KMT2D

Summary

KMT2D (lysine methyltransferase 2D, HGNC:7133) is a protein-coding gene on chromosome 12q13.12, encoding Histone-lysine N-methyltransferase 2D (O14686). 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, KMT2D Loss-of-function confers sensitivity to Immune Checkpoint Inhibitor in Colorectal Adenocarcinoma (CIViC Level B); 2 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 31.5% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome.

Source: NCBI Gene 8085 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Kabuki syndrome 1 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 7,439 total — 708 pathogenic, 264 likely-pathogenic
• Phenotypes (HPO): 269
• Druggable target: yes
• Precision-oncology evidence (CIViC): 3 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 46 cancer types
• Cancer dependency (DepMap): dependent in 31.5% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_003482

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7133
Approved symbol	KMT2D
Name	lysine methyltransferase 2D
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Aliases	ALR, MLL4, CAGL114
Ensembl gene	ENSG00000167548
Ensembl biotype	protein_coding
OMIM	602113
Entrez	8085

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 15 protein_coding, 10 nonsense_mediated_decay, 9 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000301067, ENST00000549743, ENST00000550356, ENST00000552391, ENST00000650290, ENST00000681974, ENST00000682693, ENST00000682886, ENST00000683043, ENST00000683543, ENST00000683863, ENST00000684428, ENST00000684755, ENST00000685024, ENST00000685166, ENST00000685554, ENST00000685979, ENST00000685982, ENST00000686151, ENST00000686564, ENST00000686968, ENST00000687201, ENST00000687241, ENST00000688095, ENST00000688411, ENST00000689060, ENST00000689143, ENST00000689944, ENST00000691463, ENST00000691932, ENST00000691986, ENST00000692465, ENST00000692637, ENST00000692841, ENST00000692973

RefSeq mRNA: 1 — MANE Select: NM_003482 NM_003482

CCDS: CCDS44873

Canonical transcript exons

ENST00000301067 — 55 exons

Exon	Start	End
ENSE00001114128	49054900	49055026
ENSE00001114139	49050886	49052424
ENSE00001114141	49052564	49052709
ENSE00001114142	49054307	49054416
ENSE00001114166	49053978	49054140
ENSE00001114170	49053207	49053321
ENSE00001114172	49053476	49053641
ENSE00001114175	49054528	49054751
ENSE00001114187	49052915	49053072
ENSE00001272663	49024578	49024708
ENSE00001272677	49026182	49027322
ENSE00001272689	49028009	49028141
ENSE00001272698	49028828	49028958
ENSE00001272710	49029401	49029476
ENSE00001272756	49034582	49034666
ENSE00001272775	49037125	49038989
ENSE00001272789	49039435	49039617
ENSE00001272803	49041655	49041705
ENSE00001272807	49041917	49041990
ENSE00001272814	49042089	49042330
ENSE00001272819	49042561	49042645
ENSE00001272853	49043868	49043998
ENSE00001272859	49044200	49044304
ENSE00001272861	49044403	49044522
ENSE00001272869	49044744	49044965
ENSE00001272883	49046065	49046174
ENSE00001272892	49046609	49046790
ENSE00001272898	49047965	49048069
ENSE00001272909	49048659	49048769
ENSE00001272923	49049682	49050790
ENSE00001272985	49024810	49024946
ENSE00001273006	49027803	49027930
ENSE00001273030	49029061	49029236
ENSE00001273044	49030280	49030439
ENSE00001273052	49030601	49030768
ENSE00001273067	49031175	49033964
ENSE00001273074	49034067	49034299
ENSE00001273080	49034410	49034476
ENSE00001273098	49034812	49034935
ENSE00001273111	49039222	49039358
ENSE00001273127	49039724	49041535
ENSE00001273175	49042741	49042878
ENSE00001273182	49043076	49043186
ENSE00001273190	49043363	49043428
ENSE00001273198	49043635	49043782
ENSE00001273241	49045920	49045967
ENSE00001273251	49046260	49046424
ENSE00001273280	49049105	49049218
ENSE00002152433	49018978	49021872
ENSE00002329679	49055276	49055361
ENSE00002410119	49059613	49060794
ENSE00003475225	49030893	49031033
ENSE00003916405	49022280	49022353
ENSE00003917257	49022043	49022151
ENSE00003922486	49022590	49022875

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 96.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.5584 / max 217.0966, expressed in 1808 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130792	10.2401	1761
130793	7.2037	1715
206686	0.7949	440
130788	0.7947	426
130787	0.7146	433
130789	0.4943	276
130794	0.2865	121
130790	0.0297	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.63	gold quality
medial globus pallidus	UBERON:0002477	95.07	gold quality
sural nerve	UBERON:0015488	95.04	gold quality
globus pallidus	UBERON:0001875	94.14	gold quality
tendon of biceps brachii	UBERON:0008188	94.06	gold quality
granulocyte	CL:0000094	93.91	gold quality
cardia of stomach	UBERON:0001162	93.15	gold quality
right uterine tube	UBERON:0001302	92.45	gold quality
gastrocnemius	UBERON:0001388	91.75	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.72	gold quality
left uterine tube	UBERON:0001303	91.64	gold quality
subthalamic nucleus	UBERON:0001906	91.52	gold quality
renal medulla	UBERON:0000362	91.37	gold quality
body of uterus	UBERON:0009853	91.37	gold quality
right lobe of thyroid gland	UBERON:0001119	91.32	gold quality
adenohypophysis	UBERON:0002196	91.27	gold quality
metanephros cortex	UBERON:0010533	91.27	gold quality
muscle of leg	UBERON:0001383	91.23	gold quality
left lobe of thyroid gland	UBERON:0001120	91.18	gold quality
mucosa of stomach	UBERON:0001199	91.17	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.02	gold quality
stromal cell of endometrium	CL:0002255	90.96	gold quality
skin of leg	UBERON:0001511	90.89	gold quality
right ovary	UBERON:0002118	90.87	gold quality
body of stomach	UBERON:0001161	90.86	gold quality
pylorus	UBERON:0001166	90.84	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.83	gold quality
body of tongue	UBERON:0011876	90.79	gold quality
cerebellar cortex	UBERON:0002129	90.70	gold quality
cerebellar hemisphere	UBERON:0002245	90.70	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.74
E-MTAB-6379	no	41.77

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
HOXC6	Unknown
PTGS1	Unknown

Upstream regulators (CollecTRI, top): KMT2B

miRNA regulators (miRDB)

183 targeting KMT2D, 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-4682	100.00	68.89	1258
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-6759-5P	99.99	66.54	785
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-568	99.98	69.86	2084
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-520D-5P	99.98	73.34	4883

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 31.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• suggests a central role for the MLL2 complex in the growth of ERalpha-positive cancer cells (PMID:16603732)
• Knockdown of MLL2 reveals ALR target genes and leads to alterations in cell adhesion and growth. (PMID:17178841)
• CGBP interacts with MLL1, MLL2 as well as Set1 H3-Lysine 4 (H3K4) specific methyl-transferases and plays critical roles in regulations of MLL target genes. (PMID:18082152)
• A molecular mechanism by which the recruitment of a H3K4 histone methyltransferase complex on the promoter of a NF-kappaB-dependent gene induces its expression. (PMID:19219072)
• 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)
• Mutations in MLL2 are major cause of Kabuki syndrome. (PMID:20711175)
• Data show that Pygo2 associates with MLL2 histone methyltransferase and STAGA histone acetyltransferase to facilitate their interaction with beta-catenin and Wnt1-induced, TCF/LEF-dependent transactivation in breast cancer cells. (PMID:20937768)
• Direct sequencing of all 54 exons of the MLL2 gene in 45 clinically well-defined Kabuki Syndrome patients identified 34 (75.6%) different mutations. One mutation has been described previously, all others are novel. (PMID:21280141)
• 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)
• a large spectrum of MLL2 mutations in patients with Kabuki syndrome (PMID:21658225)
• MLL2 mutations were found in 81/110 (74%) of Kabuki syndrome families (PMID:21671394)
• 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)
• 32% of diffuse large B-cell lymphoma and 89% of follicular lymphoma cases had somatic mutations in MLL2, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B (PMID:21796119)
• phenotypic variability of Kabuki syndrome suggests that MLL2 testing should be considered even in atypical patients. (PMID:22126750)
• No somatic mutations were identified in the PTCH1, MLL2, and MLL3 genes in our cohort of hepatoblastoma samples (PMID:22183980)
• we defined a role for Trithorax proteins WDR5 and MLL2 in activating the differentiation gene program in epidermal progenitor cells (PMID:22829784)
• Microdeletions and microduplications have not been identified in the MLL2 and KDM6A genes of a large cohort of patients with Kabuki syndrome. (PMID:22840376)
• This study expands the known genetic basis of Kabuki syndrome (KS) by showing mosaic mutations and large intragenic deletions and duplications of MLL2 in patients with KS. (PMID:22901312)
• results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations (PMID:23045699)
• 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)
• Studies suggest the KMT2D (MLL2) nomenclature as H3K4 methyltransferases. (PMID:23130995)
• Studies indicate that mutation screening confirmed KMT2D (MLL2) as the major causative gene for Kabuki syndrome (KS). (PMID:23131014)
• MLL2 mutations occur in a subgroup-independent manner. (PMID:23184418)
• MLL1 and MLL2 bind to SR-B1 promoter in an E2-dependent manner and control the assembly of transcription pre-initiation complex and RNA polymerase II recruitment. (PMID:23192982)
• MLL2 mutation positive patients have a more severe and typical Kabuki phenotype than the MLL2 mutation negative group. (PMID:23320472)
• these results indicate that the suppression of MLL genes, especially MLL2 and MLL5, take part in modulating breast carcinogenesis. (PMID:23754336)
• The identification of novel MLL2 mutations in patients with Kabuki syndrome. (PMID:23913813)
• Ectopic AKAP95 stimulates expression of a chromosomal reporter gene in synergy with MLL1 or MLL2, whereas AKAP95 depletion impairs retinoic acid-mediated gene induction in embryonic stem cells (PMID:23995757)
• MLL3 and MLL4 function in the regulation of enhancer activity. (PMID:24081332)
• Study supports that KMT2D has distinct roles in neoplastic cells, as opposed to normal cells. (PMID:24240169)
• Data indicate that seven genes showed statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA. (PMID:24323028)
• Identify MLL4 as a major mammalian H3K4 mono- and di-methyltransferase essential for enhancer activation during cell differentiation. (PMID:24368734)
• MLL4 (KMT2D) is a major H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3 (KMT2C) in mouse and human cells. MLL4 is enriched on enhancers and is required for enhancer activation, cell-type-specific gene expression and cell differentiation. (PMID:24368734)
• MLL4 (KMT2D) is a major H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3 (KMT2C) in mouse and human cells. MLL4 is enriched on enhancers and is required for enhancer activation, cell-type-specific gene expression and cell differentiation. (PMID:24368734)
• High levels of UTX or MLL4 are associated with poor prognosis in patients with breast cancer. (PMID:24491801)
• Like KMT2D, CHD7 interacts with members of the WAR complex, namely WDR5, ASH2L and RbBP5. We therefore propose that CHD7 and KMT2D function in the same chromatin modification machinery. (PMID:24705355)
• 10 out of the 11 mutations found in patients with Kabuki syndrome were novel. KMT2D mutations included four small deletions or insertions and four nonsense and two missense mutations. (PMID:24739679)
• Reduced or lost expression of MLL2 was commonly observed in tumor tissues as compared with paired adjacent non-tumor tissues regardless of mutation status. (PMID:25112956)
• Data identified mutations in epigenetic modifiers such as KMT2D as potential early driving events in lymphomagenesis and immune escape alterations as relapse-associated events in diffuse large B-cell lymphoma. (PMID:25123191)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	kmt2d	ENSDARG00000037060
mus_musculus	Kmt2d	ENSMUSG00000048154
rattus_norvegicus	Prkag1	ENSRNOG00000061499
drosophila_melanogaster	ash1	FBGN0005386
drosophila_melanogaster	trr	FBGN0023518
drosophila_melanogaster	Set2	FBGN0030486
drosophila_melanogaster	CG4565	FBGN0037841
drosophila_melanogaster	G9a	FBGN0040372
drosophila_melanogaster	egg	FBGN0086908
caenorhabditis_elegans	set-32	WBGENE00008062
caenorhabditis_elegans		WBGENE00008206
caenorhabditis_elegans		WBGENE00008527
caenorhabditis_elegans		WBGENE00011729
caenorhabditis_elegans	met-1	WBGENE00016603
caenorhabditis_elegans		WBGENE00018023
caenorhabditis_elegans		WBGENE00019584
caenorhabditis_elegans		WBGENE00019690
caenorhabditis_elegans		WBGENE00019883
caenorhabditis_elegans		WBGENE00020006
caenorhabditis_elegans		WBGENE00020919
caenorhabditis_elegans		WBGENE00021282

Paralogs (19): KMT2C (ENSG00000055609), SETD1A (ENSG00000099381), SUV39H1 (ENSG00000101945), EZH2 (ENSG00000106462), EZH1 (ENSG00000108799), NSD2 (ENSG00000109685), ASH1L (ENSG00000116539), KMT2A (ENSG00000118058), SETDB2 (ENSG00000136169), SETD1B (ENSG00000139718), SETDB1 (ENSG00000143379), NSD3 (ENSG00000147548), SETBP1 (ENSG00000152217), SUV39H2 (ENSG00000152455), NSD1 (ENSG00000165671), EHMT1 (ENSG00000181090), SETD2 (ENSG00000181555), EHMT2 (ENSG00000204371), KMT2B (ENSG00000272333)

Protein

Protein identifiers

Histone-lysine N-methyltransferase 2D — O14686 (reviewed: O14686)

Alternative names: ALL1-related protein, Myeloid/lymphoid or mixed-lineage leukemia protein 2

All UniProt accessions (24): A0A3B3ISC8, A0A804HHR9, A0A804HJB5, A0A8I5KNS6, A0A8I5KPB7, A0A8I5KQ09, A0A8I5KQD6, A0A8I5KQT2, A0A8I5KRH2, A0A8I5KSG1, A0A8I5KTR4, A0A8I5KU18, A0A8I5KU33, A0A8I5KU95, A0A8I5KX79, A0A8I5KYU5, A0A8I5QJ79, A0A8I5QJA0, A0A8I5QJD3, A0A8I5QJD5, A0A8I5QJE4, A0A8I5QKN1, A0A8I5QKP3, O14686

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. Acts as a coactivator for estrogen receptor by being recruited by ESR1, thereby activating transcription.

Subunit / interactions. Component of the MLL2 complex (also named ASCOM complex), at least composed of catalytic subunit KMT2D/MLL2, 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 with ESR1; interaction is direct. Interacts (via WIN motif) with WDR5.

Subcellular location. Nucleus.

Tissue specificity. Expressed in most adult tissues, including a variety of hematoipoietic cells, with the exception of the liver.

Disease relevance. Kabuki syndrome 1 (KABUK1) [MIM:147920] An autosomal dominant, congenital syndrome characterized by intellectual disability and additional features, including postnatal dwarfism, a peculiar facies characterized by long palpebral fissures with eversion of the lateral third of the lower eyelids, a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy. The disease is caused by variants affecting the gene represented in this entry. Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH) [MIM:620186] An autosomal dominant disorder characterized by choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, delayed or absent pubertal development, and thyroid abnormalities. Additional features may include developmental delay, growth failure and short stature. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. LXXLL motifs 5 and 6 are essential for the association with ESR1 nuclear receptor.

Miscellaneous. This gene mapped to a chromosomal region involved in duplications and translocations associated with cancer.

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

Isoforms (2)

UniProt ID	Names	Canonical?
O14686-1	1	yes
O14686-3	3

RefSeq proteins (1): NP_003473* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
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
IPR037890	SET_KMT2D	Domain
IPR041961	KMT2D_ePHD1	Domain
IPR041964	KMT2D_ePHD2	Domain
IPR046341	SET_dom_sf	Homologous_superfamily
IPR046999	KMT2D_PHD5	Domain
IPR047000	KMT2D_PHD3	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 (322 total): sequence variant 87, compositionally biased region 69, modified residue 38, sequence conflict 25, region of interest 25, repeat 15, strand 13, zinc finger region 12, helix 7, short sequence motif 7, binding site 6, coiled-coil region 5, domain 4, turn 4, cross-link 2, chain 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
3UVK	X-RAY DIFFRACTION	1.4
4ERQ	X-RAY DIFFRACTION	1.91
4Z4P	X-RAY DIFFRACTION	2.2
9YM8	ELECTRON MICROSCOPY	3.43
9YMF	ELECTRON MICROSCOPY	3.45
9YL3	ELECTRON MICROSCOPY	3.5
9YLE	ELECTRON MICROSCOPY	3.63
9YLY	ELECTRON MICROSCOPY	3.77
6O7G	SOLUTION NMR
8U2Y	SOLUTION NMR
9ATN	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for O14686 — 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): 5451; 5474–5475; 5477; 5525; 5527; 5532

Post-translational modifications (40): 27, 744, 1151, 1195, 1249, 1267, 1270, 1606, 1671, 1820, 1834, 1843, 1865, 2239, 2240, 2246, 2260, 2274, 2309, 2311 …

Mutagenesis-validated functional residues (1):

Position	Phenotype
5474	abolishes interaction with s-adenosyl-l-methionine.

Function

Pathways and Gene Ontology

Reactome pathways

23 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-9944997	Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
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: 823 (showing top): RRAGTTGT_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_LIPID, TGCACTT_MIR519C_MIR519B_MIR519A, CMYB_01, GOBP_GROWTH, GOBP_OOGENESIS, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, MODULE_453, CTATGCA_MIR153, GGAMTNNNNNTCCY_UNKNOWN, SREBP1_02, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_INTRACELLULAR_ESTROGEN_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (12): oocyte growth (GO:0001555), regulation of DNA-templated transcription (GO:0006355), positive regulation of cell population proliferation (GO:0008284), heterochromatin formation (GO:0031507), methylation (GO:0032259), positive regulation of intracellular estrogen receptor signaling pathway (GO:0033148), response to estrogen (GO:0043627), positive regulation of transcription by RNA polymerase II (GO:0045944), oogenesis (GO:0048477), beta-catenin-TCF complex assembly (GO:1904837), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338)

GO Molecular Function (12): transcription cis-regulatory region binding (GO:0000976), DNA binding (GO:0003677), transcription coactivator activity (GO:0003713), zinc ion binding (GO:0008270), histone H3K4 methyltransferase activity (GO:0042800), histone H3K4 monomethyltransferase activity (GO:0140945), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), acyltransferase activity (GO:0016746), metal ion binding (GO:0046872), histone H3K4 trimethyltransferase activity (GO:0140999)

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

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Epigenetic regulation by WDR5-containing histone modifying complexes	2
TCF dependent signaling in response to WNT	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
Loss of Function of KMT2D in Kabuki Syndrome	1
Signal Transduction	1
Signaling by WNT	1
RNA Polymerase II Transcription	1
Chromatin organization	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of DNA-templated transcription	2
histone H3K4 methyltransferase activity	2
developmental process involved in reproduction	1
developmental cell growth	1
oocyte development	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
metabolic process	1
estrogen receptor signaling pathway	1
positive regulation of intracellular steroid hormone receptor signaling pathway	1
regulation of intracellular estrogen receptor signaling pathway	1
response to hormone	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
germ cell development	1
female gamete generation	1
protein-containing complex assembly	1
cellular component organization	1
chromatin organization	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
nucleic acid binding	1
transcription coregulator activity	1
transition metal ion binding	1
protein-lysine N-methyltransferase activity	1
histone H3 methyltransferase activity	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
transferase activity	1
cation binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2772 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KMT2D	KDM6A	O15550	987
KMT2D	KMT2C	Q8NEZ4	972
KMT2D	KMT2A	Q03164	954
KMT2D	PAXIP1	Q6ZW49	885
KMT2D	KMT2B	Q9UMN6	850
KMT2D	CREBBP	Q92793	824
KMT2D	ASH2L	Q9UBL3	792
KMT2D	RBBP5	Q15291	782
KMT2D	TP53	P04637	782
KMT2D	WDR5	P61964	751
KMT2D	ARID1A	O14497	747
KMT2D	SETD1B	Q9UPS6	730
KMT2D	DPY30	Q9C005	723
KMT2D	NCOA6	Q14686	722
KMT2D	EP300	Q09472	678

IntAct

153 interactions, top by confidence:

A	B	Type	Score
KMT2D	WDR5	psi-mi:“MI:0914”(association)	0.910
WDR5	KMT2D	psi-mi:“MI:0915”(physical association)	0.910
KMT2D	WDR5	psi-mi:“MI:0915”(physical association)	0.910
WDR5	KMT2D	psi-mi:“MI:0914”(association)	0.910
ASH2L	KMT2D	psi-mi:“MI:0403”(colocalization)	0.890
ASH2L	KMT2D	psi-mi:“MI:0914”(association)	0.890
RBBP5	KMT2D	psi-mi:“MI:0914”(association)	0.840
KMT2D	RBBP5	psi-mi:“MI:0914”(association)	0.840
WDR5	MEN1	psi-mi:“MI:0914”(association)	0.710
NFIC	NFIB	psi-mi:“MI:2364”(proximity)	0.690
PAGR1	KMT2D	psi-mi:“MI:0914”(association)	0.640
PAXIP1	KMT2D	psi-mi:“MI:0914”(association)	0.640
AR	KMT2D	psi-mi:“MI:0914”(association)	0.600
AR	KMT2D	psi-mi:“MI:0915”(physical association)	0.600
PPIA	KMT2D	psi-mi:“MI:0407”(direct interaction)	0.560
Paxip1	KMT2D	psi-mi:“MI:0914”(association)	0.530

BioGRID (298): KMT2D (Affinity Capture-MS), KMT2D (Affinity Capture-MS), KMT2D (Reconstituted Complex), KMT2D (Co-fractionation), KMT2D (Affinity Capture-MS), KMT2D (Affinity Capture-MS), KMT2D (Affinity Capture-MS), KMT2D (Affinity Capture-MS), KMT2D (Affinity Capture-MS), KMT2D (Affinity Capture-MS), KMT2D (Affinity Capture-MS), KMT2D (Reconstituted Complex), KMT2D (Negative Genetic), KMT2D (Proximity Label-MS), KMT2D (Affinity Capture-MS)

ESM2 similar proteins: A0A0J9YWL9, A0A0J9YY54, A6QL64, D3YZV8, E9Q6E9, F1LWT0, O14686, O15069, P18583, P51843, P53353, P62521, Q0P6D6, Q2EG98, Q3BBV2, Q3V3Q4, Q4R729, Q5HY64, Q5ISE2, Q5JPF3, Q5JRC9, Q5QGU6, Q5XHX6, Q6ITT4, Q6PDK2, Q70KF4, Q86VE3, Q8CHD8, Q8N2N9, Q8N693, Q8N7U7, Q8NA70, Q8NDZ2, Q8TCU4, Q99KW3, Q9BE18, Q9BG93, Q9BG94, Q9BG96, Q9BG97

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

6 interactions.

A	Effect	B	Mechanism
KMT2D	up-regulates	ESR1	binding
KMT2D	“form complex”	HMT	binding
PAX7	up-regulates	KMT2D	binding
KMT2D	“form complex”	“MLL2 complex”	binding
Ub:E2	“up-regulates activity”	KMT2D	ubiquitination
SGK1	“down-regulates activity”	KMT2D	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 139 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	9	25.7×	2e-08
Deactivation of the beta-catenin transactivating complex	9	22.6×	3e-08
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	9	19.1×	1e-07
Gastrulation	6	16.7×	6e-05
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	9	14.2×	1e-06
Transcriptional regulation by RUNX2	5	13.6×	6e-04
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	5	11.6×	1e-03
Adipogenesis	6	10.1×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
neuron fate specification	5	28.1×	7e-05
positive regulation of miRNA transcription	11	25.6×	1e-10
transcription initiation-coupled chromatin remodeling	5	15.3×	8e-04
somatic stem cell population maintenance	7	13.9×	7e-05
anatomical structure morphogenesis	12	13.4×	2e-08
positive regulation of transcription initiation by RNA polymerase II	6	13.1×	4e-04
cartilage development	6	12.1×	5e-04
inner ear morphogenesis	5	12.0×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 46 cancer types — ACYC, ALL, ANSC, BCC, BL, BLADDER, BLCA, BRCA, CCRCC, CEAD, CESC, CHOL…(+34 more).

Clinical variants and AI predictions

ClinVar

7439 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	708
Likely pathogenic	264
Uncertain significance	2405
Likely benign	2061
Benign	859

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012175	NM_003482.4(KMT2D):c.14826dup (p.Glu4943Ter)	Pathogenic
1012322	NM_003482.4(KMT2D):c.4464del (p.Cys1489fs)	Pathogenic
1012608	NM_003482.4(KMT2D):c.4843C>T (p.Arg1615Ter)	Pathogenic
1020791	NM_003482.4(KMT2D):c.15878T>C (p.Leu5293Pro)	Pathogenic
1027388	NM_003482.4(KMT2D):c.5642_5644+1del	Pathogenic
1027396	NM_003482.4(KMT2D):c.11320C>T (p.Gln3774Ter)	Pathogenic
1027399	NM_003482.4(KMT2D):c.5468-1G>A	Pathogenic
1028116	NM_003482.4(KMT2D):c.6110-2A>G	Pathogenic
1030668	NM_003482.4(KMT2D):c.10688dup (p.Leu3564fs)	Pathogenic
1033587	NM_003482.4(KMT2D):c.204_205del (p.Leu68_Cys69insTer)	Pathogenic
1033591	NM_003482.4(KMT2D):c.7378del (p.Arg2460fs)	Pathogenic
1033593	NM_003482.4(KMT2D):c.7938del (p.Asp2647fs)	Pathogenic
1065457	NM_003482.4(KMT2D):c.9773del (p.Lys3258fs)	Pathogenic
1065471	NM_003482.4(KMT2D):c.1491_1492del (p.Pro497_Pro498insTer)	Pathogenic
1068702	NM_003482.4(KMT2D):c.11578C>T (p.Gln3860Ter)	Pathogenic
1069246	NM_003482.4(KMT2D):c.6177del (p.Tyr2060fs)	Pathogenic
1069469	NM_003482.4(KMT2D):c.2173_2174del (p.Leu725fs)	Pathogenic
1070943	NM_003482.4(KMT2D):c.3318del (p.Ser1107fs)	Pathogenic
1071461	NM_003482.4(KMT2D):c.6073_6086del (p.Ala2024_Asn2025insTer)	Pathogenic
1072673	NM_003482.4(KMT2D):c.10638del (p.Gln3546fs)	Pathogenic
1073263	NM_003482.4(KMT2D):c.16170dup (p.Leu5391fs)	Pathogenic
1073455	NM_003482.4(KMT2D):c.12737del (p.Pro4246fs)	Pathogenic
1074470	NM_003482.4(KMT2D):c.15785-1G>C	Pathogenic
1074736	NM_003482.4(KMT2D):c.206del (p.Cys69fs)	Pathogenic
1076029	NM_003482.4(KMT2D):c.10685_10688dup (p.Leu3564fs)	Pathogenic
1076682	NM_003482.4(KMT2D):c.3361del (p.Asp1121fs)	Pathogenic
1076824	NM_003482.4(KMT2D):c.13285del (p.Gln4429fs)	Pathogenic
1164061	NM_003482.4(KMT2D):c.7650del (p.Val2551fs)	Pathogenic
1172600	NM_003482.4(KMT2D):c.16469_16470del (p.Lys5490fs)	Pathogenic
1175186	NM_003482.4(KMT2D):c.14113_14123del (p.Ile4705fs)	Pathogenic

SpliceAI

6822 predictions. Top by Δscore:

Variant	Effect	Δscore
12:49021869:TTAG:T	acceptor_gain	1.0000
12:49021870:TAG:T	acceptor_gain	1.0000
12:49021872:GCTGA:G	acceptor_loss	1.0000
12:49021873:C:CC	acceptor_gain	1.0000
12:49021873:CT:C	acceptor_loss	1.0000
12:49021874:T:A	acceptor_loss	1.0000
12:49022034:T:TA	donor_gain	1.0000
12:49022035:C:A	donor_gain	1.0000
12:49022037:TCTCA:T	donor_loss	1.0000
12:49022038:CTCA:C	donor_loss	1.0000
12:49022039:TCACC:T	donor_loss	1.0000
12:49022040:CACCT:C	donor_loss	1.0000
12:49022041:A:AG	donor_loss	1.0000
12:49022041:ACCT:A	donor_gain	1.0000
12:49022042:CCTC:C	donor_gain	1.0000
12:49022044:T:TA	donor_gain	1.0000
12:49022049:T:A	donor_gain	1.0000
12:49022118:C:CT	acceptor_gain	1.0000
12:49022151:CCT:C	acceptor_loss	1.0000
12:49022152:C:T	acceptor_loss	1.0000
12:49022158:A:T	acceptor_gain	1.0000
12:49022274:TCTCA:T	donor_loss	1.0000
12:49022275:CTCAC:C	donor_loss	1.0000
12:49022276:TCACC:T	donor_loss	1.0000
12:49022277:CACCT:C	donor_loss	1.0000
12:49022278:ACCTG:A	donor_loss	1.0000
12:49022279:C:CT	donor_loss	1.0000
12:49022369:T:C	acceptor_gain	1.0000
12:49022369:T:TC	acceptor_gain	1.0000
12:49022587:TA:T	donor_loss	1.0000

AlphaMissense

35544 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:49021783:G:C	N5537K	1.000
12:49021783:G:T	N5537K	1.000
12:49021787:A:G	M5536T	1.000
12:49021789:C:A	W5535C	1.000
12:49021789:C:G	W5535C	1.000
12:49021790:C:G	W5535S	1.000
12:49021791:A:G	W5535R	1.000
12:49021791:A:T	W5535R	1.000
12:49021792:T:A	K5534N	1.000
12:49021792:T:G	K5534N	1.000
12:49021793:T:A	K5534I	1.000
12:49021794:T:C	K5534E	1.000
12:49021796:C:G	R5533P	1.000
12:49021798:A:C	C5532W	1.000
12:49021799:C:A	C5532F	1.000
12:49021799:C:G	C5532S	1.000
12:49021799:C:T	C5532Y	1.000
12:49021800:A:G	C5532R	1.000
12:49021800:A:T	C5532S	1.000
12:49021813:A:C	C5527W	1.000
12:49021814:C:A	C5527F	1.000
12:49021814:C:G	C5527S	1.000
12:49021814:C:T	C5527Y	1.000
12:49021815:A:G	C5527R	1.000
12:49021815:A:T	C5527S	1.000
12:49021819:G:C	C5525W	1.000
12:49021820:C:A	C5525F	1.000
12:49021820:C:G	C5525S	1.000
12:49021820:C:T	C5525Y	1.000
12:49021821:A:G	C5525R	1.000

dbSNP variants (sampled 300 via entrez): RS1000004931 (12:49025514 G>T), RS1000064979 (12:49028572 T>C), RS1000171826 (12:49023710 C>T), RS1000269537 (12:49054841 A>T), RS1000286737 (12:49060740 C>T), RS1000455345 (12:49024048 C>T), RS1000582361 (12:49042982 G>A,C), RS1000588051 (12:49045538 G>A,C), RS1000730378 (12:49037062 T>A,C,G), RS1000848174 (12:49020022 T>A), RS1000871885 (12:49056315 G>A,C,T), RS1000908630 (12:49019620 T>C,G), RS1000915682 (12:49062264 C>T), RS1000953165 (12:49043299 G>A,C,T), RS1001179374 (12:49025499 G>A,T)

Disease associations

OMIM: gene MIM:602113 | disease phenotypes: MIM:147920, MIM:620186, MIM:607086, MIM:211980, MIM:619681, MIM:604169, MIM:619472, MIM:254500, MIM:610805, MIM:209850, MIM:613783, MIM:615834, MIM:608911, MIM:220200, MIM:180850

GenCC curated gene-disease

Disease	Classification	Inheritance
Kabuki syndrome 1	Definitive	Autosomal dominant
choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome	Definitive	Autosomal dominant
branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome	Strong	Autosomal dominant
Kabuki syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Kabuki syndrome 1	Definitive	AD

Mondo (30): Kabuki syndrome (MONDO:0016512), Kabuki syndrome 1 (MONDO:0007843), choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome (MONDO:0035651), congenital nervous system disorder (MONDO:0002320), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), lung cancer (MONDO:0008903), dystonia, early-onset, and/or spastic paraplegia (MONDO:0859215), vein of Galen aneurysm (MONDO:0015196), intellectual disability (MONDO:0001071), left ventricular noncompaction (MONDO:0018901), eccrine porocarcinoma (MONDO:0006189), neurodevelopmental disorder (MONDO:0700092), VISS syndrome (MONDO:0859177), autism spectrum disorder (MONDO:0005258), plasma cell myeloma (MONDO:0009693)

Orphanet (17): Kabuki syndrome (Orphanet:2322), Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome (Orphanet:589856), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Vein of Galen malformation (Orphanet:1053), Left ventricular noncompaction (Orphanet:54260), Male infertility with spermatogenesis disorder (Orphanet:399775), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443), CHARGE syndrome (Orphanet:138), Renal or urinary tract malformation (Orphanet:93545), Autism spectrum disorder due to AUTS2 deficiency (Orphanet:352490), Lymphoma (Orphanet:223735), Choanal atresia (Orphanet:137914), Isolated Dandy-Walker malformation (Orphanet:217), Rare genetic intellectual disability (Orphanet:183757)

HPO phenotypes

269 total (30 of 269 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000034	Hydrocele testis
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000073	Ureteral duplication
HP:0000074	Ureteropelvic junction obstruction
HP:0000075	Renal duplication
HP:0000076	Vesicoureteral reflux
HP:0000079	Abnormality of the urinary system
HP:0000081	Duplicated collecting system
HP:0000083	Renal insufficiency
HP:0000085	Horseshoe kidney
HP:0000086	Ectopic kidney
HP:0000089	Renal hypoplasia
HP:0000110	Renal dysplasia
HP:0000122	Unilateral renal agenesis
HP:0000125	Pelvic kidney
HP:0000126	Hydronephrosis
HP:0000161	Median cleft upper lip
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000179	Thick lower lip vermilion
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000215	Thick upper lip vermilion
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005316_370	Intelligence (MTAG)	5.000000e-14
GCST006269_1090	General cognitive ability	4.000000e-11
GCST006979_1056	Heel bone mineral density	3.000000e-10
GCST007576_336	Chronotype	5.000000e-09
GCST011743_1	HDL cholesterol levels in HIV infection	9.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0009270	heel bone mineral density
EFO:0008328	chronotype measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (19)

Descriptor	Name	Tree numbers
D000550	Amblyopia	C10.228.140.055; C10.597.751.941.073; C11.966.073; C23.888.592.763.941.073
D001254	Astrocytoma	C04.557.465.625.600.380.080; C04.557.470.670.380.080; C04.557.580.625.600.380.080
D001321	Autistic Disorder	F03.625.164.113.500
D058747	CHARGE Syndrome	C09.218.458.341.186.500.250; C10.597.751.418.341.186.500.250; C10.597.751.941.162.625.250; C11.270.147.500; C11.966.075.375.250; C16.131.077.299.250; C16.320.165; C23.888.592.763.393.341.186.500.500; C23.888.592.763.941.162.625.500
D002754	Choanal Atresia	C08.460.171; C08.695.271; C09.603.171; C16.131.740.271
D003616	Dandy-Walker Syndrome	C10.228.140.252.300; C10.228.140.602.500; C10.500.205; C16.131.666.205
D057090	Eccrine Porocarcinoma	C04.557.470.200.025.500
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008223	Lymphoma	C04.557.386; C15.604.515.569; C20.683.515.761
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
D013285	Strabismus	C10.292.562.887; C11.590.810
C566906	Cakut (supp.)
C565170	Complement Component C1s Deficiency (supp.)
C537705	Kabuki syndrome (supp.)
C535877	Rubinstein Taybi like syndrome (supp.)
C536535	Vein of Galen aneurysm (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2189114 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 3 predictive associations from 3 curated evidence items; also 1 diagnostic.

Variant	Therapy	Indication	Effect	Level	CIViC
KMT2D Loss-of-function	Immune Checkpoint Inhibitor	Colorectal Adenocarcinoma	Sensitivity/Response	CIViC B	EID12583
KMT2D Loss-of-function	WRN Inhibitor HRO761 + WRN Inhibitor RO7589831	Colorectal Adenocarcinoma	Sensitivity/Response	CIViC D	EID12584
KMT2D Loss-of-function	2-Deoxy-D-glucose	Lung Adenocarcinoma	Sensitivity/Response	CIViC D	EID12778

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

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases methylation, affects binding, increases reaction, increases expression, decreases reaction (+1 more)	4
methylmercuric chloride	increases expression, affects cotreatment	2
bisphenol A	increases acetylation, increases expression, affects binding, increases reaction, increases methylation (+1 more)	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Benzo(a)pyrene	increases methylation, increases mutagenesis	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
arsenite	affects binding, decreases reaction	1
methylparaben	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
coumarin	decreases phosphorylation	1
butylparaben	increases expression	1
avobenzone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
Acetaminophen	decreases expression	1
Caffeine	affects phosphorylation	1
Coumestrol	decreases expression	1
Diethylstilbestrol	affects binding, increases reaction, decreases reaction, increases acetylation, increases expression (+1 more)	1
Ozone	affects expression, increases abundance	1
Quercetin	decreases phosphorylation	1
Ribonucleotides	affects binding	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2209113	Binding	Inhibition of MLL2 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

69 cell lines: 58 cancer cell line, 9 induced pluripotent stem cell, 1 spontaneously immortalized cell line, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0181	BV-173	Cancer cell line	Male
CVCL_0505	RL95-2	Cancer cell line	Female
CVCL_1045	22Rv1	Cancer cell line	Male
CVCL_1060	A-253	Cancer cell line	Male
CVCL_1100	Ca Ski	Cancer cell line	Female
CVCL_1473	NCI-H146	Cancer cell line	Male
CVCL_1698	SK-MG-1	Cancer cell line	Female
CVCL_2086	JURL-MK1	Cancer cell line	Male
CVCL_2206	SU-DHL-6	Cancer cell line	Male
CVCL_2207	SU-DHL-8	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00158041	PHASE4	COMPLETED	Subcutaneous Amifostine Safety Study
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00365508	PHASE4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00440960	PHASE4	COMPLETED	Anesthesia in Flexible Bronchoscopy for Lung Cancer Diagnostic
NCT00492843	PHASE4	TERMINATED	Loading Dose or Standard Dose of Intravenous Ibandronate in Treating Patients With Lung Cancer and Skeletal Metastasis
NCT00666978	PHASE4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT00675168	PHASE4	UNKNOWN	Positron Emission Tomography (PET)/Computed Tomography (CT) and Roentgen in Lung Cancer: Evaluation of Patients in General Practice
NCT00712647	PHASE4	COMPLETED	Carotene and Retinol Efficacy Trial
NCT00747773	PHASE4	COMPLETED	Cryospray Ablation of Surgical Resection Specimens To Determine Safety And Histological Effect In The Lung
NCT01060137	PHASE4	COMPLETED	Fentanyl Matrix in Lung Cancer Pain
NCT01381627	PHASE4	UNKNOWN	Safety Evaluation of Dexmedetomidine for EBUS-TBNA
NCT01741506	PHASE4	COMPLETED	Coagulation Profile in Patients Undergoing Video Assisted Thorascopic Surgery (VATS) for Lung Cancer
NCT02246023	PHASE4	COMPLETED	Fractionated Versus Target-controlled Propofol Administration in Bronchoscopy
NCT02275702	PHASE4	COMPLETED	Randomized Study of Preoperative Dexamethasone for Quality of Recovery in VATS Lung Resection Patients
NCT02346318	PHASE4	UNKNOWN	The Randomized Controlled Clinical Trial of Kushen Injection
NCT02476526	PHASE4	COMPLETED	Safety of Low Dose IV Contrast CT Scanning in Chronic Kidney Disease
NCT02490059	PHASE4	COMPLETED	Ultrathin Bronchoscopy for Solitary Pulmonary Nodules
NCT02504801	PHASE4	UNKNOWN	Efficacy of Nebulized Pulmicort Respules in Primary Lung Cancer Patients With COPD
NCT02869789	PHASE4	COMPLETED	An Investigational Immuno-therapy Study for Safety of Nivolumab in Combination With Ipilimumab to Treat Advanced Cancers
NCT03302221	PHASE4	WITHDRAWN	Regional Haemodynamic Changes in Radial Artery Assessment With Continuous Pulsed-wave Doppler Ultrasound
NCT03313544	PHASE4	UNKNOWN	Evolution of the Heart Function When Monitoring Immunotherapies Anti-cancerous Inhibiting PD-1
NCT03394222	PHASE4	COMPLETED	Effect of Preoperative Budesonide Inhalation on Arterial Blood Oxygenation and Intrapulmonary Shunt During OLV
NCT03570645	PHASE4	COMPLETED	Comparison of the Duration of Ropivacaine Combined With Dexmedetomidine or Dexamethasone on Paravertebral Block
NCT03571126	PHASE4	UNKNOWN	Olanzapine for the Prevention and Treatment of Nausea and Vomiting Induced by Chemotherapy of Lung Cancer
NCT03642457	PHASE4	TERMINATED	Efficacy Between Serratus Plane Block And Local Infiltration In Vats
NCT04145570	PHASE4	COMPLETED	A Single-Dose,ComparativeBioavailability Study ofTwo Formulations ofErlotinib150mgTabletsunderFastingConditions
NCT04155008	PHASE4	TERMINATED	Nutrition and Pharmacological Algorithm for Oncology Patients Study
NCT04613284	PHASE4	UNKNOWN	Rh-Endostatin Combined With CCRT(50 Gy) Followed by Durvalumab Maintenance for the Treatment of Specific Phase III NSCLC
NCT05463913	PHASE4	RECRUITING	Lung Nodule Detection Using Ultra-long FOV PET/CT
NCT05521789	PHASE4	RECRUITING	Erector Spinae Block for Thoracic Surgery
NCT05525338	PHASE4	RECRUITING	Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels
NCT05663242	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Lung Tumors and Its Mechanism of Action
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06105801	PHASE4	RECRUITING	EBUS-TBNA vs Transbronchial Mediastinal Cryobiopsy for Adequacy of Next Generation Sequencing
NCT06276933	PHASE4	NOT_YET_RECRUITING	A Study of Camrelizumab Combined With Chemotherapy ± Thalidomide in First-line Treatment of Patients With Advanced Non-small Cell Lung Cancer (NSCLC)
NCT06646471	PHASE4	RECRUITING	PROspective Master-protocol for Evaluation of Systemic THErapeutics in Elderly With Thoracic Malignancies
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT00002550	PHASE3	COMPLETED	Chemotherapy Plus Radiation Therapy With or Without Surgery in Treating Patients With Stage IIIA Non-small Cell Lung Cancer
NCT00002583	PHASE3	COMPLETED	Vinorelbine + Cisplatin or No Further Therapy in Non-small Cell Lung Cancer That Has Been Surgically Removed
NCT00002623	PHASE3	COMPLETED	Chemotherapy Followed by Surgery or Radiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer