KMT2E

Summary

KMT2E (lysine methyltransferase 2E (inactive), HGNC:18541) is a protein-coding gene on chromosome 7q22.3, encoding Inactive histone-lysine N-methyltransferase 2E (Q8IZD2). Associates with chromatin regions downstream of transcriptional start sites of active genes and thus regulates gene transcription. It is haploinsufficient (ClinGen: sufficient evidence).

This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a protein with an N-terminal PHD zinc finger and a central SET domain. Overexpression of the protein inhibits cell cycle progression. Alternate transcriptional splice variants have been characterized.

Source: NCBI Gene 55904 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 1,398 total — 72 pathogenic, 58 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_182931

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18541
Approved symbol	KMT2E
Name	lysine methyltransferase 2E (inactive)
Location	7q22.3
Locus type	gene with protein product
Status	Approved
Aliases	HDCMC04P, SETD5B
Ensembl gene	ENSG00000005483
Ensembl biotype	protein_coding
OMIM	608444
Entrez	55904

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 8 protein_coding, 6 nonsense_mediated_decay, 6 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000257745, ENST00000311117, ENST00000334884, ENST00000415513, ENST00000468607, ENST00000473063, ENST00000474203, ENST00000476671, ENST00000478079, ENST00000478990, ENST00000479838, ENST00000480368, ENST00000482560, ENST00000485619, ENST00000495267, ENST00000496191, ENST00000622386, ENST00000653259, ENST00000659776, ENST00000667857, ENST00000671314, ENST00000700336, ENST00000700500

RefSeq mRNA: 3 — MANE Select: NM_182931 NM_001410908, NM_018682, NM_182931

CCDS: CCDS34723, CCDS94170

Canonical transcript exons

ENST00000311117 — 27 exons

Exon	Start	End
ENSE00001210553	105038126	105038199
ENSE00001831411	105101425	105101589
ENSE00001856562	105108942	105109228
ENSE00001899722	105014205	105014535
ENSE00001929294	105110771	105110868
ENSE00001942442	105111825	105115019
ENSE00003472986	105066727	105066807
ENSE00003477593	105110280	105110368
ENSE00003492398	105076043	105076081
ENSE00003508135	105040839	105041023
ENSE00003529384	105063351	105063580
ENSE00003540034	105081688	105081797
ENSE00003543408	105077303	105077433
ENSE00003606249	105105439	105105693
ENSE00003612451	105101886	105102194
ENSE00003630234	105074643	105074815
ENSE00003654771	105076963	105077193
ENSE00003666824	105110477	105110602
ENSE00003677553	105078846	105078963
ENSE00003678005	105073619	105073677
ENSE00003722122	105062164	105062278
ENSE00003979564	105107166	105107222
ENSE00003979567	105106522	105106772
ENSE00003979568	105105859	105106003
ENSE00003979571	105107362	105107925
ENSE00003979976	105091216	105091314
ENSE00003979979	105090009	105090273

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 98.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.3796 / max 976.9348, expressed in 1823 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80317	34.6500	1818
80318	2.4557	788
80320	1.4855	401
80332	1.2491	747
80330	0.8484	377
80319	0.4429	135
80331	0.2481	94

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	98.84	gold quality
tendon	UBERON:0000043	98.62	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.58	gold quality
calcaneal tendon	UBERON:0003701	98.55	gold quality
sperm	CL:0000019	98.31	gold quality
medial globus pallidus	UBERON:0002477	98.28	gold quality
pylorus	UBERON:0001166	98.18	gold quality
buccal mucosa cell	CL:0002336	98.17	gold quality
visceral pleura	UBERON:0002401	98.07	gold quality
corpus callosum	UBERON:0002336	98.01	gold quality
globus pallidus	UBERON:0001875	97.86	gold quality
colonic epithelium	UBERON:0000397	97.83	gold quality
urethra	UBERON:0000057	97.79	gold quality
bone marrow cell	CL:0002092	97.69	gold quality
parietal pleura	UBERON:0002400	97.68	gold quality
epithelial cell of pancreas	CL:0000083	97.61	gold quality
oviduct epithelium	UBERON:0004804	97.59	gold quality
trabecular bone tissue	UBERON:0002483	97.47	gold quality
layer of synovial tissue	UBERON:0007616	97.33	gold quality
vena cava	UBERON:0004087	97.22	gold quality
kidney epithelium	UBERON:0004819	97.14	gold quality
cardia of stomach	UBERON:0001162	97.13	gold quality
superficial temporal artery	UBERON:0001614	97.12	gold quality
renal medulla	UBERON:0000362	97.03	gold quality
pancreatic ductal cell	CL:0002079	97.01	gold quality
upper arm skin	UBERON:0004263	96.94	gold quality
cortical plate	UBERON:0005343	96.78	gold quality
pericardium	UBERON:0002407	96.64	gold quality
lower lobe of lung	UBERON:0008949	96.62	gold quality
amniotic fluid	UBERON:0000173	96.61	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	5.51
E-CURD-112	yes	4.94
E-MTAB-7249	no	459.82
E-CURD-122	no	9.99
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
CCNA2	Activation
CDC6	Activation
CDK1	Activation
E2F1	Activation

Upstream regulators (CollecTRI, top): CUX1, EHMT2, GATA3, MTA3

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 26)

• MLL5 is a homolog of Drosophila trithorax located within a segment of chromosome band 7q22 implicated in myeloid leukemia. (PMID:12101424)
• MLL5 forms intranuclear protein complexes that may play an important role in chromatin remodeling and cellular growth suppression. (PMID:14718661)
• MLL5 protein has been classified into a distinct subfamily with SETD5, because its SET domain and domain architecture show high homology with SETD5 rather than the members in MLL subfamily (i.e. MLL, MLL2, MLL3 and MLL4) (PMID:18231586)
• These findings provide evidence that MLL5 might be an important cell cycle regulator, participating in cell cycle regulatory network machinery at multiple cell cycle stages. (PMID:18573682)
• Phosphorylation of MLL5 may have an indispensable role in the mitotic progression in mixed lineage leukemia cells. (PMID:20439461)
• High MLL5 expression levels are associated with a favorable outcome and may improve risk and treatment stratification in acute myeloid leukemia (PMID:21205756)
• A new isoform, MLL5beta, truncated in exon 14, regulates E6 & E7 transcription in cervical carcinoma cells. Interaction of MLL5beta with the AP-1-binding site at the distal region of the HPV18 long control region activated E6/E7 transcription. (PMID:21908553)
• MLL5 functionally interacts with Borealin, facilitates the expression of chromosomal passenger complex, and hence contributes to mitotic fidelity and genomic integrity. (PMID:22797924)
• MLL5 can associate with HCF-1 and then be recruited to E2F1-responsive promoters to stimulate H3K4 trimethylation and transcriptional activation. (PMID:23629655)
• these results indicate that the suppression of MLL genes, especially MLL2 and MLL5, take part in modulating breast carcinogenesis. (PMID:23754336)
• findings provide first insights into the molecular basis for the recruitment, exclusion, and regulation of MLL5 at chromatin (PMID:23798402)
• MLL5 is a cellular ligand for the natural cytotoxicity receptor NKp44. (PMID:23958951)
• NMR solution structure of the MLL5 PHD domain (PMID:24130829)
• KMT2E expression retained association with poor acute promyelocytic leukaemia remission rate and shorter survival while the association with disease-free survival was of marginal significance. (PMID:24796963)
• Improved outcome is observed in decitabine-treated patients who express MLL5 at high levels. (PMID:24895338)
• O-GlcNAcylation of MLL5beta at T440 residue is critical for MLL5 recruitment to the HPV16/18-long control region through its interaction with AP-1. (PMID:25670814)
• Suggest a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult glioblastomas. (PMID:26626085)
• MLL5 interacts with OGT and USP7 to form a stable ternary complex. Upregulation of MLL5 expression was correlated with increased expression of OGT and USP7 in human primary cervical adenocarcinomas. (PMID:26678539)
• MLL5 preserves spindle bipolarity through maintaining cytosolic PLK1 in a nonaggregated form. (PMID:27002166)
• three dimensional structure of MLL5 SET domain unveils the structural basis for its lack of methyltransferase activity (PMID:27812132)
• In the duloxetine-treated subsample (N=186), we observed suggestive associations with ZNF385D (rs4261893; beta=-0.46, P=1.55 x 10(-5)), NCAM1 (rs2303377; beta=0.45, P=1.76 x 10(-5)) and MLL5 (rs117986340; beta=0.91, P=3.04 x 10(-5)). (PMID:28696415)
• Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy. (PMID:31079897)
• ODLURO syndrome: personal experience and review of the literature. (PMID:32691224)
• MLL5, a histone modifying enzyme, regulates androgen receptor activity in prostate cancer cells by recruiting co-regulators, HCF1 and SET1. (PMID:33050986)
• Clinical Characteristics and Genotype-Phenotype Correlation in Children with KMT2E Gene-Related Neurodevelopmental Disorders: Report of Two New Cases and Review of Published Literature. (PMID:33111303)
• MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model. (PMID:33824267)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	kmt2e	ENSDARG00000007523
mus_musculus	Kmt2e	ENSMUSG00000029004
rattus_norvegicus	Kmt2e	ENSRNOG00000021614
drosophila_melanogaster	upSET	FBGN0036398
caenorhabditis_elegans		WBGENE00012845
caenorhabditis_elegans		WBGENE00013106
caenorhabditis_elegans		WBGENE00017482

Paralogs (1): SETD5 (ENSG00000168137)

Protein

Protein identifiers

Inactive histone-lysine N-methyltransferase 2E — Q8IZD2 (reviewed: Q8IZD2)

Alternative names: Myeloid/lymphoid or mixed-lineage leukemia protein 5

All UniProt accessions (12): Q8IZD2, A0A087WYW5, A0A590UK87, A0A8J9FJW2, A0A8V8TR58, C9JNE1, C9JQ68, C9JYI9, F8WAU9, H7C4F3, H7C5C4, S4R363

UniProt curated annotations — full annotation on UniProt →

Function. Associates with chromatin regions downstream of transcriptional start sites of active genes and thus regulates gene transcription. Chromatin interaction is mediated via the binding to tri-methylated histone H3 at ‘Lys-4’ (H3K4me3). Key regulator of hematopoiesis involved in terminal myeloid differentiation and in the regulation of hematopoietic stem cell (HSCs) self-renewal by a mechanism that involves DNA methylation. Also acts as an important cell cycle regulator, participating in cell cycle regulatory network machinery at multiple cell cycle stages including G1/S transition, S phase progression and mitotic entry. Recruited to E2F1 responsive promoters by HCFC1 where it stimulates tri-methylation of histone H3 at ‘Lys-4’ and transcriptional activation and thereby facilitates G1 to S phase transition. During myoblast differentiation, required to suppress inappropriate expression of S-phase-promoting genes and maintain expression of determination genes in quiescent cells. Cellular ligand for NCR2/NKp44, may play a role as a danger signal in cytotoxicity and NK-cell-mediated innate immunity.

Subunit / interactions. Component of a complex composed of KMT2E (isoform 3), OGT and USP7; the complex stabilizes KMT2E, preventing KMT2E ubiquitination and proteasomal-mediated degradation. Isoform 3 interacts (via N-terminus) with OGT (via TRP repeats). Isoform 3 interacts with deubiquitinating enzyme USP7 (via MATH domain). Isoform 3 interacts (via HBM motif) with HCFC1 (via Kelch domain). Isoform 3 interacts with E2F1; the interaction is probably indirect and is mediated via HCFC1.

Subcellular location. Chromosome. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Nucleus speckle Nucleus. Nucleoplasm. Nucleus speckle Cytoplasm. Cell membrane.

Tissue specificity. Widely expressed in both adult and fetal tissues. Highest levels of expression observed in fetal thymus and kidney and in adult hematopoietic tissues, jejunum and cerebellum. Isoform NKp44L: Not detected on circulating cells from healthy individuals, but is expressed on a large panel of tumor and transformed cells.

Post-translational modifications. Ubiquitinated. Deubiquitinated by USP7. O-glycosylated at Ser-435 and Thr-440 in the SET domain by OGT which probably prevents KMT2E proteasomal-mediated degradation.

Disease relevance. O’Donnell-Luria-Rodan syndrome (ODLURO) [MIM:618512] A neurodevelopmental disorder characterized by global developmental delay, speech delay, intellectual disability and a subtle facial gestalt. Additional common features include autism, seizures, hypotonia and functional gastrointestinal abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The PHD-type domain binds specifically histone H3 tri-methylated at ‘Lys-4’ (H3K4me3), thus promoting binding to chromatin. The SET domain does not bind the methyl group donor S-adenosyl-L-methionine and histone 3 H3K4 peptide as a large loop prevents the docking of the ‘Lys-4’ side chain. The C-terminus domain is responsible for the localization to the centrosome during mitosis.

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

Isoforms (8)

UniProt ID	Names	Canonical?
Q8IZD2-1	1	yes
Q8IZD2-2	2
Q8IZD2-3	3
Q8IZD2-4	4
Q8IZD2-5	5
Q8IZD2-6	6
Q8IZD2-7	7
Q8IZD2-8	NKp44L

RefSeq proteins (3): NP_001397837, NP_061152, NP_891847* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001214	SET_dom	Domain
IPR001965	Znf_PHD	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR019786	Zinc_finger_PHD-type_CS	Conserved_site
IPR019787	Znf_PHD-finger	Domain
IPR044434	KMT2E_SET	Domain
IPR046341	SET_dom_sf	Homologous_superfamily

Pfam: PF00856, PF20826

UniProt features (108 total): compositionally biased region 24, sequence variant 13, splice variant 12, strand 10, binding site 8, sequence conflict 8, region of interest 7, modified residue 6, mutagenesis site 6, helix 4, turn 3, glycosylation site 2, chain 1, domain 1, coiled-coil region 1, short sequence motif 1, zinc finger region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4L58	X-RAY DIFFRACTION	1.48
5HT6	X-RAY DIFFRACTION	2.09
2LV9	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZD2-F1	44.57	0.08

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 (8): 121; 123; 135; 138; 143; 146; 160; 163

Post-translational modifications (6): 623, 837, 845, 1070, 1273, 1359

Glycosylation sites (2): 435, 440

Mutagenesis-validated functional residues (6):

Position	Phenotype
63–66	abolishes interaction with hcfc1.
125	no effect on binding to tri-methylated ’lys-4’ of histone h3 (h3k4me3).
128	severe reduction in the binding to tri-methylated ’lys-4’ of histone h3 (h3k4me3).
131	severe reduction in the binding to tri-methylated ’lys-4’ of histone h3 (h3k4me3).
141	loss of binding to tri-methylated ’lys-4’ of histone h3 (h3k4me3).
411	fails to activate the cell cycle regulated element (ccre) in the cyclin a promoter.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 368 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, FREAC2_01, GOBP_MYELOID_CELL_HOMEOSTASIS, TGCGCANK_UNKNOWN, GCANCTGNY_MYOD_Q6, GOBP_ERYTHROCYTE_HOMEOSTASIS, GCM_ZNF198, GOBP_CELL_CYCLE_PHASE_TRANSITION, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, TGACCTY_ERR1_Q2, TAL1ALPHAE47_01, FOXO4_01, FOXO1_01

GO Biological Process (10): neutrophil mediated immunity (GO:0002446), regulation of DNA-templated transcription (GO:0006355), erythrocyte differentiation (GO:0030218), epigenetic regulation of gene expression (GO:0040029), neutrophil activation (GO:0042119), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of G1/S transition of mitotic cell cycle (GO:1900087), chromatin organization (GO:0006325), regulation of gene expression (GO:0010468), regulation of cell cycle (GO:0051726)

GO Molecular Function (6): transcription coactivator activity (GO:0003713), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), histone H3K4me3 reader activity (GO:0140002), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (15): chromatin (GO:0000785), euchromatin (GO:0000791), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), plasma membrane (GO:0005886), nuclear body (GO:0016604), nuclear speck (GO:0016607), protein-containing complex (GO:0032991), Set3 complex (GO:0034967), Rpd3L-Expanded complex (GO:0070210), chromosome (GO:0005694), cytoskeleton (GO:0005856), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
chromatin	3
intracellular membraneless organelle	3
DNA-templated transcription	2
regulation of gene expression	2
histone deacetylase complex	2
nuclear chromosome	2
myeloid leukocyte mediated immunity	1
regulation of RNA biosynthetic process	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
chromatin remodeling	1
granulocyte activation	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
G1/S transition of mitotic cell cycle	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of cell cycle G1/S phase transition	1
regulation of G1/S transition of mitotic cell cycle	1
cellular component organization	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cell cycle	1
regulation of cellular process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
transition metal ion binding	1
protein binding	1
histone H3 reader activity	1
binding	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
membrane	1
cell periphery	1
nucleoplasm	1

Protein interactions and networks

STRING

2248 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KMT2E	NCR2	O95944	979
KMT2E	NCR3	O14931	871
KMT2E	RARA	P10276	710
KMT2E	USP7	Q93009	710
KMT2E	SETD1A	O15047	693
KMT2E	SETD1B	Q9UPS6	693
KMT2E	NCR3LG1	Q68D85	682
KMT2E	NCR1	O76036	662
KMT2E	NCOR2	Q9Y618	625
KMT2E	NCOR1	O75376	590
KMT2E	SRPK2	P78362	555
KMT2E	CRABP1	P29762	548
KMT2E	SMYD3	Q9H7B4	543
KMT2E	SLAMF6	Q96DU3	542
KMT2E	BMI1	P35226	513

IntAct

18 interactions, top by confidence:

A	B	Type	Score
PIP	TBKBP1	psi-mi:“MI:0914”(association)	0.530
TP53	KMT2E	psi-mi:“MI:0915”(physical association)	0.520
KMT2E	TP53	psi-mi:“MI:0915”(physical association)	0.520
CRK	KMT2E	psi-mi:“MI:0407”(direct interaction)	0.440
NCR2	KMT2E	psi-mi:“MI:0915”(physical association)	0.400
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
PIP	RBM47	psi-mi:“MI:0914”(association)	0.350
KMT2E	MYB	psi-mi:“MI:0915”(physical association)	0.000
KMT2E		psi-mi:“MI:0915”(physical association)	0.000
	KMT2E	psi-mi:“MI:0915”(physical association)	0.000
KMT2E	hspQ	psi-mi:“MI:0915”(physical association)	0.000
KMT2E	LAMTOR5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (74): KMT2E (Synthetic Growth Defect), OGT (Affinity Capture-Western), KMT2E (Affinity Capture-Western), KMT2E (Affinity Capture-Western), USP7 (Affinity Capture-Western), HCFC1 (Affinity Capture-MS), ILF2 (Affinity Capture-MS), RBM39 (Affinity Capture-MS), DHX30 (Affinity Capture-MS), DDX18 (Affinity Capture-MS), TRIM25 (Affinity Capture-MS), OGT (Affinity Capture-MS), TOP2A (Affinity Capture-MS), DDX50 (Affinity Capture-MS), ZNF768 (Affinity Capture-MS)

ESM2 similar proteins: A1L209, A2AWT3, B0W8L4, B1PM81, B3M881, B3NHQ1, B4GZZ4, B4IFU5, B4J1U4, B4J1U5, B4KY72, B4LDA6, B4MVH6, B4PJ01, B4QPV0, F4IDY7, O94818, O94880, P61406, P97496, Q08AX9, Q14CW9, Q17CJ5, Q2LYX9, Q3UG20, Q498T3, Q5RBA1, Q5RIX9, Q5TYQ8, Q5ZK36, Q5ZKG2, Q66KD5, Q69ZW3, Q6DD45, Q6DFC8, Q6P2L6, Q7PXG4, Q7ZUF2, Q7ZX31, Q8IZD2

Diamond homologs: A2VE56, A5DDB7, A8MW92, O44498, P36124, Q08923, Q10362, Q1MTR4, Q3UG20, Q4V9H5, Q5F3G6, Q6BNY5, Q6C0K9, Q8BLG0, Q8CCJ9, Q8IZD2, Q99MY8, Q9BVI0, Q9NR48, Q9U263, Q9VGA4, Q9Y7V2, P42948, Q6IQX0, Q12830, Q9FEN9, Q9W0T1, Q6L4L4, Q9FMS5, Q2LAE1, Q5XJV7, Q7X6Y7, Q945S8, Q9C0A6, Q9M1X9, Q9VW15, Q9VYD1, A0A286Y9D1, A1YVX4, A2A8L1

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
KMT2E	“up-regulates activity”	RARA	binding
KMT2E	“up-regulates activity”	NCR2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1398 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	72
Likely pathogenic	58
Uncertain significance	704
Likely benign	367
Benign	86

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068746	NM_182931.3(KMT2E):c.529C>T (p.Gln177Ter)	Pathogenic
1076869	NM_182931.3(KMT2E):c.303del (p.Ser102fs)	Pathogenic
1098295	NM_182931.3(KMT2E):c.3034C>T (p.Gln1012Ter)	Pathogenic
1098298	NM_182931.3(KMT2E):c.1646_1650del (p.Ile549fs)	Pathogenic
1098299	NM_182931.3(KMT2E):c.2164_2167del (p.Lys722fs)	Pathogenic
1098300	NM_182931.3(KMT2E):c.2714dup (p.Met906fs)	Pathogenic
1303403	NM_182931.3(KMT2E):c.3218_3219del (p.Arg1073fs)	Pathogenic
1308241	NM_182931.3(KMT2E):c.2616_2619del (p.Lys872fs)	Pathogenic
1679214	NM_182931.3(KMT2E):c.3908C>G (p.Ser1303Ter)	Pathogenic
1700104	NM_182931.3(KMT2E):c.3241_3257del (p.Asn1081fs)	Pathogenic
1708384	NM_182931.3(KMT2E):c.1785_1786del (p.Arg597fs)	Pathogenic
1709654	NM_182931.3(KMT2E):c.3853dup (p.Ser1285fs)	Pathogenic
1803638	NM_182931.3(KMT2E):c.5036del (p.Pro1679fs)	Pathogenic
1805445	NM_182931.3(KMT2E):c.847C>T (p.Arg283Ter)	Pathogenic
1806295	NM_182931.3(KMT2E):c.1474_1478dup (p.Lys494fs)	Pathogenic
1808606	GRCh37/hg19 7q22.2-22.3(chr7:104497480-105121286)x1	Pathogenic
1879699	NM_182931.3(KMT2E):c.1729_1733del (p.Glu577fs)	Pathogenic
1998886	NM_182931.3(KMT2E):c.3313_3314dup (p.Cys1106fs)	Pathogenic
1999059	NM_182931.3(KMT2E):c.2683del (p.Tyr895fs)	Pathogenic
2007780	NM_182931.3(KMT2E):c.2334_2337del (p.Tyr779fs)	Pathogenic
2023840	NM_182931.3(KMT2E):c.4883dup (p.Pro1629fs)	Pathogenic
2571293	NM_182931.3(KMT2E):c.916del (p.Arg306fs)	Pathogenic
2571294	NM_182931.3(KMT2E):c.3524_3525insTTAG (p.Lys1175delinsAsnTer)	Pathogenic
2614530	NM_182931.3(KMT2E):c.871C>T (p.Gln291Ter)	Pathogenic
2627141	NM_182931.3(KMT2E):c.1068_1074del (p.Tyr358fs)	Pathogenic
2691874	NM_182931.3(KMT2E):c.1710dup (p.Lys571fs)	Pathogenic
2702200	NM_182931.3(KMT2E):c.4668C>G (p.Tyr1556Ter)	Pathogenic
2703001	NM_182931.3(KMT2E):c.364A>G (p.Ile122Val)	Pathogenic
2734369	NM_182931.3(KMT2E):c.1657del (p.Thr553fs)	Pathogenic
2782781	NM_182931.3(KMT2E):c.3406_3409del (p.Thr1136fs)	Pathogenic

SpliceAI

4477 predictions. Top by Δscore:

Variant	Effect	Δscore
7:105040834:AACAG:A	acceptor_gain	1.0000
7:105040835:ACAG:A	acceptor_gain	1.0000
7:105040837:AG:A	acceptor_gain	1.0000
7:105040838:GG:G	acceptor_gain	1.0000
7:105041018:TTCA:T	donor_gain	1.0000
7:105041022:GA:G	donor_gain	1.0000
7:105041024:G:GG	donor_gain	1.0000
7:105054409:A:T	donor_gain	1.0000
7:105062162:A:AG	acceptor_gain	1.0000
7:105062163:G:GG	acceptor_gain	1.0000
7:105063341:A:AG	acceptor_gain	1.0000
7:105063345:A:AG	acceptor_gain	1.0000
7:105063346:TTCA:T	acceptor_loss	1.0000
7:105063347:TCA:T	acceptor_loss	1.0000
7:105063348:CAG:C	acceptor_loss	1.0000
7:105063349:A:AC	acceptor_loss	1.0000
7:105063349:A:AG	acceptor_gain	1.0000
7:105063349:AG:A	acceptor_gain	1.0000
7:105063350:G:GG	acceptor_gain	1.0000
7:105063350:GG:G	acceptor_gain	1.0000
7:105063350:GGAC:G	acceptor_gain	1.0000
7:105063350:GGACC:G	acceptor_gain	1.0000
7:105063499:G:GT	donor_gain	1.0000
7:105063576:TGCAG:T	donor_loss	1.0000
7:105063577:GCAGG:G	donor_loss	1.0000
7:105063578:CAG:C	donor_loss	1.0000
7:105063579:AG:A	donor_loss	1.0000
7:105063580:GG:G	donor_loss	1.0000
7:105063581:GT:G	donor_loss	1.0000
7:105063582:T:G	donor_loss	1.0000

AlphaMissense

12160 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:105062268:T:C	L59S	1.000
7:105063359:T:A	N65K	1.000
7:105063359:T:G	N65K	1.000
7:105063364:G:A	G67D	1.000
7:105063525:T:A	C121S	1.000
7:105063525:T:C	C121R	1.000
7:105063526:G:A	C121Y	1.000
7:105063526:G:C	C121S	1.000
7:105063527:C:G	C121W	1.000
7:105063531:T:A	C123S	1.000
7:105063531:T:C	C123R	1.000
7:105063532:G:A	C123Y	1.000
7:105063532:G:C	C123S	1.000
7:105063533:T:G	C123W	1.000
7:105063537:T:C	F125L	1.000
7:105063538:T:C	F125S	1.000
7:105063539:T:A	F125L	1.000
7:105063539:T:G	F125L	1.000
7:105063562:T:A	I133N	1.000
7:105063562:T:G	I133S	1.000
7:105063567:T:A	C135S	1.000
7:105063567:T:C	C135R	1.000
7:105063568:G:A	C135Y	1.000
7:105063568:G:C	C135S	1.000
7:105063568:G:T	C135F	1.000
7:105063569:T:G	C135W	1.000
7:105063576:T:A	C138S	1.000
7:105063576:T:C	C138R	1.000
7:105063577:G:C	C138S	1.000
7:105063578:C:G	C138W	1.000

dbSNP variants (sampled 300 via entrez): RS1000020336 (7:105078410 CTA>C), RS1000049049 (7:105051931 G>T), RS1000096257 (7:105066031 G>A,T), RS1000112301 (7:105086830 C>T), RS1000119584 (7:105033383 A>G), RS1000184031 (7:105075105 G>T), RS1000226698 (7:105072367 GC>G), RS1000233694 (7:105086462 C>T), RS1000235985 (7:105033651 A>AC), RS1000242165 (7:105112546 A>G,T), RS1000316704 (7:105027688 A>G), RS1000341012 (7:105066916 G>C), RS1000406142 (7:105068472 A>G), RS1000417026 (7:105085118 CAT>C), RS1000435823 (7:105067229 G>C)

Disease associations

OMIM: gene MIM:608444 | disease phenotypes: MIM:618512, MIM:617755, MIM:616579

GenCC curated gene-disease

Disease	Classification	Inheritance
O’Donnell-Luria-Rodan syndrome	Definitive	Autosomal dominant
syndromic intellectual disability	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (9): O’Donnell-Luria-Rodan syndrome (MONDO:0032793), neurodevelopmental disorder (MONDO:0700092), neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (MONDO:0060596), intellectual disability, autosomal dominant 40 (MONDO:0014699), complex neurodevelopmental disorder (MONDO:0100038), autism spectrum disorder (MONDO:0005258), epilepsy (MONDO:0005027), intellectual disability (MONDO:0001071), syndromic intellectual disability (MONDO:0000508)

Orphanet (5): BPTF-related intellectual disability-facial dysmorphism-skeletal anomalies syndrome (Orphanet:686482), CHAMP1-related intellectual disability-facial dysmorphism-behavioral abnormalities syndrome (Orphanet:692193), Non-specific syndromic intellectual disability (Orphanet:528084), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000293	Full cheeks
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000629	Periorbital fullness
HP:0000718	Aggressive behavior
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0001182	Tapered finger
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001273	Abnormal corpus callosum morphology
HP:0001290	Generalized hypotonia
HP:0001999	Abnormal facial shape
HP:0002013	Vomiting
HP:0002500	Abnormal cerebral white matter morphology
HP:0002808	Kyphosis
HP:0003593	Infantile onset
HP:0006579	Prolonged neonatal jaundice
HP:0011220	Prominent forehead
HP:0011968	Feeding difficulties
HP:0012166	Skin-picking
HP:0012448	Delayed myelination
HP:0031936	Delayed ability to walk
HP:0100716	Self-injurious behavior
HP:0200134	Epileptic encephalopathy

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST002539_67	Schizophrenia	1.000000e-09
GCST003219_47	Advanced age-related macular degeneration	1.000000e-09
GCST004521_190	Autism spectrum disorder or schizophrenia	3.000000e-10
GCST004521_221	Autism spectrum disorder or schizophrenia	5.000000e-11
GCST004946_4	Schizophrenia	2.000000e-12
GCST005316_9	Intelligence (MTAG)	3.000000e-09
GCST006803_102	Schizophrenia	7.000000e-11
GCST006922_16	Regular attendance at a religious group	8.000000e-10
GCST007325_190	General risk tolerance (MTAG)	2.000000e-08
GCST007556_45	Autism spectrum disorder	3.000000e-08
GCST008103_107	Bipolar disorder	4.000000e-06
GCST009523_48	Household income	2.000000e-08
GCST009524_22	Household income (MTAG)	3.000000e-10
GCST90002398_386	Neutrophil count	1.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0004337	intelligence
EFO:0009592	social interaction measurement
EFO:0008579	risk-taking behaviour
EFO:0009695	household income
EFO:0004833	neutrophil count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523393 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs117986340	Efficacy	3	duloxetine	Major Depressive Disorder

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs117986340	KMT2E	3	2.50	1	duloxetine

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

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects binding, increases reaction, decreases expression, increases expression	3
Valproic Acid	affects expression, decreases expression	3
Estradiol	decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
beta-lapachone	decreases expression	1
cypermethrin	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
jinfukang	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Ethanol	decreases expression	1
Coumestrol	affects cotreatment, decreases expression	1
Endosulfan	decreases expression	1
Formaldehyde	decreases expression	1
Chlordecone	affects binding, decreases reaction	1
Lead	affects splicing	1
Phthalic Acids	decreases methylation	1
Testosterone	decreases expression	1
Tretinoin	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Copper Sulfate	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4377353	Binding	Binding affinity to MLL5 (unknown origin) assessed as induction of thermal shifts at 20 uM measured for 25 mins by SYPRO orange dye thermal shift assay	Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1). — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice