KMT2C

Summary

KMT2C (lysine methyltransferase 2C, HGNC:13726) is a protein-coding gene on chromosome 7q36.1, encoding Histone-lysine N-methyltransferase 2C (Q8NEZ4). Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4). In precision oncology, KMT2C Mutation OR KMT2A Mutation confers sensitivity to Immunotherapy in Cancer (CIViC Level B); 1 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein with an AT hook DNA-binding domain, a DHHC-type zinc finger, six PHD-type zinc fingers, a SET domain, a post-SET domain and a RING-type zinc finger. This protein is a member of the ASC-2/NCOA6 complex (ASCOM), which possesses histone methylation activity and is involved in transcriptional coactivation.

Source: NCBI Gene 58508 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 2,659 total — 103 pathogenic, 75 likely-pathogenic
• Phenotypes (HPO): 59
• Druggable target: yes
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 39 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_170606

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13726
Approved symbol	KMT2C
Name	lysine methyltransferase 2C
Location	7q36.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1506, HALR
Ensembl gene	ENSG00000055609
Ensembl biotype	protein_coding
OMIM	606833
Entrez	58508

Gene structure

Transcript identifiers

Ensembl transcripts: 70 — 31 protein_coding, 26 retained_intron, 9 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000262189, ENST00000360104, ENST00000418061, ENST00000418673, ENST00000424877, ENST00000452749, ENST00000473186, ENST00000485241, ENST00000489110, ENST00000490130, ENST00000558665, ENST00000679393, ENST00000679560, ENST00000679567, ENST00000679645, ENST00000679882, ENST00000680029, ENST00000680039, ENST00000680479, ENST00000680867, ENST00000680877, ENST00000680969, ENST00000681033, ENST00000681082, ENST00000681635, ENST00000681755, ENST00000681838, ENST00000681923, ENST00000682040, ENST00000682116, ENST00000682137, ENST00000682176, ENST00000682280, ENST00000682283, ENST00000682301, ENST00000682629, ENST00000682824, ENST00000682916, ENST00000683038, ENST00000683120, ENST00000683159, ENST00000683178, ENST00000683185, ENST00000683200, ENST00000683254, ENST00000683337, ENST00000683397, ENST00000683490, ENST00000683502, ENST00000683616, ENST00000683621, ENST00000683625, ENST00000683640, ENST00000683670, ENST00000683800, ENST00000683886, ENST00000684069, ENST00000684140, ENST00000684261, ENST00000684262, ENST00000684278, ENST00000684307, ENST00000684330, ENST00000684391, ENST00000684398, ENST00000684550, ENST00000684623, ENST00000684649, ENST00000684685, ENST00000684768

RefSeq mRNA: 1 — MANE Select: NM_170606 NM_170606

CCDS: CCDS5931

Canonical transcript exons

ENST00000262189 — 59 exons

Exon	Start	End
ENSE00001596960	152330601	152330739
ENSE00001629216	152252546	152252715
ENSE00001635330	152249876	152249953
ENSE00001666640	152251939	152252090
ENSE00001721204	152263016	152263130
ENSE00001749065	152311798	152311946
ENSE00001774010	152315138	152315338
ENSE00001783379	152273705	152273867
ENSE00001791110	152250853	152250966
ENSE00001799851	152265038	152265209
ENSE00001803163	152309966	152310075
ENSE00002299709	152358587	152358675
ENSE00003460315	152185558	152185631
ENSE00003460404	152222001	152222066
ENSE00003487164	152134925	152136924
ENSE00003491000	152180711	152182594
ENSE00003496744	152194009	152194128
ENSE00003497517	152169186	152169249
ENSE00003514253	152158863	152159072
ENSE00003515323	152138796	152138904
ENSE00003518698	152224435	152224616
ENSE00003525823	152167146	152167378
ENSE00003526887	152145153	152145295
ENSE00003531961	152187262	152187476
ENSE00003533044	152151442	152151581
ENSE00003540014	152154010	152154146
ENSE00003550085	152171264	152171342
ENSE00003550997	152144713	152144881
ENSE00003556745	152220523	152220735
ENSE00003560633	152155910	152156057
ENSE00003571980	152247902	152248620
ENSE00003572423	152187715	152187847
ENSE00003583949	152205106	152205225
ENSE00003588938	152139186	152139259
ENSE00003592800	152222573	152222682
ENSE00003596579	152154267	152154445
ENSE00003598315	152139675	152139791
ENSE00003599264	152146599	152146735
ENSE00003599583	152194229	152194261
ENSE00003603416	152152705	152152954
ENSE00003606952	152150900	152151007
ENSE00003607503	152195907	152196011
ENSE00003615297	152182974	152183156
ENSE00003622470	152207300	152207428
ENSE00003624714	152148033	152149152
ENSE00003626265	152224015	152224179
ENSE00003628418	152238707	152238826
ENSE00003629215	152176191	152178010
ENSE00003636551	152230220	152230321
ENSE00003639325	152156205	152156346
ENSE00003647416	152202934	152203064
ENSE00003668340	152235817	152235933
ENSE00003679828	152174131	152174242
ENSE00003680108	152194440	152194568
ENSE00003680506	152229923	152230027
ENSE00003680525	152162117	152163826
ENSE00003684517	152199279	152199459
ENSE00003684641	152179834	152180126
ENSE00003850683	152435626	152436003

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 98.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.5378 / max 1056.1115, expressed in 1800 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86979	18.7973	1784
86981	3.4355	1268
86980	0.3050	128

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.31	gold quality
caput epididymis	UBERON:0004358	97.99	gold quality
upper arm skin	UBERON:0004263	97.81	gold quality
epithelial cell of pancreas	CL:0000083	97.65	gold quality
corpus epididymis	UBERON:0004359	97.59	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.51	gold quality
calcaneal tendon	UBERON:0003701	97.43	gold quality
sural nerve	UBERON:0015488	97.37	gold quality
bone marrow cell	CL:0002092	97.17	gold quality
oviduct epithelium	UBERON:0004804	97.08	gold quality
seminal vesicle	UBERON:0000998	97.02	gold quality
cauda epididymis	UBERON:0004360	96.95	gold quality
left ventricle myocardium	UBERON:0006566	96.89	gold quality
secondary oocyte	CL:0000655	96.77	gold quality
corpus callosum	UBERON:0002336	96.63	gold quality
deltoid	UBERON:0001476	96.29	gold quality
tibialis anterior	UBERON:0001385	96.27	gold quality
trabecular bone tissue	UBERON:0002483	96.06	gold quality
parietal pleura	UBERON:0002400	95.97	gold quality
tendon	UBERON:0000043	95.81	gold quality
colonic epithelium	UBERON:0000397	95.81	gold quality
visceral pleura	UBERON:0002401	95.76	gold quality
medial globus pallidus	UBERON:0002477	95.72	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.69	gold quality
parotid gland	UBERON:0001831	95.59	gold quality
globus pallidus	UBERON:0001875	95.58	gold quality
skin of hip	UBERON:0001554	95.56	gold quality
vastus lateralis	UBERON:0001379	95.48	gold quality
quadriceps femoris	UBERON:0001377	95.36	gold quality
pylorus	UBERON:0001166	95.21	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	2059.27
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CD274	Activation
HOXC6	Unknown

miRNA regulators (miRDB)

310 targeting KMT2C, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-1184	99.99	68.19	1458

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• PTIP and PA1 are both components of the MLL3- and MLL4-containing histone H3 K4 methyltransferase complex that also includes ASH2L, RBBP5, WDR5, hDPY-30, NCOA6, and JmjC domain-containing putative histone demethylase UTX. (PMID:17500065)
• There were no MLL3 mutations in Korean patients with colorectal carcinomas. (PMID:17614854)
• analysis identified 1 somatic mutation of MLL3 among 57 colon tumors (1.8%), encoding a heterozygous missense mutation, S3449F; study identified also several novel non-synonymous germline variants of MLL3, likely representing previously unidentified SNPs (PMID:19215798)
• Study show that the C-terminal SET domain of MLL3 and MLL4 directly interacts with INI1, an integral subunit of Swi/Snf. (PMID:19221051)
• ASCOM-MLL3 and ASCOM-MLL4 play redundant but essential roles in FXR transactivation via their histone 3 lysine 4 trimethylation activity. (PMID:19556342)
• sequenced all 59 exons of MLL3 (14.7 Kb coding sequence) in 38 breast cancers from Chinese women, and found three somatic mutations in two of the cases, including one frameshift mutation (c.2687 ins A) (PMID:21116761)
• The trimethylation of histone H3 at Lys 4 by the MLL2/MLL3 subunits of ASCOM, enhanced by the hormone-induced displacement of the H3K4 demethylase KDM5B, stabilizes NURF binding. (PMID:21447625)
• These studies demonstrated that HOXC6 is an estrogen-responsive gene, and that histone methylases MLL2 and MLL3, in coordination with ERalpha and ERbeta, transcriptionally regulate HOXC6 in an estrogen-dependent manner. (PMID:21683083)
• Frameshift mutations of MLL3 in both colorectal cancer cells and primary tumor that were more common in cases with microsatellite instability. (PMID:21853109)
• p53-dependent histone 3-lysine-4-trimethylation of small heterodimer partner requires MLL3 (PMID:22034226)
• No somatic mutations were identified in the PTCH1, MLL2, and MLL3 genes in our cohort of hepatoblastoma samples (PMID:22183980)
• the second PHD finger (PHD2) of MLL1 is an E3 ubiquitin ligase in the presence of the E2-conjugating enzyme CDC34. This activity is conserved in the second PHD finger of MLL4, the closest homolog to MLL1 but not in MLL2 or MLL3. (PMID:23129768)
• frameshift mutations of MLL genes and loss of expression of MLL3 protein are common in gastric and colorectal cancers with MSI-H. (PMID:23259788)
• Germ line mutation of MLL3 was found in a pedigee having colorectal cancer and acute myeloid leukemia. (PMID:23429989)
• Mll3 genetic variantsare associated with gastric cancer. (PMID:23991983)
• MLL3 and MLL4 function in the regulation of enhancer activity. (PMID:24081332)
• Label-free quantitative comparison of DN urinary exosomes vs control group and SRM further validation, resulted in the discovery of a panel of three proteins (AMBP, MLL3 and VDAC1) which changes in DN. (PMID:24211404)
• concluded that this novel missense (S3660L) mutation in MLL3 gene is likely to increase the gastric cancer risk (PMID:24965397)
• MLL3 expression plays a vital role in gastric cancer development, and that this protein is an important marker for the prognosis of gastric cancer. (PMID:25222251)
• Taken together, our study suggested that downregulation of MLL3 was very important in the progression of ESCC (PMID:25273170)
• We propose that MLL3 and MLL4 are broadly required for controlling MAFA and MAFB transactivation during development and postnatally. (PMID:26180087)
• solution structures of the MLL3 core complex assembled with and without WDR5 by small angle x-ray scattering show similar overall topologies (PMID:26324722)
• Study found that rs6943984 and rs4725443 of the MLL3 gene were significantly associated with the risk of larynx cancer. (PMID:26818916)
• inactivation of MLL3 and TET2 may play an important role in the tumorigenesis process of HTLV-I-induced acute adult T-cell leukemia. (PMID:26880370)
• a minimized human RBBP5-ASH2L heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases (PMID:26886794)
• we demonstrate that low KMT2C and KMT2D expression in biopsies defines better outcome groups in pancreatic ductal adenocarcinoma (PMID:27280393)
• MLL3 binding was dependent on FOXA1, indicating that FOXA1 recruits MLL3 to chromatin. MLL3 silencing decreased H3K4me1 at enhancer elements but had no appreciable impact on H3K4me3 at enhancer elements. We propose a mechanism whereby the pioneer factor FOXA1 recruits the chromatin modifier MLL3 to facilitate the deposition of H3K4me1 histone marks, subsequently demarcating active enhancer elements (PMID:27926873)
• Overexpression of KMT2C is associated with Estrogen Receptor-positive Breast Cancer. (PMID:27986439)
• In the present study, we identified that MLL3 was upregulated in human dilated cardiomyopathy (DCM) hearts and remodeled mouse hearts, suggesting that MLL3 has a potential role in the pathological processes of DCM and heart failure. (PMID:28805231)
• Our data indicate that KMT2C ELs are associated with specific genetic features and that SPRY4 ELs may add prognostic information. (PMID:28940816)
• Somatic MLL3 mutations are associated with metastatic NUT midline carcinoma. (PMID:28967088)
• trr and G9a also have common direct targets, including the Drosophila ortholog of Arc (Arc1), a key regulator of synaptic plasticity. Our data highlight the clinical and molecular convergence between the KMT2 and EHMT protein families, which may contribute to a molecular network underlying a larger group of intellectual disability / autism spectrum disorder -related disorders. (PMID:29069077)
• KMT2C is a key regulator of ERalpha activity whose loss uncouples breast cancer proliferation from hormone abundance. (PMID:29755131)
• This study provides mechanistic insight into the oncogenic effects of PHD-associated mutations in MLL3. (PMID:29785026)
• histone methyltransferase mixed-lineage leukemia protein 3 (MLL3) is identified as a critical regulator of PD-L1 in prostate cancer cells. (PMID:30385408)
• Study identifies a binding mode of the extended PHD domain of MLL3/4 for the histone H4 N-terminal fragment and provides insights into a trans-histone regulatory mechanism of MLL3/4-mediated H3K4 methylation. (PMID:30604749)
• downregulation of KMT2C in bladder cancer cells leads to extensive changes in the epigenetic status and the expression of DNA damage response and DNA repair genes. (PMID:30665945)
• Mutations in FRG1 and KMT2C were found to be associated with a younger age especially after correcting for tobacco smoking and sex in Chinese patients with lung adenocarcinoma. (PMID:30821106)
• multistage EMPD tissue sequencing revealed KMT2C gene occurring early in EMPD oncogenesis, and that multifocal EMPD samples share the same early gene mutations, suggesting clonal origin of multifocal EMPD. (PMID:30905357)
• This is the first study to preliminarily elucidate the role of KMT2C mutations in Chinese patients with breast cancer. (PMID:31146111)

Cross-species orthologs

22 orthologs

Organism	Symbol	Gene ID
danio_rerio	kmt2cb	ENSDARG00000075560
danio_rerio	kmt2ca	ENSDARG00000079312
mus_musculus	Kmt2c	ENSMUSG00000038056
rattus_norvegicus	Kmt2c	ENSRNOG00000061080
drosophila_melanogaster	ash1	FBGN0005386
drosophila_melanogaster	trr	FBGN0023518
drosophila_melanogaster	Set2	FBGN0030486
drosophila_melanogaster	CG4565	FBGN0037841
drosophila_melanogaster	G9a	FBGN0040372
drosophila_melanogaster	egg	FBGN0086908
caenorhabditis_elegans	set-32	WBGENE00008062
caenorhabditis_elegans		WBGENE00008206
caenorhabditis_elegans		WBGENE00008527
caenorhabditis_elegans		WBGENE00011729
caenorhabditis_elegans	met-1	WBGENE00016603
caenorhabditis_elegans		WBGENE00018023
caenorhabditis_elegans		WBGENE00019584
caenorhabditis_elegans		WBGENE00019690
caenorhabditis_elegans		WBGENE00019883
caenorhabditis_elegans		WBGENE00020006
caenorhabditis_elegans		WBGENE00020919
caenorhabditis_elegans		WBGENE00021282

Paralogs (19): 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), SETD2 (ENSG00000181555), EHMT2 (ENSG00000204371), KMT2B (ENSG00000272333)

Protein

Protein identifiers

Histone-lysine N-methyltransferase 2C — Q8NEZ4 (reviewed: Q8NEZ4)

Alternative names: Homologous to ALR protein, Myeloid/lymphoid or mixed-lineage leukemia protein 3

All UniProt accessions (39): A0A7P0T8F0, A0A7P0T9K8, A0A7P0T9N3, A0A7P0T9Q7, A0A7P0T9U9, A0A7P0TA60, A0A7P0TAI3, A0A7P0TAQ8, A0A7P0TBM6, A0A7P0Z448, A0A804HHW0, A0A804HI08, A0A804HIF3, A0A804HIG3, A0A804HIK3, A0A804HIM1, A0A804HIM6, A0A804HIS4, A0A804HIW6, A0A804HJ27, A0A804HJ77, A0A804HJR9, A0A804HJT1, A0A804HJU5, A0A804HJV8, A0A804HK48, A0A804HKJ1, A0A804HKQ3, A0A804HKS3, A0A804HKW4, A0A804HLA5, A0A804HLD4, C9J4Z5, Q8NEZ4, H0Y765, H0YNL4, H7BY37, H7C212, H7C2V8

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). Part of chromatin remodeling machinery predominantly forms H3K4me1 methylation marks at active chromatin sites where transcription and DNA repair take place. Likely plays a redundant role with KMT2D in enriching H3K4me1 mark on primed and active enhancer elements.

Subunit / interactions. Component of the MLL3 complex (also named ASCOM complex), at least composed of catalytic subunit KMT2C/MLL3, ASH2L, RBBP5, WDR5, NCOA6, DPY30, KDM6A, PAXIP1/PTIP, PAGR1 and alpha- and beta-tubulin. 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 (via WIN motif) with WDR5.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in testis and ovary, followed by brain and liver. Also expressed in placenta, peripherical blood, fetal thymus, heart, lung and kidney. Within brain, expression was highest in hippocampus, caudate nucleus, and substantia nigra. Not detected in skeletal muscle and fetal liver.

Disease relevance. Kleefstra syndrome 2 (KLEFS2) [MIM:617768] A form of Kleefstra syndrome, an autosomal dominant disease characterized by variable intellectual disability, psychomotor developmental delay, seizures, behavioral abnormalities, and facial dysmorphisms. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The SET domain interacts with histone H3 but not H2A, H2B and H4, and may have a H3 lysine specific methylation activity.

Miscellaneous. Found in a critical region of chromosome 7, which is commonly deleted in malignant myeloid disorders. Partial duplication of the KMT2C gene are found in the juxtacentromeric region of chromosomes 1, 2, 13 and 21. Juxtacentromeric reshuffling of the KMT2C gene has generated the BAGE genes.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NEZ4-1	1	yes
Q8NEZ4-2	2
Q8NEZ4-3	3

RefSeq proteins (1): NP_733751* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000637	HMGI/Y_DNA-bd_CS	Conserved_site
IPR001214	SET_dom	Domain
IPR001841	Znf_RING	Domain
IPR001965	Znf_PHD	Domain
IPR003616	Post-SET_dom	Domain
IPR003888	FYrich_N	Conserved_site
IPR003889	FYrich_C	Conserved_site
IPR009071	HMG_box_dom	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR019787	Znf_PHD-finger	Domain
IPR034732	EPHD	Domain
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR037877	PHD3_KMT2C	Domain
IPR041967	KMT2C_ePHD1	Domain
IPR041968	KMT2C_ePHD2	Domain
IPR046341	SET_dom_sf	Homologous_superfamily
IPR047003	KMT2C_PHD4	Domain
IPR047004	KMT2C_PHD2	Domain
IPR047005	KMT2C_PHD6	Domain

Pfam: PF00628, PF00856, PF05964, PF05965, PF13771, PF13832

Catalyzed reactions (Rhea), 1 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)

UniProt features (203 total): compositionally biased region 47, modified residue 24, strand 21, region of interest 20, sequence variant 16, helix 15, turn 12, zinc finger region 11, sequence conflict 9, coiled-coil region 7, binding site 6, domain 5, mutagenesis site 5, splice variant 2, chain 1, short sequence motif 1, DNA-binding region 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
4ERY	X-RAY DIFFRACTION	1.3
6MLC	X-RAY DIFFRACTION	1.8
3UVL	X-RAY DIFFRACTION	2.2
7W6L	X-RAY DIFFRACTION	2.26
5F6K	X-RAY DIFFRACTION	2.41
5F59	X-RAY DIFFRACTION	2.8
6KIW	ELECTRON MICROSCOPY	4
2YSM	SOLUTION NMR
2YUK	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for Q8NEZ4 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (6): 4825; 4848–4849; 4851; 4899; 4901; 4906

Post-translational modifications (24): 46, 89, 113, 200, 758, 854, 1301, 1508, 1772, 1987, 2009, 2454, 2571, 2802, 2809, 2828, 2832, 2867, 3714, 3758 …

Mutagenesis-validated functional residues (5):

Position	Phenotype
4779	confers a wrad-dependent gain-of-function histone h3 dimethylation activity. converts h3k4me1 into h3k4me2.
4786	confers a wrad-dependent gain-of-function histone h3 dimethylation activity. converts h3k4me1 into h3k4me2.
4848	abolishes interaction with s-adenosyl-l-methionine.
4877	confers a wrad-dependent gain-of-function histone h3 dimethylation activity. converts h3k4me1 into h3k4me2.
4900	confers a wrad-dependent gain-of-function histone h3 dimethylation activity. converts h3k4me1 into h3k4me2.

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
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-9818564	Epigenetic regulation of gene expression by MLL3 and MLL4 complexes
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-9909649	Regulation of PD-L1(CD274) transcription
R-HSA-1266738	Developmental Biology
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-5619507	Activation of HOX genes during differentiation
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878171	Transcriptional regulation by RUNX1
R-HSA-9851695	Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes
R-HSA-9917777	Epigenetic regulation by WDR5-containing histone modifying complexes

MSigDB gene sets: 339 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, ROVERSI_GLIOMA_COPY_NUMBER_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, NKX61_01, BILD_HRAS_ONCOGENIC_SIGNATURE, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, OCT1_07, TGANTCA_AP1_C, TGACATY_UNKNOWN, AACTTT_UNKNOWN, CUI_TCF21_TARGETS_2_DN, GOBP_CHROMATIN_REMODELING, GOBP_METHYLATION, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN

GO Biological Process (5): methylation (GO:0032259), positive regulation of transcription by RNA polymerase II (GO:0045944), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (13): DNA binding (GO:0003677), transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), zinc ion binding (GO:0008270), acyltransferase activity (GO:0016746), histone methyltransferase activity (GO:0042054), histone H3K4 methyltransferase activity (GO:0042800), histone H3K4 monomethyltransferase activity (GO:0140945), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), metal ion binding (GO:0046872), histone H3K4 trimethyltransferase activity (GO:0140999)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), histone methyltransferase complex (GO:0035097), MLL3/4 complex (GO:0044666)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Epigenetic regulation by WDR5-containing histone modifying complexes	2
Gene expression (Transcription)	2
Chromatin modifying enzymes	1
Activation of HOX genes during differentiation	1
Transcriptional regulation by RUNX1	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
Regulation of PD-L1(CD274) expression	1
RNA Polymerase II Transcription	1
Chromatin organization	1
Developmental Biology	1
Generic Transcription Pathway	1
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1
Epigenetic regulation of gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of DNA-templated transcription	2
nucleic acid binding	2
histone H3K4 methyltransferase activity	2
cellular anatomical structure	2
metabolic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
cellular component organization	1
chromatin organization	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription coregulator activity	1
transition metal ion binding	1
transferase activity	1
protein methyltransferase activity	1
histone modifying activity	1
protein-lysine N-methyltransferase activity	1
histone H3 methyltransferase activity	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
nucleoplasm	1
methyltransferase complex	1
nuclear protein-containing complex	1
histone methyltransferase complex	1

Protein interactions and networks

STRING

2988 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KMT2C	PAXIP1	Q6ZW49	998
KMT2C	KDM6A	O15550	997
KMT2C	ASH2L	Q9UBL3	996
KMT2C	NCOA6	Q14686	995
KMT2C	WDR5	P61964	994
KMT2C	DPY30	Q9C005	991
KMT2C	RBBP5	Q15291	985
KMT2C	KMT2D	O14686	972
KMT2C	SETD1A	O15047	971
KMT2C	KMT2B	Q9UMN6	941
KMT2C	SETD1B	Q9UPS6	940
KMT2C	PAGR1	Q9BTK6	905
KMT2C	KMT2A	Q03164	839
KMT2C	TP53	P04637	808
KMT2C	H3-3A	P06351	788
KMT2C	H3C1	P02295	788

IntAct

105 interactions, top by confidence:

A	B	Type	Score
ASH2L	WDR5	psi-mi:“MI:0915”(physical association)	0.950
ASH2L	NCOA6	psi-mi:“MI:0914”(association)	0.930
WDR5	KMT2D	psi-mi:“MI:0915”(physical association)	0.910
ASH2L	KMT2D	psi-mi:“MI:0914”(association)	0.890
DPY30	WDR5	psi-mi:“MI:0914”(association)	0.860
RBBP5	KMT2D	psi-mi:“MI:0914”(association)	0.840
KMT2C	NCOA6	psi-mi:“MI:0915”(physical association)	0.830
KMT2C	NCOA6	psi-mi:“MI:0914”(association)	0.830
KMT2C	RBBP5	psi-mi:“MI:0915”(physical association)	0.800
KMT2C	RBBP5	psi-mi:“MI:0914”(association)	0.800
KMT2C	WDR5	psi-mi:“MI:0914”(association)	0.770
WDR5	KMT2C	psi-mi:“MI:0915”(physical association)	0.770
ASH2L	SETD1A	psi-mi:“MI:0914”(association)	0.760
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
RING1	CBX4	psi-mi:“MI:0914”(association)	0.730
WDR5	MEN1	psi-mi:“MI:0914”(association)	0.710
TP53	WDR5	psi-mi:“MI:0914”(association)	0.690
PAGR1	KMT2D	psi-mi:“MI:0914”(association)	0.640
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
ASH2L	KMT2C	psi-mi:“MI:0915”(physical association)	0.620
ASH2L	RBBP5	psi-mi:“MI:0914”(association)	0.600
CDC73	CSTF2	psi-mi:“MI:0914”(association)	0.580

BioGRID (228): HIST1H3A (Biochemical Activity), KMT2C (Two-hybrid), KMT2C (Affinity Capture-MS), HIST3H3 (Biochemical Activity), WDR5 (Reconstituted Complex), RBBP5 (Reconstituted Complex), ASH2L (Reconstituted Complex), DPY30 (Reconstituted Complex), KMT2C (Reconstituted Complex), KMT2C (Two-hybrid), FOXA1 (Co-localization), KMT2C (Affinity Capture-MS), KMT2C (Affinity Capture-RNA), WDR5 (Reconstituted Complex), RBBP5 (Reconstituted Complex)

ESM2 similar proteins: A0A0R4IYX6, A0A1L8H0H2, A5X7A0, A7XYJ6, E1BE02, F6NSX9, F8VPJ6, O35914, O57415, P37275, P59598, P59759, Q03172, Q13029, Q2KHR2, Q3UH06, Q5EXX3, Q5R7F2, Q5ZIE8, Q5ZLR2, Q62947, Q63755, Q64318, Q6NRM0, Q6ZPY7, Q76L83, Q7LBC6, Q7YR76, Q80VX4, Q86V15, Q8BHZ4, Q8BLG0, Q8BRH4, Q8BX22, Q8BZ32, Q8C0C0, Q8IZQ8, Q8NEZ4, Q8R5I7, Q8VIM5

Diamond homologs: A6H5X4, F4I443, O08550, O14686, P55200, Q03164, Q08DR0, Q2HJ93, Q4R9C4, Q5F4A1, Q5I0E2, Q5I0J8, Q5R5Z2, Q5RJY2, Q6PDK2, Q7L622, Q8BRH4, Q8BVM9, Q8IWS0, Q8NEZ4, Q9D4J7, Q9UIL8, Q9UMN6, A7E2Z2, A8XI75, C6KTD2, E9PYH6, E9Q5F9, F4K1J4, G0SDW4, O15047, O17514, O43463, O54864, O65312, O96028, P0CB22, P0CO26, P0CO27, P20659

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
KMT2C	“up-regulates quantity by expression”	CD274	“transcriptional regulation”
KMT2C	“form complex”	“MLL3 complex”	binding
Ub:E2	“up-regulates activity”	KMT2C	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 92 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	12	44.3×	8e-15
Deactivation of the beta-catenin transactivating complex	11	35.6×	1e-12
Activation of HOX genes during differentiation	5	30.5×	2e-05
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	8	21.9×	2e-07
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	10	20.3×	5e-09
TCF dependent signaling in response to WNT	9	14.7×	5e-07
Signaling by WNT	9	14.0×	7e-07
PKMTs methylate histone lysines	6	13.4×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
transcription initiation-coupled chromatin remodeling	7	30.8×	4e-07
positive regulation of miRNA transcription	8	26.7×	1e-07
somatic stem cell population maintenance	6	17.1×	1e-04
anatomical structure morphogenesis	8	12.8×	2e-05
transcription by RNA polymerase II	15	12.2×	3e-10
chromatin remodeling	11	9.2×	3e-06
glucose homeostasis	6	9.0×	2e-03
neuron differentiation	7	8.1×	1e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 39 cancer types — ACC, ACYC, AML, ANSC, BCC, BLCA, BRCA, CCRCC, CEAD, CESC, CHOL, COAD…(+27 more).

Clinical variants and AI predictions

ClinVar

2659 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	103
Likely pathogenic	75
Uncertain significance	1182
Likely benign	711
Benign	224

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1033181	NM_170606.3(KMT2C):c.8543del (p.Asn2848fs)	Pathogenic
1216345	NM_170606.3(KMT2C):c.1468del (p.Arg490fs)	Pathogenic
1216958	NM_170606.3(KMT2C):c.6082C>T (p.Arg2028Ter)	Pathogenic
1299749	NM_170606.3(KMT2C):c.6938_6939del (p.Phe2313fs)	Pathogenic
1300598	NM_170606.3(KMT2C):c.3709C>T (p.Arg1237Ter)	Pathogenic
1331597	NM_170606.3(KMT2C):c.7431del (p.His2478fs)	Pathogenic
1335702	NM_170606.3(KMT2C):c.3084_3085del (p.Cys1028_Asp1029delinsTer)	Pathogenic
1685915	NM_170606.3(KMT2C):c.2532+1del	Pathogenic
1695217	NM_170606.3(KMT2C):c.739+1G>A	Pathogenic
1699406	NM_170606.3(KMT2C):c.5419C>T (p.Gln1807Ter)	Pathogenic
1700103	NM_170606.3(KMT2C):c.6449del (p.Gly2150fs)	Pathogenic
1709075	NM_170606.3(KMT2C):c.2829_2832dup (p.Val945fs)	Pathogenic
1711190	NM_170606.3(KMT2C):c.6570_6573del (p.Phe2190fs)	Pathogenic
1727001	NM_170606.3(KMT2C):c.1759_1769del (p.Gln587fs)	Pathogenic
1878498	NM_170606.3(KMT2C):c.103del (p.Arg35fs)	Pathogenic
1992339	NM_170606.3(KMT2C):c.14006_14007del (p.Ser4669fs)	Pathogenic
2073580	NM_170606.3(KMT2C):c.8965_8970delinsAGTACCTT (p.Val2989fs)	Pathogenic
2237329	NM_170606.3(KMT2C):c.3989T>G (p.Leu1330Ter)	Pathogenic
2304891	NM_170606.3(KMT2C):c.11316_11317del (p.Gly3773fs)	Pathogenic
2430044	NM_170606.3(KMT2C):c.5716C>T (p.Arg1906Ter)	Pathogenic
2475685	NM_170606.3(KMT2C):c.7123C>T (p.Gln2375Ter)	Pathogenic
2499063	NM_170606.3(KMT2C):c.4476dup (p.Ser1493fs)	Pathogenic
2572190	NM_170606.3(KMT2C):c.10266_10267del (p.Arg3423fs)	Pathogenic
2572632	NM_170606.3(KMT2C):c.4845G>A (p.Trp1615Ter)	Pathogenic
2579994	NM_170606.3(KMT2C):c.9235C>T (p.Arg3079Ter)	Pathogenic
2673135	NM_170606.3(KMT2C):c.4092+1G>A	Pathogenic
280488	NM_170606.3(KMT2C):c.5409_5413dup (p.Gly1805fs)	Pathogenic
3116016	NM_170606.3(KMT2C):c.14318del (p.Val4773fs)	Pathogenic
3236481	NM_170606.3(KMT2C):c.9915del (p.Met3306fs)	Pathogenic
3236482	NM_170606.3(KMT2C):c.5481_5485del (p.Lys1827fs)	Pathogenic

SpliceAI

10773 predictions. Top by Δscore:

Variant	Effect	Δscore
7:152138790:TCTTA:T	donor_loss	1.0000
7:152138791:CTTAC:C	donor_loss	1.0000
7:152138792:TTA:T	donor_loss	1.0000
7:152138793:TACCT:T	donor_loss	1.0000
7:152138794:A:C	donor_loss	1.0000
7:152138795:CC:C	donor_loss	1.0000
7:152138795:CCT:C	donor_gain	1.0000
7:152139255:CGGTT:C	acceptor_gain	1.0000
7:152139256:GGTTC:G	acceptor_loss	1.0000
7:152139257:GTTC:G	acceptor_loss	1.0000
7:152139258:TT:T	acceptor_gain	1.0000
7:152139258:TTCT:T	acceptor_loss	1.0000
7:152139259:TCTGA:T	acceptor_loss	1.0000
7:152139260:C:CC	acceptor_gain	1.0000
7:152139260:CT:C	acceptor_loss	1.0000
7:152139261:T:A	acceptor_loss	1.0000
7:152139670:CCTA:C	donor_loss	1.0000
7:152139671:CTA:C	donor_loss	1.0000
7:152139698:T:A	donor_gain	1.0000
7:152139788:GCCCC:G	acceptor_loss	1.0000
7:152139790:CC:C	acceptor_gain	1.0000
7:152139790:CCCT:C	acceptor_loss	1.0000
7:152139791:CC:C	acceptor_gain	1.0000
7:152139791:CCTA:C	acceptor_loss	1.0000
7:152146597:A:AC	donor_gain	1.0000
7:152146598:C:CT	donor_gain	1.0000
7:152146598:CTG:C	donor_gain	1.0000
7:152148027:CGTTA:C	donor_loss	1.0000
7:152148030:TACCT:T	donor_loss	1.0000
7:152148031:ACC:A	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000012312 (7:152371677 G>T), RS1000015086 (7:152432983 C>T), RS1000018879 (7:152351893 C>A,T), RS1000048482 (7:152352014 A>G), RS1000062206 (7:152326112 T>C), RS1000085163 (7:152143755 C>G), RS1000095045 (7:152269223 G>C), RS1000095711 (7:152218576 T>C), RS1000097976 (7:152324468 A>G), RS1000152585 (7:152351743 G>A,C), RS1000153599 (7:152336910 A>G), RS1000157019 (7:152168238 G>C), RS1000159262 (7:152319741 C>A), RS1000174997 (7:152255389 C>G,T), RS1000194433 (7:152290591 A>C,T)

Disease associations

OMIM: gene MIM:606833 | disease phenotypes: MIM:617768, MIM:610253, MIM:209850, MIM:617829, MIM:619681, MIM:254500

GenCC curated gene-disease

Disease	Classification	Inheritance
Kleefstra syndrome 2	Definitive	Autosomal dominant
neurodevelopmental disorder	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Mondo (13): Kleefstra syndrome 2 (MONDO:0054701), Kleefstra syndrome 1 (MONDO:0027407), neurodevelopmental disorder (MONDO:0700092), autism, susceptiblity to (MONDO:0020836), intellectual disability (MONDO:0001071), developmental and epileptic encephalopathy 92 (MONDO:0020631), autism spectrum disorder (MONDO:0005258), syndromic intellectual disability (MONDO:0000508), Kleefstra syndrome (MONDO:0012455), dystonia, early-onset, and/or spastic paraplegia (MONDO:0859215), Kleefstra syndrome due to a point mutation (MONDO:0016865), plasma cell myeloma (MONDO:0009693), microcephaly (MONDO:0001149)

Orphanet (8): Kleefstra syndrome (Orphanet:261494), Rare genetic syndromic intellectual disability (Orphanet:183763), Kleefstra syndrome due to a point mutation (Orphanet:261652), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443), Rare genetic intellectual disability (Orphanet:183757), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000076	Vesicoureteral reflux
HP:0000077	Abnormality of the kidney
HP:0000078	Abnormality of the genital system
HP:0000164	Abnormality of the dentition
HP:0000179	Thick lower lip vermilion
HP:0000193	Bifid uvula
HP:0000232	Everted lower lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000519	Developmental cataract
HP:0000540	Hypermetropia
HP:0000574	Thick eyebrow
HP:0000695	Natal tooth
HP:0000708	Atypical behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000826	Precocious puberty
HP:0000974	Hyperextensible skin
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001321	Cerebellar hypoplasia
HP:0001357	Plagiocephaly

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002720_4	Kidney function decline traits	2.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006836	rapid kidney function decline

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D065886	Neurodevelopmental Disorders	F03.625
C563043	Kleefstra Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2189113 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items; also 1 oncogenic, 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
KMT2C Mutation OR KMT2A Mutation	Immunotherapy	Cancer	Sensitivity/Response	CIViC B	EID12031
KMT2C Loss	Aromatase Inhibitor	Breast Cancer	Resistance	CIViC B	EID6484

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)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases reaction, affects binding, increases reaction, increases expression	6
Estradiol	increases reaction, decreases expression, increases expression, decreases reaction, affects binding	5
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
(+)-JQ1 compound	increases expression	2
Ethanol	affects cotreatment, increases expression, decreases expression	2
Cisplatin	affects cotreatment, decreases expression	2
Diethylstilbestrol	affects binding, increases reaction, increases expression, decreases reaction	2
Dronabinol	increases expression	2
Valproic Acid	affects expression, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
alpha-cobratoxin	decreases expression, decreases reaction	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	affects cotreatment, decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Vorinostat	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Doxorubicin	decreases expression	1

ChEMBL screening assays

29 unique, capped per target: 29 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2209112	Binding	Inhibition of MLL3 using core histone as substrate preincubated for 10 mins followed by addition of [3H]SAM and incubated for 60 mins	Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. — ACS Med Chem Lett

Cellosaurus cell lines

14 cell lines: 14 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_9827	MGH-U3	Cancer cell line	Male
CVCL_B1VC	Abcam HeLa KMT2C KO	Cancer cell line	Female
CVCL_B7B0	PMAC1	Cancer cell line	Male
CVCL_B7B3	PMAC4	Cancer cell line	Male
CVCL_B7IM	BC-PAK1	Cancer cell line	Female
CVCL_C6MY	USZ22-EMC2	Cancer cell line	Male
CVCL_F0K0	JXQ-3D-783R1	Cancer cell line	Female
CVCL_F0K1	JXQ-3D-783R2	Cancer cell line	Female
CVCL_F0K2	JXQ-3D-783R3	Cancer cell line	Female
CVCL_F0K9	JXQ-3D-3975R1	Cancer cell line	Male

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