KDM6A

Summary

KDM6A (lysine demethylase 6A, HGNC:12637) is a protein-coding gene on chromosome Xp11.3, encoding Lysine-specific demethylase 6A (O15550). Histone demethylase that specifically demethylates ‘Lys-27’ of histone H3, thereby playing a central role in histone code. It is haploinsufficient (ClinGen: sufficient evidence).

This gene is located on the X chromosome and is the corresponding locus to a Y-linked gene which encodes a tetratricopeptide repeat (TPR) protein. The encoded protein of this gene contains a JmjC-domain and catalyzes the demethylation of tri/dimethylated histone H3. Multiple alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 7403 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Kabuki syndrome 2 (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 1,587 total — 120 pathogenic, 57 likely-pathogenic
• Phenotypes (HPO): 241
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 18 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 20 downstream targets (CollecTRI)
• MANE Select transcript: NM_001291415

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12637
Approved symbol	KDM6A
Name	lysine demethylase 6A
Location	Xp11.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000147050
Ensembl biotype	protein_coding
OMIM	300128
Entrez	7403

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 14 retained_intron, 13 protein_coding, 12 nonsense_mediated_decay

ENST00000377967, ENST00000382899, ENST00000431196, ENST00000475233, ENST00000479423, ENST00000484732, ENST00000485072, ENST00000536777, ENST00000543216, ENST00000611820, ENST00000621147, ENST00000674541, ENST00000674564, ENST00000674586, ENST00000674659, ENST00000674739, ENST00000674867, ENST00000675157, ENST00000675182, ENST00000675440, ENST00000675514, ENST00000675525, ENST00000675546, ENST00000675577, ENST00000675816, ENST00000676026, ENST00000676062, ENST00000676085, ENST00000676133, ENST00000676343, ENST00000676389, ENST00000682127, ENST00000682908, ENST00000683021, ENST00000683425, ENST00000684352, ENST00000867282, ENST00000867283, ENST00000967038

RefSeq mRNA: 14 — MANE Select: NM_001291415 NM_001291415, NM_001291416, NM_001291417, NM_001291418, NM_001291421, NM_001410742, NM_001419809, NM_001419810, NM_001419811, NM_001419812, NM_001419813, NM_001419814, NM_001419815, NM_021140

CCDS: CCDS14265, CCDS94599, CCDS94600, CCDS94601, CCDS94603, CCDS94604

Canonical transcript exons

ENST00000611820 — 30 exons

Exon	Start	End
ENSE00000978491	45060022	45060156
ENSE00000978492	45061324	45061419
ENSE00000978493	45062647	45062748
ENSE00000978495	45069579	45070357
ENSE00000978499	45082576	45082640
ENSE00001332671	45060609	45060764
ENSE00001612540	45037655	45037689
ENSE00001664216	45078400	45078505
ENSE00001673565	45053829	45053955
ENSE00001687145	45089743	45089930
ENSE00001708464	45079146	45079351
ENSE00001721695	45059006	45059104
ENSE00001728550	45059247	45059466
ENSE00001729094	45063422	45063817
ENSE00001745559	45076697	45076826
ENSE00001755153	45051709	45051802
ENSE00001766242	45034931	45034985
ENSE00001771679	45090723	45090864
ENSE00001786164	44873924	44873987
ENSE00001800315	45085865	45085979
ENSE00003499409	45082715	45082789
ENSE00003516695	44974666	44974715
ENSE00003540925	45110079	45110249
ENSE00003549806	44961284	44961392
ENSE00003572873	45010961	45011019
ENSE00003612563	45020610	45020730
ENSE00003686355	45083460	45083608
ENSE00003734606	45107410	45107536
ENSE00003898088	44873188	44873712
ENSE00003898120	45111382	45112779

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 93.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.6639 / max 293.3452, expressed in 1797 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196075	16.6825	1786
196076	2.8024	1119
196074	0.8349	524
196077	0.7499	370
196078	0.5942	294

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	93.35	gold quality
oocyte	CL:0000023	91.41	gold quality
bone marrow cell	CL:0002092	90.35	gold quality
bone marrow	UBERON:0002371	89.47	gold quality
left ovary	UBERON:0002119	88.74	gold quality
monocyte	CL:0000576	88.57	gold quality
mononuclear cell	CL:0000842	88.52	gold quality
skin of abdomen	UBERON:0001416	88.42	gold quality
germinal epithelium of ovary	UBERON:0001304	88.38	gold quality
leukocyte	CL:0000738	88.25	gold quality
ectocervix	UBERON:0012249	88.10	gold quality
ovary	UBERON:0000992	87.82	gold quality
vagina	UBERON:0000996	87.81	gold quality
colonic epithelium	UBERON:0000397	87.80	gold quality
skin of leg	UBERON:0001511	87.75	gold quality
calcaneal tendon	UBERON:0003701	87.65	gold quality
right ovary	UBERON:0002118	87.54	gold quality
lower esophagus mucosa	UBERON:0035834	87.54	gold quality
ventricular zone	UBERON:0003053	87.28	gold quality
skin of hip	UBERON:0001554	86.99	gold quality
body of uterus	UBERON:0009853	86.70	gold quality
zone of skin	UBERON:0000014	86.64	gold quality
uterine cervix	UBERON:0000002	86.31	gold quality
mucosa of stomach	UBERON:0001199	86.23	gold quality
granulocyte	CL:0000094	86.22	gold quality
endocervix	UBERON:0000458	86.21	gold quality
blood	UBERON:0000178	86.14	gold quality
cartilage tissue	UBERON:0002418	85.77	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.74	gold quality
jejunal mucosa	UBERON:0000399	85.39	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ENAD-21	no	589.25
E-MTAB-6386	no	277.07
E-ANND-3	no	5.65

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

20 targets.

Target	Regulation
ELF4	Repression
ELK3	Repression
ERG	Repression
ETS2	Repression
ETV6	Repression
FLI1	Repression
HOXA1	Activation
HOXA10	Activation
HOXA11	Activation
HOXA13	Activation
HOXA5	Activation
HOXA7	Activation
HOXA9	Activation
HOXC11	Activation
HOXC13	Activation
HOXC4	Activation
HOXC6	Activation
HOXC8	Activation
SPI1	Repression
ZBTB16	Activation

Upstream regulators (CollecTRI, top): E2F4

miRNA regulators (miRDB)

155 targeting KDM6A, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
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-656-3P	100.00	72.15	2788
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
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-4789-5P	99.98	70.76	2721
HSA-MIR-12136	99.98	72.81	5713

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• UTX associates with MLL3- and MLL4-containing histone H3 K4 methyltransferase complex(es) that also include ASH2L, RBBP5, WDR5, hDPY-30, PTIP, PA1, NCOA6. (PMID:17500065)
• the human JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3 (PMID:17713478)
• study shows that UTX is a di- and trimethyl H3K27 demethylase; results suggest a concerted mechanism for transcriptional activation in which cycles of H3K4 methylation by MLL2/3 are linked with the demethylation of H3K27 through UTX (PMID:17761849)
• critical role for UTX in regulating H3K27 methylation at the HOX gene loci and in animal posterior development (PMID:17851529)
• The JmjC domain-containing protein UTX specifically demethylates mono-, di- and trimethylated K27 of histone H3 in vitro. (PMID:18003914)
• UTX and JMJD3 may function as H3K27 demethylases in vivo (PMID:18003914)
• Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types (PMID:19330029)
• identification of inactivating mutations in two genes–SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C, a histone H3 lysine 4 demethylase–as well as mutations in the histone H3 lysine 27 demethylase, UTX in clear cell renal cell carcinoma (PMID:20054297)
• UTX removes H3K27me3 and maintains expression of several RB-binding proteins, enabling cell cycle arrest (PMID:20123895)
• The role of the H3K27 demethylases Jmjd3 and UTX in gene expression, is discussed. (PMID:21209387)
• KDM6A- and KDM6B-responsive Homeobox genes are expressed at significantly higher levels, suggesting that HPV16 E7 results in reprogramming of host epithelial cells (PMID:21245294)
• UXT is a potential interactor of HBV Pol. (PMID:21515470)
• inhibition measurements showed significant selectivity between KDM4C and KDM6A (PMID:21575637)
• Novel UTX, DNMT3A, and EZH2 mutations were found in 8%, 10%, and 5.5% of patients with chronic myelomonocytic leukemia. (PMID:21828135)
• H3K27 demethylation by JMJD3 at a poised enhancer of anti-apoptotic gene BCL2 determines ERalpha ligand dependency (PMID:21841772)
• Correlating with the loss of H3K27me3, human papillomavirus 16 E6/E7-expressing cells exhibited derepression of specific EZH2-, KMD6A-, and BMI1-targeted HOX genes. (PMID:21865393)
• clarified how UTX discriminates H3K27me3/2 from the other methyllysines with distinct roles (PMID:22002947)
• This study identifies KDM6A mutations as another cause of Kabuki syndrome and highlights the growing role of histone methylases and histone demethylases in multiple-congenital-anomaly and intellectual-disability syndromes. (PMID:22197486)
• demonstrate that UTX directly associates with the promoters of the Mll1, Runx1, and Scl genes and modulate their transcription by controlling H3K27me3 marks on respective promoter regions. (PMID:22306297)
• PAN RNA interacts with demethylases JMJD3 and UTX, and the histone methyltransferase MLL2 (PMID:22589717)
• identification of Utx as a novel mediator with distinct functions during the re-establishment of pluripotency and germ cell development (PMID:22801502)
• Microdeletions and microduplications have not been identified in the MLL2 and KDM6A genes of a large cohort of patients with Kabuki syndrome. (PMID:22840376)
• KDM6A contributes to the activation of WNT3 and DKK1 at different differentiation stages when WNT3 and DKK1 are required for mesendoderm and definitive endoderm differentiation. (PMID:22907667)
• This study demonistrated that KDM6A mutations were most commonly identified in subgroups in medulloblastoma. (PMID:23184418)
• KDM6A is overexpressed in breast cancer patients with an unfavorable prognosis (mortality at 1 year, p=8.65E-7). (PMID:23266085)
• UTX regulates stem cell migration and hematopoiesis. (PMID:23365460)
• UTX histone demethylase plays important functional role in epigenetic alteration of HOX clusters during retinoic acid-induced neural differentiation. (PMID:23527641)
• PBRM1, KDM6A, SETD2 and BAP1 were unmethylated in all tumor and normal specimens. (PMID:23644518)
• The identification of novel KDM6A mutations in patients with Kabuki syndrome. (PMID:23913813)
• Both Ezh2 and Kdm6a were shown to affect expression of master regulatory genes involved in adipogenesis and osteogenesis. (PMID:24123378)
• results demonstrate that UTX is implicated in IL-4 mediated transcriptional activation of the ALOX15 gene (PMID:24465480)
• High levels of UTX or MLL4 are associated with poor prognosis in patients with breast cancer. (PMID:24491801)
• A report of novel KDM6A mutations in patients with Kabuki syndrome. (PMID:24527667)
• One girl had a novel splice-site mutation in KDM6A. (PMID:24739679)
• Results show that UTX interacts with the retinoic acid receptor alpha (RARalpha) and this interaction is essential for proper differentiation of leukemic U937 cells in response to retinoic acid. (PMID:25071154)
• This study is the first to identify frequent BAP1 and BRCA pathway alterations in bladder cancer, show TERT promoter alterations are independent of other bladder cancer gene alterations, and show KDM6A loss is a driver of the bladder cancer phenotype. (PMID:25225064)
• Mutations in KMT2D gene were identified in 10/16 (62%) of the patients, whereas none of the patients had KDM6A mutations. (PMID:25281733)
• H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia (PMID:25320243)
• Our results provide further support for the similar roles of KMT2D and KDM6A in the etiology of KS by using a vertebrate model organism to provide direct evidence of their roles in the development of organs and tissues affected in KS patients. (PMID:25972376)
• Kabuki syndrome may be caused by mutations in one of two histone methyltransferase genes: KMT2D and KDM6A. (PMID:26049589)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	kdm6a	ENSDARG00000061759
mus_musculus	Kdm6a	ENSMUSG00000037369
rattus_norvegicus	Kdm6a	ENSRNOG00000052721
drosophila_melanogaster	Utx	FBGN0260749
caenorhabditis_elegans		WBGENE00007813
caenorhabditis_elegans		WBGENE00009089
caenorhabditis_elegans		WBGENE00017046
caenorhabditis_elegans		WBGENE00017571

Paralogs (2): KDM6B (ENSG00000132510), UTY (ENSG00000183878)

Protein

Protein identifiers

Lysine-specific demethylase 6A — O15550 (reviewed: O15550)

Alternative names: Histone demethylase UTX, Ubiquitously-transcribed TPR protein on the X chromosome, Ubiquitously-transcribed X chromosome tetratricopeptide repeat protein, [histone H3]-trimethyl-L-lysine(27) demethylase 6A

All UniProt accessions (19): O15550, A0A087WUN6, A0A087X0R0, A0A6Q8PFD0, A0A6Q8PFK0, A0A6Q8PG32, A0A6Q8PG92, A0A6Q8PGG6, A0A6Q8PGN0, A0A6Q8PH94, A0A6Q8PHB6, A0A6Q8PHJ0, A0A804HIZ7, A0A804HJA2, A0A804HLJ3, F5H5V6, F5H6S1, F8W8R6, H0Y6V5

UniProt curated annotations — full annotation on UniProt →

Function. Histone demethylase that specifically demethylates ‘Lys-27’ of histone H3, thereby playing a central role in histone code. Demethylates trimethylated and dimethylated but not monomethylated H3 ‘Lys-27’. Plays a central role in regulation of posterior development, by regulating HOX gene expression. Demethylation of ‘Lys-27’ of histone H3 is concomitant with methylation of ‘Lys-4’ of histone H3, and regulates the recruitment of the PRC1 complex and monoubiquitination of histone H2A. Plays a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression.

Subunit / interactions. Interacts with TLE1. Component of the MLL2/3 complex (also named ASCOM complex), at least composed of KMT2D/MLL2 or KMT2C/MLL3, ASH2L, RBBP5, WDR5, NCOA6, DPY30, KDM6A (or KDM6B), PAXIP1/PTIP, PAGR1 and alpha- and beta-tubulin. Interacts with SUPT6H. Interacts with SMARCA4. Interacts with PROSER1.

Subcellular location. Nucleus.

Disease relevance. Kabuki syndrome 2 (KABUK2) [MIM:300867] A congenital intellectual disability syndrome with 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.

Miscellaneous. Escapes X chromosome inactivation.

Similarity. Belongs to the UTX family.

RefSeq proteins (14): NP_001278344, NP_001278345, NP_001278346, NP_001278347, NP_001278350, NP_001397671, NP_001406738, NP_001406739, NP_001406740, NP_001406741, NP_001406742, NP_001406743, NP_001406744, NP_066963 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003347	JmjC_dom	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR046941	KDM6_GATAL_sf	Homologous_superfamily
IPR048560	KDM6A_B-like_GATAL	Domain
IPR048562	KDM6A_B-like_C-hel	Domain
IPR051630	Corepressor-Demethylase	Family

Pfam: PF02373, PF13181, PF21322, PF21326

Enzyme classification (BRENDA):

• EC 1.14.11.68 — [histone H3]-trimethyl-L-lysine27 demethylase (BRENDA: 8 organisms, 20 substrates, 7 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• N(6),N(6),N(6)-trimethyl-L-lysyl(27)-[histone H3] + 2 2-oxoglutarate + 2 O2 = N(6)-methyl-L-lysyl(27)-[histone H3] + 2 formaldehyde + 2 succinate + 2 CO2 (RHEA:60224)

UniProt features (94 total): helix 21, strand 19, repeat 8, region of interest 8, sequence variant 8, compositionally biased region 7, binding site 7, modified residue 5, sequence conflict 4, turn 4, chain 1, mutagenesis site 1, domain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6FUL	X-RAY DIFFRACTION	1.65
3AVR	X-RAY DIFFRACTION	1.8
3AVS	X-RAY DIFFRACTION	1.85
6FUK	X-RAY DIFFRACTION	2
6G8F	X-RAY DIFFRACTION	2.04

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15550-F1	71.55	0.48

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 (7): 1146; 1148; 1226; 1331; 1334; 1358; 1361

Post-translational modifications (5): 519, 549, 769, 827, 829

Mutagenesis-validated functional residues (1):

Position	Phenotype
1146	abolishes histone demethylase activity.

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-3214842	HDMs demethylate histones
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
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-9821002	Chromatin modifications during the maternal to zygotic transition (MZT)
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-1266738	Developmental Biology
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization
R-HSA-5619507	Activation of HOX genes during differentiation
R-HSA-74160	Gene expression (Transcription)
R-HSA-9816359	Maternal to zygotic transition (MZT)
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: 755 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, RRAGTTGT_UNKNOWN, FREAC2_01, BROWNE_HCMV_INFECTION_6HR_DN, HNF3ALPHA_Q6, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, FOXO4_01, FOXO1_01, GGGTGGRR_PAX4_03, YY1_Q6, NKX62_Q2, FREAC3_01, YY1_02, BLALOCK_ALZHEIMERS_DISEASE_UP

GO Biological Process (25): chromatin remodeling (GO:0006338), heart development (GO:0007507), regulation of gene expression (GO:0010468), response to hypoxia (GO:0001666), in utero embryonic development (GO:0001701), neural tube closure (GO:0001843), heart morphogenesis (GO:0003007), respiratory system process (GO:0003016), chromatin organization (GO:0006325), positive regulation of gene expression (GO:0010628), neural tube development (GO:0021915), somite rostral/caudal axis specification (GO:0032525), multicellular organism growth (GO:0035264), positive regulation of cell size (GO:0045793), positive regulation of transcription by RNA polymerase II (GO:0045944), mesodermal cell differentiation (GO:0048333), embryonic organ development (GO:0048568), notochord morphogenesis (GO:0048570), cellular response to vitamin D (GO:0071305), cellular response to hypoxia (GO:0071456), cellular response to transforming growth factor beta stimulus (GO:0071560), circulatory system development (GO:0072359), negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway (GO:1903298), cellular response to angiotensin (GO:1904385), cellular response to endothelin (GO:1990859)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), chromatin DNA binding (GO:0031490), histone demethylase activity (GO:0032452), metal ion binding (GO:0046872), histone H3K27me2/H3K27me3 demethylase activity (GO:0071558), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), identical protein binding (GO:0042802), dioxygenase activity (GO:0051213)

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

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Epigenetic regulation by WDR5-containing histone modifying complexes	2
Developmental Biology	2
Chromatin modifying enzymes	1
Activation of HOX genes during differentiation	1
Maternal to zygotic transition (MZT)	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
Gene expression (Transcription)	1
Chromatin organization	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
animal organ development	2
gene expression	2
chordate embryonic development	2
chromatin organization	1
circulatory system development	1
regulation of macromolecule biosynthetic process	1
response to stress	1
response to decreased oxygen levels	1
primary neural tube formation	1
tube closure	1
heart development	1
animal organ morphogenesis	1
system process	1
respiratory gaseous exchange by respiratory system	1
cellular component organization	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
nervous system development	1
tube development	1
epithelium development	1
embryonic axis specification	1
somitogenesis	1
anterior/posterior axis specification	1
multicellular organismal process	1
developmental growth	1
regulation of cell size	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
mesoderm formation	1
cell differentiation	1
embryo development	1
notochord development	1
embryonic organ morphogenesis	1
response to vitamin D	1
cellular response to vitamin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
response to hypoxia	1
cellular response to stress	1

Protein interactions and networks

STRING

8452 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KDM6A	KMT2C	Q8NEZ4	997
KDM6A	PAXIP1	Q6ZW49	995
KDM6A	NCOA6	Q14686	991
KDM6A	KMT2D	O14686	987
KDM6A	WDR5	P61964	987
KDM6A	RBBP5	Q15291	968
KDM6A	PAGR1	Q9BTK6	918
KDM6A	EZH2	Q15910	910
KDM6A	ASH2L	Q9UBL3	896
KDM6A	KDM5C	P41229	884
KDM6A	SETD1A	O15047	863
KDM6A	H3-3A	P06351	830
KDM6A	DNMT1	P26358	829
KDM6A	H3C1	P02295	817
KDM6A	DPY30	Q9C005	808

IntAct

128 interactions, top by confidence:

A	B	Type	Score
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
KDM6A	RBBP5	psi-mi:“MI:0914”(association)	0.790
WDR5	KDM6A	psi-mi:“MI:0915”(physical association)	0.770
PAGR1	KDM6A	psi-mi:“MI:0914”(association)	0.730
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
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
AR	KMT2D	psi-mi:“MI:0914”(association)	0.600
KDM6A	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
GSC2	KDM6A	psi-mi:“MI:0915”(physical association)	0.560
KDM6A	SOX2	psi-mi:“MI:0915”(physical association)	0.540
KDM6A	KLF4	psi-mi:“MI:0915”(physical association)	0.540
Paxip1	KMT2D	psi-mi:“MI:0914”(association)	0.530
NCOA6	UTY	psi-mi:“MI:0914”(association)	0.530
KDM6A	KMT2D	psi-mi:“MI:0914”(association)	0.530
KMT2D	KDM6A	psi-mi:“MI:0914”(association)	0.530

BioGRID (245): KDM6A (Affinity Capture-Western), KDM6A (Affinity Capture-MS), KDM6A (Affinity Capture-Western), KDM6A (Affinity Capture-Western), KDM6A (Affinity Capture-Western), KDM6A (Negative Genetic), MSH6 (Negative Genetic), KDM6A (Negative Genetic), PTEN (Positive Genetic), KDM6A (Proximity Label-MS), KDM6A (Affinity Capture-MS), KDM6A (Affinity Capture-MS), KDM6A (Affinity Capture-MS), KDM6A (Affinity Capture-RNA), KDM6A (Affinity Capture-Western)

ESM2 similar proteins: A0A1L8GR68, A2A791, B2GUN4, E1BP74, E1BZ85, F1QLG5, F7AQ22, O00472, O15164, O15550, O70546, O88974, O95789, P49140, P55265, P70365, Q14202, Q14596, Q15047, Q15788, Q4PJW2, Q5R413, Q5RC94, Q5RDJ2, Q5VZL5, Q64127, Q69Z66, Q6H8Q1, Q6KC51, Q6NXK2, Q6P3Y5, Q6PFK1, Q7Z3K3, Q8BJ34, Q8BL65, Q8BZH4, Q8CHY6, Q8IZD4, Q8TEW8, Q8VIG2

Diamond homologs: O14607, O15054, O15550, O70546, P79457, Q5NCY0, Q6B4Z3, Q95QK3, A0A096LPI5, O14628, Q6UX73, Q86U02, Q8N769, Q8N7M2, Q8NDZ0

SIGNOR signaling

24 interactions.

A	Effect	B	Mechanism
KDM6A	“down-regulates activity”	H3C1	demethylation
KDM6A	“up-regulates quantity by expression”	HOXA1	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	HOXA10	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	HOXA11	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	HOXA13	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	HOXA5	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	HOXA7	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	HOXA9	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	HOXC11	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	HOXC13	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	HOXC6	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	HOXC8	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	HOXC4	“transcriptional regulation”
KDM6A	“down-regulates quantity by repression”	ELF4	“transcriptional regulation”
KDM6A	“down-regulates quantity by repression”	ETV6	“transcriptional regulation”
KDM6A	“down-regulates quantity by repression”	ERG	“transcriptional regulation”
KDM6A	“down-regulates quantity by repression”	FLI1	“transcriptional regulation”
KDM6A	“down-regulates quantity by repression”	ETS2	“transcriptional regulation”
KDM6A	“down-regulates quantity by repression”	SPI1	“transcriptional regulation”
KDM6A	“down-regulates quantity by repression”	ELK3	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	ZBTB16	“transcriptional regulation”
KDM6A	“down-regulates activity”	“Histone H3”	demethylation
“MLL2 complex”	“up-regulates quantity by stabilization”	KDM6A	binding
2-oxoglutarate(2-)	“up-regulates activity”	KDM6A	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 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
Deactivation of the beta-catenin transactivating complex	11	31.3×	1e-11
Formation of WDR5-containing histone-modifying complexes	8	25.9×	1e-07
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	7	16.8×	1e-05
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	9	16.1×	3e-07
Gastrulation	5	15.8×	4e-04
Transcriptional regulation by RUNX2	5	15.5×	4e-04
TCF dependent signaling in response to WNT	10	14.4×	2e-07
Signaling by WNT	10	13.7×	3e-07

GO biological processes:

GO term	Partners	Fold	FDR
neuron fate specification	6	39.0×	1e-06
positive regulation of miRNA transcription	11	29.6×	2e-11
transcription initiation-coupled chromatin remodeling	6	21.3×	3e-05
anatomical structure morphogenesis	15	19.3×	4e-13
somatic stem cell population maintenance	8	18.4×	2e-06
branching involved in ureteric bud morphogenesis	5	17.0×	5e-04
inner ear morphogenesis	6	16.7×	1e-04
positive regulation of transcription initiation by RNA polymerase II	5	12.6×	1e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 18 cancer types — ALL, BLADDER, BLCA, BRCA, ESCA, ESCC, GBC, HCC, HNSC, LUSC, MBL, PAAD…(+6 more).

Clinical variants and AI predictions

ClinVar

1587 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	120
Likely pathogenic	57
Uncertain significance	578
Likely benign	368
Benign	121

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067136	NM_001291415.2(KDM6A):c.2858+1G>A	Pathogenic
1071021	NC_000023.10:g.(?44894176)(44896934_?)del	Pathogenic
1071579	NM_001291415.2(KDM6A):c.565-1G>A	Pathogenic
1071788	NM_001291415.2(KDM6A):c.348C>A (p.Tyr116Ter)	Pathogenic
1183996	NM_001291415.2(KDM6A):c.655-2371_782del	Pathogenic
1191456	NM_001291415.2(KDM6A):c.619+4_619+7del	Pathogenic
1338587	NM_001291415.2(KDM6A):c.3138del (p.Asn1046fs)	Pathogenic
1340327	GRCh37/hg19 Xp11.3(chrX:44715970-44741826)x0	Pathogenic
1360596	NM_001291415.2(KDM6A):c.2284C>T (p.Gln762Ter)	Pathogenic
1452097	NM_001291415.2(KDM6A):c.1177C>T (p.Arg393Ter)	Pathogenic
1454641	NM_001291415.2(KDM6A):c.2858+2T>C	Pathogenic
1459416	NM_001291415.2(KDM6A):c.3384del (p.Gly1129fs)	Pathogenic
1471961	NM_001291415.2(KDM6A):c.225+1G>A	Pathogenic
1526797	GRCh37/hg19 Xp11.3(chrX:44939212-44985773)	Pathogenic
1684286	NM_001291415.2(KDM6A):c.2597_2598del (p.Ser866fs)	Pathogenic
1708049	NM_001291415.2(KDM6A):c.3494dup (p.Ser1166fs)	Pathogenic
1711707	NM_001291415.2(KDM6A):c.2328_2329del (p.Leu777fs)	Pathogenic
1805035	NM_001291415.2(KDM6A):c.2379dup (p.Ala794fs)	Pathogenic
1805249	NM_001291415.2(KDM6A):c.1164del (p.Ala389fs)	Pathogenic
190247	NM_001291415.2(KDM6A):c.2671_2674del (p.Asn891fs)	Pathogenic
2091420	NM_001291415.2(KDM6A):c.1537C>T (p.Gln513Ter)	Pathogenic
2097180	NM_001291415.2(KDM6A):c.444G>A (p.Trp148Ter)	Pathogenic
211254	NM_001291415.2(KDM6A):c.1699del (p.Val567fs)	Pathogenic
2133290	NM_001291415.2(KDM6A):c.349C>T (p.Gln117Ter)	Pathogenic
2426671	NC_000023.10:g.(?44941801)(44945244_?)del	Pathogenic
2426672	NC_000023.10:g.(?44820509)(44896954_?)del	Pathogenic
2429725	NM_001291415.2(KDM6A):c.705_706del (p.Asn236fs)	Pathogenic
2429810	NM_001291415.2(KDM6A):c.3190dup (p.Trp1064fs)	Pathogenic
2436899	NM_001291415.2(KDM6A):c.3300+1del	Pathogenic
2442333	NM_001291415.2(KDM6A):c.357C>G (p.Tyr119Ter)	Pathogenic

SpliceAI

5428 predictions. Top by Δscore:

Variant	Effect	Δscore
X:44873712:GGTAC:G	donor_loss	1.0000
X:44873919:CACA:C	acceptor_loss	1.0000
X:44873920:ACAGC:A	acceptor_loss	1.0000
X:44873921:CA:C	acceptor_loss	1.0000
X:44873922:A:AG	acceptor_gain	1.0000
X:44873922:AGCC:A	acceptor_gain	1.0000
X:44873923:G:GT	acceptor_gain	1.0000
X:44873923:GC:G	acceptor_gain	1.0000
X:44873923:GCC:G	acceptor_gain	1.0000
X:44873923:GCCG:G	acceptor_gain	1.0000
X:44873923:GCCGC:G	acceptor_gain	1.0000
X:44932025:A:AG	donor_gain	1.0000
X:44961278:TTCTA:T	acceptor_loss	1.0000
X:44961279:TCTA:T	acceptor_loss	1.0000
X:44961280:CTA:C	acceptor_loss	1.0000
X:44961281:TAGGC:T	acceptor_loss	1.0000
X:44961282:A:AG	acceptor_gain	1.0000
X:44961282:AG:A	acceptor_gain	1.0000
X:44961282:AGGCT:A	acceptor_gain	1.0000
X:44961283:G:GG	acceptor_gain	1.0000
X:44961283:GG:G	acceptor_gain	1.0000
X:44961283:GGC:G	acceptor_gain	1.0000
X:44961283:GGCT:G	acceptor_gain	1.0000
X:44961283:GGCTG:G	acceptor_gain	1.0000
X:44961388:AAAAG:A	donor_loss	1.0000
X:44961390:AAGG:A	donor_loss	1.0000
X:44961391:AGGTA:A	donor_loss	1.0000
X:44961393:G:T	donor_loss	1.0000
X:44961394:T:A	donor_loss	1.0000
X:44974665:GC:G	acceptor_gain	1.0000

AlphaMissense

9545 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:44961369:T:C	L104P	1.000
X:45010985:G:C	G137R	1.000
X:45020686:G:T	G174W	1.000
X:45020687:G:A	G174E	1.000
X:45053898:T:C	L273P	1.000
X:45053949:T:C	L290P	1.000
X:45053951:G:A	G291R	1.000
X:45053951:G:C	G291R	1.000
X:45053952:G:A	G291E	1.000
X:45053952:G:T	G291V	1.000
X:45059038:C:A	A303D	1.000
X:45059040:T:C	F304L	1.000
X:45059041:T:C	F304S	1.000
X:45059042:T:A	F304L	1.000
X:45059042:T:G	F304L	1.000
X:45059049:T:C	Y307H	1.000
X:45059049:T:G	Y307D	1.000
X:45059058:T:C	S310P	1.000
X:45059091:T:A	W321R	1.000
X:45059091:T:C	W321R	1.000
X:45059093:G:C	W321C	1.000
X:45059093:G:T	W321C	1.000
X:45059101:T:A	I324K	1.000
X:45059103:G:C	G325R	1.000
X:45059103:G:T	G325C	1.000
X:45059104:G:A	G325D	1.000
X:45059104:G:T	G325V	1.000
X:45059252:T:A	L327Q	1.000
X:45059252:T:C	L327P	1.000
X:45059254:T:G	Y328D	1.000

dbSNP variants (sampled 300 via entrez): RS1000006115 (X:44922398 G>T), RS1000020896 (X:44997944 T>C), RS1000043586 (X:45032311 A>G), RS1000043854 (X:45043815 T>A), RS1000068722 (X:44944996 G>C), RS1000087004 (X:44933647 G>A), RS1000098073 (X:44941321 G>A,C), RS1000099154 (X:44878884 G>A,C), RS1000110696 (X:45099780 A>G), RS1000131996 (X:45004939 A>C,G,T), RS1000159139 (X:44954618 G>T), RS1000176117 (X:44876816 A>G), RS1000180657 (X:45107975 T>A,G), RS1000209178 (X:44872665 A>G), RS1000219244 (X:45071841 C>G,T)

Disease associations

OMIM: gene MIM:300128 | disease phenotypes: MIM:300867, MIM:147920, MIM:109800, MIM:618866

GenCC curated gene-disease

Disease	Classification	Inheritance
Kabuki syndrome 2	Definitive	X-linked
Kabuki syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Kabuki syndrome 2	Definitive	XL

Mondo (14): Kabuki syndrome 2 (MONDO:0010465), peripheral precocious puberty (MONDO:0015791), Kabuki syndrome 1 (MONDO:0007843), intellectual disability (MONDO:0001071), dilated cardiomyopathy (MONDO:0005021), prostate cancer (MONDO:0008315), autism spectrum disorder (MONDO:0005258), urinary bladder cancer (MONDO:0001187), neurodevelopmental disorder (MONDO:0700092), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), tremor, hereditary essential, 6 (MONDO:0030027), CHARGE syndrome (MONDO:0008965), anemia (MONDO:0002280), Kabuki syndrome (MONDO:0016512)

Orphanet (9): Kabuki syndrome (Orphanet:2322), Rare peripheral precocious puberty (Orphanet:178040), Dilated cardiomyopathy (Orphanet:217604), Familial prostate cancer (Orphanet:1331), Multiple congenital anomalies/dysmorphic syndrome (Orphanet:68341), CHARGE syndrome (Orphanet:138), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Bladder cancer (Orphanet:157980)

HPO phenotypes

241 total (30 of 241 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
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:0000196	Lower lip pit
HP:0000202	Orofacial cleft
HP:0000215	Thick upper lip vermilion
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion

GWAS associations

0 associations (top):

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D000740	Anemia	C15.378.050
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
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C537705	Kabuki syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2069164 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 7,561 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL70927	DEFERIPRONE	4	7,561

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 1.14.11.- Histone demethylases

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
GSK-J1	Inhibition	7.28	pIC50
GSK-J4	Inhibition	5.18	pIC50
KDM5 inhibitor N71	Inhibition	4.22	pIC50

ChEMBL bioactivities

7 potent at pChembl≥5 of 14 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.28	IC50	53	nM	CHEMBL3188597
6.70	IC50	200	nM	CHEMBL1230640
5.38	IC50	4200	nM	DEFERIPRONE
5.18	IC50	6600	nM	CHEMBL3183531
5.18	IC50	6600	nM	CHEMBL5274906
5.05	IC50	9000	nM	CHEMBL3183531

PubChem BioAssay actives

9 with measured affinity, of 66 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[[2-pyridin-2-yl-6-(1,2,4,5-tetrahydro-3-benzazepin-3-yl)pyrimidin-4-yl]amino]propanoic acid	2145043: Inhibition of KDM6A (919 to 1401 residues)(unknown origin) by Alphalisa assay	ic50	0.0530	uM
ethyl 2-[[[2-[2-(dimethylamino)ethyl-ethylamino]-2-oxoethyl]amino]methyl]pyridine-4-carboxylate	1289440: Inhibition of KDM6A (919 to 1401 residues) (unknown origin) expressed in Escherichia coli using biotinylated histone H3 as substrate preincubated for 10 mins followed by substrate addition measured after 10 mins by AlphaLisa assay	ic50	0.1000	uM
methyl 2-[[[2-[2-(dimethylamino)ethyl-ethylamino]-2-oxoethyl]amino]methyl]pyridine-4-carboxylate	1289440: Inhibition of KDM6A (919 to 1401 residues) (unknown origin) expressed in Escherichia coli using biotinylated histone H3 as substrate preincubated for 10 mins followed by substrate addition measured after 10 mins by AlphaLisa assay	ic50	0.1000	uM
8-hydroxyquinoline-5-carboxylic acid	1916577: Inhibition of KDM6A (unknown origin) expressed in Escherichia coli using Biotin-H3(14-34)K27me3 peptide and measured after 1 hrs by alpha screen assay	ic50	0.2000	uM
[(5S)-5-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-6-aminohexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-6-aminohexanoyl]amino]-5-amino-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-3-hydroxybutanoyl]amino]-6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S)-1-[[(2S,3R)-1-[[2-(carboxymethylamino)-2-oxoethyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-6-oxohexyl]-trimethylazanium	1802884: AlphaScreen Assay from Article 10.1074/jbc.M114.555052: “Human UTY(KDM6C) is a male-specific N¿-methyl lysyl demethylase.”	kd	2.0000	uM
Deferiprone	1872468: Inhibition of KDM6A (unknown origin)	ic50	4.2000	uM
1-methoxy-4-[[2-pyridin-2-yl-6-(1,2,4,5-tetrahydro-3-benzazepin-3-yl)pyrimidin-4-yl]amino]butan-2-one	1934063: Inhibition of KDM6A (unknown origin ) by TR-FRET assay	ic50	6.6000	uM
ethyl 3-[[2-pyridin-2-yl-6-(1,2,4,5-tetrahydro-3-benzazepin-3-yl)pyrimidin-4-yl]amino]propanoate	2145043: Inhibition of KDM6A (919 to 1401 residues)(unknown origin) by Alphalisa assay	ic50	6.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
methylmercuric chloride	increases expression	2
trichostatin A	decreases expression, increases expression	2
Formaldehyde	increases expression, decreases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases activity, increases expression	1
geldanamycin	increases expression	1
testosterone enanthate	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
cobaltous chloride	increases expression	1
periodate-oxidized adenosine	affects expression	1
aflatoxin B2	decreases methylation	1
hydroquinone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases response to substance, increases expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	increases expression	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Vehicle Emissions	decreases expression, decreases reaction	1
Benzo(a)pyrene	affects methylation	1
Berberine	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Drugs, Chinese Herbal	increases expression	1

ChEMBL screening assays

40 unique, capped per target: 36 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2071961	Binding	Inhibition of KDM6A	Inhibitor scaffold for the histone lysine demethylase KDM4C (JMJD2C). — Bioorg Med Chem Lett
CHEMBL5210083	Functional	Affinity Phenotypic Cellular interaction (Inhibition of TNF release (in LPS stimulated human macrophages derived from PBMC)) EUB0000217b KDM6A/UTX	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomics Library wave 3

Cellosaurus cell lines

13 cell lines: 13 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_2067	HDQ-P1	Cancer cell line	Female
CVCL_A5RY	ARD-EZH2i-R	Cancer cell line	Female
CVCL_A5RZ	ARD-pUTX	Cancer cell line	Female
CVCL_B1V5	Abcam HeLa KDM6A KO	Cancer cell line	Female
CVCL_B8J7	Abcam HCT 116 KDM6A KO	Cancer cell line	Male
CVCL_B8Y1	Abcam MCF-7 KDM6A KO	Cancer cell line	Female
CVCL_B9LI	Abcam A-549 KDM6A KO	Cancer cell line	Male
CVCL_SU48	HAP1 KDM6A (-) 1	Cancer cell line	Male
CVCL_SU49	HAP1 KDM6A (-) 2	Cancer cell line	Male
CVCL_SU50	HAP1 KDM6A (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT04722315	EARLY_PHASE1	COMPLETED	Study of Modified Atkins Diet in Kabuki Syndrome
NCT01314534	Not specified	COMPLETED	French Kabuki Syndrome Network. Epidemiology, Management of Patients and Research by Array-CGH
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03547609	Not specified	COMPLETED	Assessment of Memory in Children With Kabuki Syndrom
NCT03855631	Not specified	COMPLETED	Exploiting Epigenome Editing in Kabuki Syndrome: a New Route Towards Gene Therapy for Rare Genetic Disorders
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD