7(SETD2):c.820C>T (p.Gln274Ter)	Pathogenic
222956	NM_014159.7(SETD2):c.2028del (p.Pro677fs)	Pathogenic
2287559	NM_014159.7(SETD2):c.3439C>T (p.Gln1147Ter)	Pathogenic
2443035	NM_014159.7(SETD2):c.2749dup (p.Ser917fs)	Pathogenic
2446610	NM_014159.7(SETD2):c.6325C>T (p.Arg2109Ter)	Pathogenic
2582584	NM_014159.7(SETD2):c.1771C>T (p.Gln591Ter)	Pathogenic
3160637	NM_014159.7(SETD2):c.3199C>T (p.Gln1067Ter)	Pathogenic
3254633	NM_014159.7(SETD2):c.5881_5882insT (p.Glu1961fs)	Pathogenic
3337637	NM_014159.7(SETD2):c.2420_2421del (p.Asn806_Ser807insTer)	Pathogenic
3364978	NM_014159.7(SETD2):c.208C>T (p.Arg70Ter)	Pathogenic
3377050	NM_014159.7(SETD2):c.6284dup (p.Asp2096fs)	Pathogenic
3440198	NM_014159.7(SETD2):c.7350+1G>A	Pathogenic
3663855	NM_014159.7(SETD2):c.6148C>T (p.Gln2050Ter)	Pathogenic
373426	NM_014159.7(SETD2):c.4774C>T (p.Arg1592Ter)	Pathogenic

SpliceAI

4222 predictions. Top by Δscore:

Variant	Effect	Δscore
3:47017268:A:T	acceptor_gain	1.0000
3:47017735:GACAT:G	acceptor_gain	1.0000
3:47017736:ACAT:A	acceptor_gain	1.0000
3:47017736:ACATC:A	acceptor_gain	1.0000
3:47017737:CAT:C	acceptor_gain	1.0000
3:47017737:CATC:C	acceptor_gain	1.0000
3:47017738:AT:A	acceptor_gain	1.0000
3:47017738:ATCT:A	acceptor_loss	1.0000
3:47017738:ATCTG:A	acceptor_gain	1.0000
3:47017739:TCTGC:T	acceptor_gain	1.0000
3:47017740:C:CC	acceptor_gain	1.0000
3:47017740:CTG:C	acceptor_loss	1.0000
3:47017743:C:CT	acceptor_gain	1.0000
3:47017747:C:CT	acceptor_gain	1.0000
3:47017748:A:T	acceptor_gain	1.0000
3:47019754:CCTTA:C	donor_loss	1.0000
3:47019755:CTTA:C	donor_loss	1.0000
3:47019756:TTAC:T	donor_loss	1.0000
3:47019758:A:AC	donor_gain	1.0000
3:47019759:C:CC	donor_gain	1.0000
3:47019759:C:CT	donor_loss	1.0000
3:47019759:CCT:C	donor_gain	1.0000
3:47019776:T:TA	donor_gain	1.0000
3:47019836:GAGGC:G	acceptor_gain	1.0000
3:47019837:AGGC:A	acceptor_gain	1.0000
3:47019838:GGC:G	acceptor_gain	1.0000
3:47019839:GC:G	acceptor_gain	1.0000
3:47019839:GCC:G	acceptor_loss	1.0000
3:47019840:CC:C	acceptor_gain	1.0000
3:47019841:C:CA	acceptor_loss	1.0000

AlphaMissense

16870 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:47017125:A:C	Y2555D	1.000
3:47017135:A:C	F2551L	1.000
3:47017135:A:T	F2551L	1.000
3:47017137:A:G	F2551L	1.000
3:47017149:A:C	Y2547D	1.000
3:47017157:A:C	I2544S	1.000
3:47017157:A:T	I2544N	1.000
3:47017161:A:G	Y2543H	1.000
3:47017171:T:A	K2539N	1.000
3:47017171:T:G	K2539N	1.000
3:47017173:T:C	K2539E	1.000
3:47017181:A:T	V2536E	1.000
3:47017194:A:G	C2532R	1.000
3:47017216:A:C	C2524W	1.000
3:47017226:A:G	L2521P	1.000
3:47017231:C:A	K2519N	1.000
3:47017231:C:G	K2519N	1.000
3:47017241:A:T	V2516D	1.000
3:47017244:C:T	G2515D	1.000
3:47017246:G:C	H2514Q	1.000
3:47017246:G:T	H2514Q	1.000
3:47017248:G:C	H2514D	1.000
3:47017250:G:A	T2513I	1.000
3:47017253:A:C	L2512R	1.000
3:47017253:A:G	L2512P	1.000
3:47017253:A:T	L2512Q	1.000
3:47017638:C:A	K2511N	1.000
3:47017638:C:G	K2511N	1.000
3:47017640:T:C	K2511E	1.000
3:47017642:C:G	R2510P	1.000

dbSNP variants (sampled 300 via entrez): RS1000029107 (3:47071331 C>A), RS1000029112 (3:47059655 T>A,C), RS1000059938 (3:47064344 T>G), RS1000063164 (3:47072101 G>A), RS1000086867 (3:47160824 G>A), RS1000088373 (3:47079055 G>A), RS1000131150 (3:47023735 T>C), RS1000133175 (3:47064758 A>T), RS1000133464 (3:47016551 C>A,T), RS1000155001 (3:47070679 A>G), RS1000170484 (3:47091493 T>C), RS1000200909 (3:47018457 T>G), RS1000204016 (3:47099291 A>G), RS1000227605 (3:47145238 G>A), RS1000246125 (3:47024102 G>A)

Disease associations

OMIM: gene MIM:612778 | disease phenotypes: MIM:616831, MIM:209850, MIM:620155, MIM:620157, MIM:213000, MIM:217990, MIM:308350, MIM:220200

GenCC curated gene-disease

Disease	Classification	Inheritance
Luscan-Lumish syndrome	Definitive	Autosomal dominant
Rabin-Pappas syndrome	Strong	Autosomal dominant
SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome	Strong	Autosomal dominant
SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth	Strong	Autosomal dominant
Sotos syndrome	Supportive	Autosomal dominant
intellectual developmental disorder, autosomal dominant 70	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome	Strong	AD
SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth	Definitive	AD

Mondo (19): Luscan-Lumish syndrome (MONDO:0014791), autism (MONDO:0005260), Rabin-Pappas syndrome (MONDO:0859331), intellectual developmental disorder, autosomal dominant 70 (MONDO:0859333), neurodevelopmental disorder (MONDO:0700092), congenital portosystemic shunt (MONDO:0018811), intellectual disability (MONDO:0001071), autism spectrum disorder (MONDO:0005258), teratoma (MONDO:0002601), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), corpus callosum, agenesis of (MONDO:0009022), obesity disorder (MONDO:0011122), genetic developmental and epileptic encephalopathy (MONDO:0100062), Dandy-Walker syndrome (MONDO:0009072), hereditary ataxia (MONDO:0100309)

Orphanet (12): Luscan-Lumish syndrome (Orphanet:597738), Congenital portosystemic shunt (Orphanet:480531), Isolated cerebellar agenesis (Orphanet:1398), Isolated corpus callosum agenesis (Orphanet:200), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Isolated Dandy-Walker malformation (Orphanet:217), Hereditary ataxia (Orphanet:183518), Acute megakaryoblastic leukemia in children without Down syndrome (Orphanet:329469), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

67 total (30 of 67 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000147	Polycystic ovaries
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000494	Downslanted palpebral fissures
HP:0000518	Cataract
HP:0000541	Retinal detachment
HP:0000582	Upslanted palpebral fissure
HP:0000609	Optic nerve hypoplasia
HP:0000629	Periorbital fullness
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000739	Anxiety

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST002223_52	HDL cholesterol	4.000000e-09
GCST003264_1050	Post bronchodilator FEV1/FVC ratio	3.000000e-06
GCST004232_73	HDL cholesterol levels	1.000000e-08
GCST004608_75	Granulocyte percentage of myeloid white cells	2.000000e-16
GCST004609_112	Monocyte percentage of white cells	6.000000e-10
GCST004610_58	White blood cell count	3.000000e-19
GCST004616_142	Platelet distribution width	6.000000e-20
GCST004618_60	White blood cell count (basophil)	3.000000e-09
GCST004625_71	Monocyte count	1.000000e-12
GCST004627_96	Lymphocyte count	3.000000e-50
GCST004632_142	Lymphocyte percentage of white cells	3.000000e-18
GCST004691_3	Huntington’s disease progression	2.000000e-06
GCST006611_64	HDL cholesterol	5.000000e-10
GCST007483_26	Waist-to-hip ratio adjusted for BMI (additive genetic model)	5.000000e-07
GCST007500_46	Waist-to-hip ratio adjusted for BMI (additive genetic model)	9.000000e-06
GCST007931_65	Medication use (HMG CoA reductase inhibitors)	2.000000e-08
GCST010002_422	Refractive error	4.000000e-14
GCST010988_140	Adult body size	3.000000e-10
GCST90002379_39	Basophil count	3.000000e-17
GCST90002381_147	Eosinophil count	2.000000e-09
GCST90002382_565	Eosinophil percentage of white cells	1.000000e-11
GCST90002388_193	Lymphocyte count	1.000000e-116
GCST90002389_19	Lymphocyte percentage of white cells	2.000000e-21
GCST90002394_244	Monocyte percentage of white cells	1.000000e-13
GCST90002395_369	Mean platelet volume	2.000000e-14
GCST90002398_121	Neutrophil count	8.000000e-11
GCST90002399_398	Neutrophil percentage of white cells	1.000000e-14
GCST90002399_399	Neutrophil percentage of white cells	4.000000e-17
GCST90002401_441	Platelet distribution width	2.000000e-32
GCST90002407_47	White blood cell count	1.000000e-29

EFO canonical traits (16, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004713	FEV/FVC ratio
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0007984	platelet component distribution width
EFO:0005090	basophil count
EFO:0005091	monocyte count
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0008336	disease progression measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D061085	Agenesis of Corpus Callosum	C10.500.034; C16.131.666.034; C23.300.008
D001321	Autistic Disorder	F03.625.164.113.500
D003616	Dandy-Walker Syndrome	C10.228.140.252.300; C10.228.140.602.500; C10.500.205; C16.131.666.205
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D058495	Sotos Syndrome	C16.131.077.889; C16.131.260.905; C16.320.180.905
D013724	Teratoma	C04.557.465.910
C562568	Cerebellar Hypoplasia (supp.)
C531684	Hereditary spinal ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3108647 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 3,728 (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
CHEMBL1214186	SINEFUNGIN	2	2,165
CHEMBL1232461	MOLIBRESIB	2	1,538
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)

ChEMBL bioactivities

58 potent at pChembl≥5 of 60 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.52	IC50	3	nM	CHEMBL5078908
8.30	IC50	5	nM	CHEMBL5178972
8.15	IC50	7	nM	CHEMBL5073608
8.10	IC50	8	nM	CHEMBL5091591
8.10	IC50	8	nM	CHEMBL5093241
8.05	IC50	9	nM	CHEMBL5178972
7.96	IC50	11	nM	CHEMBL5206271
7.96	IC50	11	nM	CHEMBL5195440
7.92	IC50	12	nM	CHEMBL5082544
7.92	IC50	12	nM	CHEMBL5082960
7.92	IC50	12	nM	CHEMBL5094380
7.92	IC50	12	nM	CHEMBL5189290
7.85	IC50	14	nM	CHEMBL5206271
7.82	IC50	15	nM	CHEMBL5071957
7.82	IC50	15	nM	CHEMBL5195440
7.77	IC50	17	nM	CHEMBL5072597
7.75	IC50	18	nM	CHEMBL5076615
7.75	IC50	18	nM	EZM-0414
7.70	IC50	20	nM	CHEMBL5091591
7.64	IC50	23	nM	CHEMBL5088515
7.64	IC50	23	nM	CHEMBL5091591
7.57	IC50	27	nM	CHEMBL5184871
7.54	IC50	29	nM	CHEMBL5073608
7.51	IC50	31	nM	EZM-0414
7.39	IC50	41	nM	CHEMBL5189290
7.39	Kd	41	nM	MOLIBRESIB
7.25	IC50	56	nM	CHEMBL5077994
7.22	IC50	60	nM	MOLIBRESIB
7.19	IC50	64	nM	CHEMBL5082544
7.18	IC50	66	nM	CHEMBL5091735
7.13	IC50	74	nM	CHEMBL5071957
7.03	IC50	93	nM	CHEMBL5094380
7.00	IC50	101	nM	CHEMBL5071333
6.93	IC50	118	nM	CHEMBL5080149
6.90	IC50	127	nM	CHEMBL5088515
6.87	IC50	134	nM	CHEMBL5184871
6.83	IC50	147	nM	CHEMBL5072302
6.79	IC50	162	nM	CHEMBL5077994
6.76	IC50	175	nM	CHEMBL5078908
6.63	IC50	235	nM	CHEMBL5076615
6.59	IC50	257	nM	CHEMBL5082960
6.47	IC50	340	nM	CHEMBL5080149
6.42	IC50	384	nM	CHEMBL5093241
6.42	IC50	379	nM	CHEMBL5072597
6.40	IC50	397	nM	CHEMBL5071333
6.35	IC50	449	nM	CHEMBL5072302
6.32	IC50	480	nM	CHEMBL6174023
6.27	IC50	540	nM	CHEMBL5091735
6.17	IC50	674	nM	CHEMBL5085128
6.10	IC50	800	nM	CHEMBL3414624

PubChem BioAssay actives

56 with measured affinity, of 143 total; 30 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[3-[4-(dimethylamino)piperidin-1-yl]-5-fluorophenyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.0030	uM
N-[(1R,3S)-3-[(3aS,6aS)-4-acetyl-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrol-1-yl]cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1870235: Inhibition of SETD2 in human A549 cells assessed as reduction in H3K36me3 incubated for 3 days by in-cell western assay	ic50	0.0050	uM
N-[3-[3-[acetyl(methyl)amino]pyrrolidin-1-yl]-5-fluorophenyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	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	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.0080	uM
N-[3-chloro-5-[4-(dimethylamino)piperidin-1-yl]phenyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.0080	uM
N-[(1R,3S)-3-[(8aS)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1870235: Inhibition of SETD2 in human A549 cells assessed as reduction in H3K36me3 incubated for 3 days by in-cell western assay	ic50	0.0110	uM
N-[(1R,3S)-3-[(3aS,6aS)-1-acetyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-5-yl]cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1870234: Inhibition of SETD2 (1434 to 1711 residues) (unknown origin) using SAM and biotin-Ahx-RKSAPATGGVKKPHR-NH2 as substrate preincubated for 30 mins followed by substrate addition by topcount scintillation counting method	ic50	0.0110	uM
ethane;4-fluoro-7-methyl-N-[(1R,3S)-3-[(3R)-3-[methyl(methylsulfonyl)amino]pyrrolidin-1-yl]cyclohexyl]-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.0120	uM
4-fluoro-7-methyl-N-[(1R,3S)-3-pyridin-4-ylcyclohexyl]-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.0120	uM
N-[3-[3-[acetyl(methyl)amino]pyrrolidin-1-yl]phenyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.0120	uM
N-[3-(4-acetylpiperazin-1-yl)-5-fluorophenyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1870234: Inhibition of SETD2 (1434 to 1711 residues) (unknown origin) using SAM and biotin-Ahx-RKSAPATGGVKKPHR-NH2 as substrate preincubated for 30 mins followed by substrate addition by topcount scintillation counting method	ic50	0.0120	uM
N-[(1R,3S)-3-[(3R)-3-[acetyl(methyl)amino]pyrrolidin-1-yl]cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.0150	uM
N-[3-[4-(dimethylamino)piperidin-1-yl]-5-methylphenyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.0170	uM
N-[(1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1870234: Inhibition of SETD2 (1434 to 1711 residues) (unknown origin) using SAM and biotin-Ahx-RKSAPATGGVKKPHR-NH2 as substrate preincubated for 30 mins followed by substrate addition by topcount scintillation counting method	ic50	0.0180	uM
N-[3-[4-(dimethylamino)piperidin-1-yl]phenyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.0180	uM
N-[(1R,3S)-3-[(3S)-3-[acetyl(methyl)amino]pyrrolidin-1-yl]cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.0230	uM
N-[3-(4-acetylpiperazin-1-yl)phenyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1870234: Inhibition of SETD2 (1434 to 1711 residues) (unknown origin) using SAM and biotin-Ahx-RKSAPATGGVKKPHR-NH2 as substrate preincubated for 30 mins followed by substrate addition by topcount scintillation counting method	ic50	0.0270	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	2179197: Binding affinity against SETD2 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0410	uM
4-fluoro-7-methyl-N-[(1R,3S)-3-(4-methylsulfonylpiperazin-1-yl)cyclohexyl]-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.0560	uM
4-fluoro-7-methyl-N-[3-(4-methylpiperazin-1-yl)phenyl]-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.0660	uM
4-fluoro-7-methyl-N-(3-morpholin-4-ylphenyl)-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.1010	uM
4-fluoro-7-methyl-N-[(1R,3S)-3-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl]-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.1180	uM
4-fluoro-7-methyl-N-[(1R,3S)-3-morpholin-4-ylcyclohexyl]-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.1470	uM
N-[cyclopropyl-(3-methyl-2-pyridinyl)methyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.6740	uM
(2S)-2-amino-4-[[(2S,3R,4S,5S)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propylamino]butanoic acid	1882375: Inhibition of SETD2 (unknown origin)	ic50	0.8000	uM
(2S,5S)-2-amino-6-[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]-5-(propylamino)hexanoic acid	1199204: Inhibition of human SETD2 (1347 to 1711) using histamine H3 (20 to 50) as substrate assessed as transfer of [3H]-Me of [3H-Me]-SAM to peptide substrate after 4 hrs by scintillation counting analysis	ic50	0.8000	uM
7-methyl-N-(3-morpholin-4-ylphenyl)-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	0.8180	uM
N-[(1R,3R)-3-(4-acetylpiperazin-1-yl)cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide	1870234: Inhibition of SETD2 (1434 to 1711 residues) (unknown origin) using SAM and biotin-Ahx-RKSAPATGGVKKPHR-NH2 as substrate preincubated for 30 mins followed by substrate addition by topcount scintillation counting method	ic50	1.2400	uM
N-[cyclopropyl-(3-methyl-2-pyridinyl)methyl]-7-methyl-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	2.0800	uM
N-[cyclopropyl-(3-methyl-2-pyridinyl)methyl]-5-fluoro-7-methyl-1H-indole-2-carboxamide	1818174: Inhibition of SETD2 (unknown origin) preincubated for 30 mins followed by SAM substrate addition measured after 2 hrs by plate reader method	ic50	5.4600	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
TAK-243	decreases sumoylation	1
geldanamycin	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
N-methyladenosine	decreases abundance, decreases methylation, increases abundance, increases methylation	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
coumarin	decreases phosphorylation	1
cupric oxide	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	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
(+)-JQ1 compound	increases expression	1
Vorinostat	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Berberine	increases expression	1
Cadmium	decreases expression	1
Caffeine	affects phosphorylation	1
Deferoxamine	affects expression, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1

ChEMBL screening assays

64 unique, capped per target: 64 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3111728	Binding	Inhibition of SETD2 (unknown origin)-mediated incorporation of methyl group from [3H]-SAM into peptide substrate up to 50 uM by scintillation proximity assay	Discovery and development of potent and selective inhibitors of histone methyltransferase g9a. — ACS Med Chem Lett

Cellosaurus cell lines

13 cell lines: 10 cancer cell line, 2 transformed cell line, 1 hybrid cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3GV	Abcam HEK293T SETD2 KO	Transformed cell line	Female
CVCL_B7ZB	Abcam Raji SETD2 KO	Cancer cell line	Male
CVCL_B9VV	Abcam HeLa SETD2 KO	Cancer cell line	Female
CVCL_C0A4	Abcam THP-1 SETD2 KO	Cancer cell line	Male
CVCL_C7BS	Abcam PC-3 SETD2 KO	Cancer cell line	Male
CVCL_D6AF	HyCyte A-375 KO-hSETD2	Cancer cell line	Female
CVCL_D7HH	Ubigene HEK293T SETD2 KO	Transformed cell line	Female
CVCL_D8A2	Ubigene A-549 SETD2 KO	Cancer cell line	Male
CVCL_D8FM	Ubigene CNE-1 SETD2 KO	Hybrid cell line
CVCL_E0NB	Ubigene HeLa SETD2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms