KMT5B

Summary

KMT5B (lysine methyltransferase 5B, HGNC:24283) is a protein-coding gene on chromosome 11q13.2, encoding Histone-lysine N-methyltransferase KMT5B (Q4FZB7). Histone methyltransferase that specifically methylates monomethylated ‘Lys-20’ (H4K20me1) and dimethylated ‘Lys-20’ (H4K20me2) of histone H4 to produce respectively dimethylated ‘Lys-20’ (H4K20me2) and trimethylated ‘Lys-20’ (H4K20me3) and thus regulates transcription and mainte…. It is a selective cancer dependency (DepMap: 11.7% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein that contains a SET domain. SET domains appear to be protein-protein interaction domains that mediate interactions with a family of proteins that display similarity with dual-specificity phosphatases (dsPTPases). The function of this gene has not been determined. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 51111 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 262 total — 30 pathogenic, 37 likely-pathogenic
• Phenotypes (HPO): 36
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 11.7% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_017635

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24283
Approved symbol	KMT5B
Name	lysine methyltransferase 5B
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Aliases	CGI-85
Ensembl gene	ENSG00000110066
Ensembl biotype	protein_coding
OMIM	610881
Entrez	51111

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 10 protein_coding, 7 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000304363, ENST00000323599, ENST00000401547, ENST00000402185, ENST00000402789, ENST00000405515, ENST00000427752, ENST00000434573, ENST00000441488, ENST00000453170, ENST00000458496, ENST00000466295, ENST00000524672, ENST00000533271, ENST00000615954, ENST00000700520, ENST00000700521, ENST00000700522, ENST00000700523, ENST00000700524, ENST00000700525, ENST00000700526

RefSeq mRNA: 16 — MANE Select: NM_017635 NM_001300907, NM_001300908, NM_001300909, NM_001363566, NM_001369424, NM_001369425, NM_001369426, NM_001369427, NM_001369428, NM_001369429, NM_001369430, NM_001369431, NM_001369432, NM_001369433, NM_016028, NM_017635

CCDS: CCDS31623, CCDS44660, CCDS76444, CCDS86221, CCDS91518, CCDS91519

Canonical transcript exons

ENST00000304363 — 11 exons

Exon	Start	End
ENSE00001265186	68180132	68180200
ENSE00001390157	68189917	68190152
ENSE00001924982	68154863	68159171
ENSE00003465018	68185781	68185928
ENSE00003489280	68166982	68167178
ENSE00003548992	68171543	68171709
ENSE00003567993	68171015	68171151
ENSE00003570269	68175018	68175183
ENSE00003621644	68171232	68171251
ENSE00003653203	68173804	68173913
ENSE00003844893	68213138	68213296

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 96.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.6784 / max 212.7934, expressed in 1795 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120991	9.1109	1743
120990	6.6035	1561
120993	0.8818	567
120992	0.8323	515
120989	0.2500	87

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	96.12	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.66	gold quality
visceral pleura	UBERON:0002401	95.62	gold quality
caput epididymis	UBERON:0004358	95.42	gold quality
sperm	CL:0000019	95.08	gold quality
pylorus	UBERON:0001166	95.02	gold quality
ganglionic eminence	UBERON:0004023	94.67	gold quality
cardia of stomach	UBERON:0001162	94.48	gold quality
ventricular zone	UBERON:0003053	94.44	gold quality
parietal pleura	UBERON:0002400	94.38	gold quality
superior surface of tongue	UBERON:0007371	94.30	gold quality
pleura	UBERON:0000977	93.91	gold quality
esophagus squamous epithelium	UBERON:0006920	93.85	gold quality
bronchial epithelial cell	CL:0002328	93.83	gold quality
mammary duct	UBERON:0001765	93.77	gold quality
corpus epididymis	UBERON:0004359	93.59	gold quality
corpus callosum	UBERON:0002336	93.57	gold quality
hair follicle	UBERON:0002073	93.56	gold quality
bronchus	UBERON:0002185	93.48	gold quality
epithelium of bronchus	UBERON:0002031	93.46	gold quality
nipple	UBERON:0002030	93.32	gold quality
secondary oocyte	CL:0000655	93.31	gold quality
epithelium of mammary gland	UBERON:0003244	93.25	gold quality
tibia	UBERON:0000979	93.22	gold quality
trabecular bone tissue	UBERON:0002483	93.21	gold quality
male germ cell	CL:0000015	93.05	gold quality
renal medulla	UBERON:0000362	93.00	gold quality
trachea	UBERON:0003126	93.00	gold quality
jejunal mucosa	UBERON:0000399	92.77	gold quality
sural nerve	UBERON:0015488	92.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.61

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
EID3	Activation

Upstream regulators (CollecTRI, top): MYC, NCOA2

miRNA regulators (miRDB)

196 targeting KMT5B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-8075	99.97	67.20	962

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 11.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 17)

• The data indicate that Suv4-20 generates nearly ubiquitous dimethylation that facilitates the DNA damage response and selective trimethylation that is involved in heterochromatin formation.[Suv4-20] (PMID:18296440)
• dissect the GRIP1:Suv4-20h1 interaction in vitro and in vivo and examine its potential involvement in hormone-dependent transcriptional regulation by GR (PMID:19074285)
• SUV420H1 and SUV420H2 isoforms have different in their cellular localization and effects on myogenic differentiation (PMID:21206904)
• This study suggests a novel role of FRG1 as epigenetic regulator of muscle differentiation and indicates that Suv4-20h1 has a gene-specific function in myogenesis. (PMID:23720823)
• The crystal structure of SUV420H1 was used to characterize substrate selectivity and product specificity. (PMID:24396869)
• Strong statistical evidence for a causal role of SUV420H1 in autism. (PMID:26235986)
• overexpression of SUV420H1 may result in activation of the ERK signaling pathway (PMID:26586479)
• epsilon-globin expression is regulated by SUV4-20h1. (PMID:26802048)
• Altogether, these results reveal Suv4-20h-mediated histone H4K20 tri-methylation as a critical determinant in the selection of active replication initiation sites in heterochromatin regions of mammalian genomes. (PMID:28778956)
• SUV420H1 is a protein lysine methyltransferase that introduces di- and trimethylation of H4K20 and is frequently mutated in human cancers. Somatic Cancer Mutations in the SUV420H1 Protein Lysine Methyltransferase Modulate Its Catalytic Activity. (PMID:31255706)
• Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich’s ataxia patient cells. (PMID:33028632)
• Epigenetic Regulation by Suv4-20h1 in Cardiopulmonary Progenitor Cells Is Required to Prevent Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease. (PMID:34247492)
• Genome-wide association study identifies susceptibility loci for acute myeloid leukemia. (PMID:34716350)
• Loss-of-function of KMT5B leads to neurodevelopmental disorder and impairs neuronal development and neurogenesis. (PMID:35331928)
• Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice. (PMID:36897941)
• Catalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1. (PMID:37595555)
• Histone methyltransferase SUV420H1/KMT5B contributes to poor prognosis in hepatocellular carcinoma. (PMID:38082550)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kmt5b	ENSDARG00000041081
mus_musculus	Kmt5b	ENSMUSG00000045098
rattus_norvegicus	Kmt5b	ENSRNOG00000016790

Paralogs (1): KMT5C (ENSG00000133247)

Protein

Protein identifiers

Histone-lysine N-methyltransferase KMT5B — Q4FZB7 (reviewed: Q4FZB7)

Alternative names: Lysine N-methyltransferase 5B, Lysine-specific methyltransferase 5B, Suppressor of variegation 4-20 homolog 1, [histone H4]-N-methyl-L-lysine20 N-methyltransferase KMT5B, [histone H4]-lysine20 N-methyltransferase KMT5B

All UniProt accessions (13): Q4FZB7, A0A8V8TPR6, A0A8V8TQA0, A0A8V8TQB9, A0A8V8TQY7, A0A8V8TR96, B5MCB3, B7WNX0, C9J6S5, C9JFG1, C9JP58, F8WFA4, H7BXP2

UniProt curated annotations — full annotation on UniProt →

Function. Histone methyltransferase that specifically methylates monomethylated ‘Lys-20’ (H4K20me1) and dimethylated ‘Lys-20’ (H4K20me2) of histone H4 to produce respectively dimethylated ‘Lys-20’ (H4K20me2) and trimethylated ‘Lys-20’ (H4K20me3) and thus regulates transcription and maintenance of genome integrity. In vitro also methylates unmodified ‘Lys-20’ (H4K20me0) of histone H4 and nucleosomes. H4 ‘Lys-20’ trimethylation represents a specific tag for epigenetic transcriptional repression. Mainly functions in pericentric heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin in these regions. KMT5B is targeted to histone H3 via its interaction with RB1 family proteins (RB1, RBL1 and RBL2). Plays a role in myogenesis by regulating the expression of target genes, such as EID3. Facilitates TP53BP1 foci formation upon DNA damage and proficient non-homologous end-joining (NHEJ)-directed DNA repair by catalyzing the di- and trimethylation of ‘Lys-20’ of histone H4. May play a role in class switch reconbination by catalyzing the di- and trimethylation of ‘Lys-20’ of histone H4.

Subunit / interactions. Homodimer (PubMed:24396869, Ref.14). Interacts with HP1 proteins CBX1, CBX3 and CBX5. Interacts with RB1 family proteins RB1, RBL1 and RBL2. Interacts (via C-terminus) with FRG1.

Subcellular location. Nucleus. Chromosome.

Disease relevance. Intellectual developmental disorder, autosomal dominant 51 (MRD51) [MIM:617788] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by 6,7-Dichloro-N-cyclopentyl-4-(pyridin-4-yl)phthalazin-1-amine (A-196) with an IC(50) of 25 nM. A-196 is competitive with the histone peptide substrate H4K20me1 but non competitive with S-adenosyl-L-methionine.

Induction. Strongly down-regulated in breast cancer cells.

Similarity. Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. Suvar4-20 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q4FZB7-1	1	yes
Q4FZB7-2	2
Q4FZB7-4	3

RefSeq proteins (16): NP_001287836, NP_001287837, NP_001287838, NP_001350495, NP_001356353, NP_001356354, NP_001356355, NP_001356356, NP_001356357, NP_001356358, NP_001356359, NP_001356360, NP_001356361, NP_001356362, NP_057112, NP_060105* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001214	SET_dom	Domain
IPR025790	Suv4-20_animal	Family
IPR039977	Suv4-20/Set9	Family
IPR041938	Hist-Lys_N-MTase_N	Homologous_superfamily
IPR044424	KMT5B_SET	Domain
IPR046341	SET_dom_sf	Homologous_superfamily

Pfam: PF00856

Catalyzed reactions (Rhea), 3 shown:

• L-lysyl(20)-[histone H4] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl(20)-[histone H4] + S-adenosyl-L-homocysteine + H(+) (RHEA:60344)
• N(6)-methyl-L-lysyl(20)-[histone H4] + S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl(20)-[histone H4] + S-adenosyl-L-homocysteine + H(+) (RHEA:60348)
• N(6),N(6)-dimethyl-L-lysyl(20)-[histone H4] + S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl(20)-[histone H4] + S-adenosyl-L-homocysteine + H(+) (RHEA:61992)

UniProt features (78 total): helix 12, compositionally biased region 11, binding site 10, strand 10, sequence conflict 8, mutagenesis site 6, region of interest 5, sequence variant 5, splice variant 4, turn 4, chain 1, domain 1, cross-link 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3S8P	X-RAY DIFFRACTION	1.85
8T68	X-RAY DIFFRACTION	1.9
5CPR	X-RAY DIFFRACTION	2.22
5WBV	X-RAY DIFFRACTION	2.3
8T9F	ELECTRON MICROSCOPY	2.6
7YRD	ELECTRON MICROSCOPY	3.2
8T9H	ELECTRON MICROSCOPY	3.37
8JHG	ELECTRON MICROSCOPY	3.58
8JHF	ELECTRON MICROSCOPY	3.68
7YRG	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q4FZB7-F1	55.49	0.21

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 (10): 98; 203–206; 210; 257; 272–273; 275; 319; 320; 321; 324

Post-translational modifications (1): 555

Mutagenesis-validated functional residues (6):

Position	Phenotype
229	km for h4k20me1rise to 17 um. 8-fold decrease in catalytic efficiency.
229	abolishes histone methyltransferase activity (h4-k20 specific).
251	abolishes histone methyltransferase activity (h4-k20 specific).
264	abolishes histone methyltransferase activity (h4-k20 specific).
281	abolishes histone methyltransferase activity (h4-k20 specific).
311	km for h4k20me1rise to 8.5 um. 3-fold decrease in catalytic efficiency.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

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

MSigDB gene sets: 412 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_B_CELL_ACTIVATION, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GCM_ZNF198, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GCM_PPM1D, PID_REG_GR_PATHWAY, CACCAGC_MIR138

GO Biological Process (7): DNA repair (GO:0006281), muscle organ development (GO:0007517), methylation (GO:0032259), positive regulation of isotype switching (GO:0045830), positive regulation of double-strand break repair via nonhomologous end joining (GO:2001034), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338)

GO Molecular Function (12): chromatin binding (GO:0003682), histone methyltransferase activity (GO:0042054), histone H4K20 methyltransferase activity (GO:0042799), metal ion binding (GO:0046872), histone H4 methyltransferase activity (GO:0140939), histone H4K20me methyltransferase activity (GO:0140941), histone H4K20 monomethyltransferase activity (GO:0140944), S-adenosyl-L-methionine binding (GO:1904047), protein binding (GO:0005515), methyltransferase activity (GO:0008168), protein-lysine N-methyltransferase activity (GO:0016279), transferase activity (GO:0016740)

GO Cellular Component (14): condensed chromosome, centromeric region (GO:0000779), fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), centrosome (GO:0005813), plasma membrane (GO:0005886), cilium (GO:0005929), microtubule cytoskeleton (GO:0015630), ciliary basal body (GO:0036064), cytoplasmic ribonucleoprotein granule (GO:0036464), intercellular bridge (GO:0045171), mitotic spindle (GO:0072686), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Chromatin organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
binding	2
protein methyltransferase activity	2
cation binding	2
histone H4K20 methyltransferase activity	2
nuclear lumen	2
intracellular membraneless organelle	2
microtubule organizing center	2
DNA metabolic process	1
DNA damage response	1
animal organ development	1
muscle structure development	1
metabolic process	1
positive regulation of immunoglobulin production	1
positive regulation of immunoglobulin mediated immune response	1
isotype switching	1
regulation of isotype switching	1
positive regulation of DNA recombination	1
positive regulation of B cell activation	1
positive regulation of developmental process	1
double-strand break repair via nonhomologous end joining	1
positive regulation of double-strand break repair	1
regulation of double-strand break repair via nonhomologous end joining	1
cellular component organization	1
chromatin organization	1
histone modifying activity	1
protein-lysine N-methyltransferase activity	1
histone H4 methyltransferase activity	1
histone methyltransferase activity	1
sulfur compound binding	1
transferase activity, transferring one-carbon groups	1
lysine N-methyltransferase activity	1
catalytic activity	1
chromosome, centromeric region	1
condensed chromosome	1
nucleolus	1
intracellular membrane-bounded organelle	1
centriole	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KMT5B	DNMT3A	Q9Y6K1	912
KMT5B	CSNK2A2	P19784	849
KMT5B	KMT5A	Q9NQR1	842
KMT5B	SUV39H1	O43463	820
KMT5B	DNMT1	P26358	819
KMT5B	SETDB1	Q15047	812
KMT5B	H4C7	Q99525	778
KMT5B	H4C16	P02304	770
KMT5B	CBX1	P23197	728
KMT5B	CBX5	P45973	726
KMT5B	SUV39H2	Q9H5I1	724
KMT5B	PRMT5	O14744	703
KMT5B	SETD2	Q9BYW2	664
KMT5B	ADNP	Q9H2P0	658
KMT5B	CBX3	Q13185	655

IntAct

17 interactions, top by confidence:

A	B	Type	Score
KMT5B	TSPYL2	psi-mi:“MI:0915”(physical association)	0.560
KMT5B	YWHAZ	psi-mi:“MI:0915”(physical association)	0.400
KMT5B	HERC5	psi-mi:“MI:0915”(physical association)	0.400
KMT5B	SMARCD1	psi-mi:“MI:0915”(physical association)	0.370
BRD1	MRPS14	psi-mi:“MI:0914”(association)	0.350
KSR1	DDX39A	psi-mi:“MI:0914”(association)	0.350
KSR1	FBLL1	psi-mi:“MI:0914”(association)	0.350
KSR1		psi-mi:“MI:0914”(association)	0.350
MOB1A	CSTA	psi-mi:“MI:0914”(association)	0.350
KMT5B	CARS1	psi-mi:“MI:0914”(association)	0.350
YWHAQ	KMT5B	psi-mi:“MI:0915”(physical association)	0.000
YWHAG	KMT5B	psi-mi:“MI:0915”(physical association)	0.000
KMT5B	TSPYL2	psi-mi:“MI:0915”(physical association)	0.000
pagA	KMT5B	psi-mi:“MI:0915”(physical association)	0.000
KMT5B		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (41): ESR1 (Biochemical Activity), SUV420H1 (Biochemical Activity), SUV420H1 (Affinity Capture-MS), SUV420H1 (Affinity Capture-MS), SUV420H1 (Synthetic Lethality), TSPYL2 (Two-hybrid), SUV420H1 (Proximity Label-MS), SUV420H1 (Proximity Label-MS), SUV420H1 (Affinity Capture-MS), SUV420H1 (Affinity Capture-MS), SUV420H1 (Affinity Capture-MS), SUV420H1 (Negative Genetic), SUV420H1 (Affinity Capture-MS), MOB1A (Affinity Capture-MS), SUV420H1 (Affinity Capture-RNA)

ESM2 similar proteins: A0JMK9, A0JMT0, A0JMZ1, A1L3I5, A2BIL7, A6QLA6, A8DZJ1, A8PUI7, B0BLU1, B7ZD04, O13024, Q0IHP2, Q12495, Q12830, Q13111, Q1MTN9, Q1W1G1, Q24595, Q2YDJ0, Q32N93, Q3T8J9, Q4FZB7, Q535K8, Q5BKG8, Q5R1T0, Q5R789, Q65Z40, Q68F53, Q6DD45, Q6INS5, Q6NZY4, Q76FK4, Q7Z5K2, Q801E2, Q86BP6, Q8IYH5, Q8K298, Q8RWK8, Q8WML3, Q98TA5

Diamond homologs: A0JMZ4, A8WTV9, P0C2N5, P0C2N6, Q09265, Q0U3A4, Q29RP8, Q2H8D5, Q2TZH4, Q3U8K7, Q4FZB7, Q4I8C9, Q4X1W8, Q5RJX8, Q5U3H2, Q6C519, Q6GP17, Q6Q783, Q86Y97, Q9USK2, Q9W5E0, Q1E9C0, Q0C9E6, Q5AZY3, Q7SBJ9, P0CY36, Q54D67, Q4I5R3, Q4PBL3, Q6CXP5, Q6FX50, Q8IE95

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
FRG1	“down-regulates activity”	KMT5B	binding
KMT5B	“up-regulates quantity by expression”	EID3	“transcriptional regulation”
KMT5B	“down-regulates activity”	H4C1	methylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	37
Uncertain significance	120
Likely benign	45
Benign	6

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065196	NM_017635.5(KMT5B):c.609C>A (p.Tyr203Ter)	Pathogenic
1164062	NM_017635.5(KMT5B):c.833A>T (p.Asn278Ile)	Pathogenic
1164063	NM_017635.5(KMT5B):c.541C>G (p.His181Asp)	Pathogenic
1172593	NM_017635.5(KMT5B):c.234_235del (p.Cys78_Glu79delinsTer)	Pathogenic
1185561	NM_017635.5(KMT5B):c.2393dup (p.Asn798fs)	Pathogenic
1678827	NM_017635.5(KMT5B):c.1166dup (p.Asn389fs)	Pathogenic
1679298	NM_017635.5(KMT5B):c.1530_1534del (p.His512fs)	Pathogenic
1683944	NM_017635.5(KMT5B):c.554_557del (p.Tyr185fs)	Pathogenic
1708391	NM_017635.5(KMT5B):c.1411G>T (p.Glu471Ter)	Pathogenic
1895457	NM_017635.5(KMT5B):c.96dup (p.Gln33fs)	Pathogenic
2539732	NM_017635.5(KMT5B):c.2192del (p.Asn731fs)	Pathogenic
2573668	NM_017635.5(KMT5B):c.2176_2177delinsC (p.Ser726fs)	Pathogenic
2687918	NM_017635.5(KMT5B):c.1823del (p.Gly608fs)	Pathogenic
3377205	NM_017635.5(KMT5B):c.973G>T (p.Glu325Ter)	Pathogenic
3377210	NM_017635.5(KMT5B):c.1298_1301del (p.Asn433fs)	Pathogenic
3535574	NM_017635.5(KMT5B):c.2373T>A (p.Tyr791Ter)	Pathogenic
3764547	NM_017635.5(KMT5B):c.913del (p.Cys305fs)	Pathogenic
446521	NM_017635.5(KMT5B):c.725del (p.Leu242fs)	Pathogenic
446522	NM_017635.5(KMT5B):c.1557_1558del (p.Asn520fs)	Pathogenic
4532162	NM_017635.5(KMT5B):c.1208del (p.Lys403fs)	Pathogenic
4685484	NM_017635.5(KMT5B):c.609C>G (p.Tyr203Ter)	Pathogenic
4685486	NM_017635.5(KMT5B):c.1727del (p.Gly576fs)	Pathogenic
4686118	NM_017635.5(KMT5B):c.290del (p.Thr97fs)	Pathogenic
521728	NM_017635.5(KMT5B):c.658C>T (p.Arg220Ter)	Pathogenic
559640	NM_017635.5(KMT5B):c.255del (p.Ser86fs)	Pathogenic
560605	NM_017635.5(KMT5B):c.219del (p.Ala74fs)	Pathogenic
666575	NM_017635.5(KMT5B):c.856C>T (p.Arg286Ter)	Pathogenic
802695	NM_017635.5(KMT5B):c.668_672del (p.Lys223fs)	Pathogenic
976356	NM_017635.5(KMT5B):c.329C>G (p.Ser110Ter)	Pathogenic
985030	NM_017635.5(KMT5B):c.780_781del (p.Ala261fs)	Pathogenic

SpliceAI

2469 predictions. Top by Δscore:

Variant	Effect	Δscore
11:68166976:A:AC	donor_gain	1.0000
11:68166977:C:CC	donor_gain	1.0000
11:68166977:CTTA:C	donor_gain	1.0000
11:68167174:CCCGT:C	acceptor_gain	1.0000
11:68167175:CCGT:C	acceptor_gain	1.0000
11:68167175:CCGTC:C	acceptor_gain	1.0000
11:68167176:CGT:C	acceptor_gain	1.0000
11:68167176:CGTC:C	acceptor_gain	1.0000
11:68167177:GTC:G	acceptor_loss	1.0000
11:68167178:TC:T	acceptor_loss	1.0000
11:68167179:C:CA	acceptor_loss	1.0000
11:68167179:C:CC	acceptor_gain	1.0000
11:68167180:T:G	acceptor_loss	1.0000
11:68171012:TA:T	donor_loss	1.0000
11:68171013:A:AC	donor_gain	1.0000
11:68171014:C:CC	donor_gain	1.0000
11:68171014:C:CT	donor_loss	1.0000
11:68171014:CCTTT:C	donor_gain	1.0000
11:68171147:ACAAA:A	acceptor_gain	1.0000
11:68171148:CAAA:C	acceptor_gain	1.0000
11:68171148:CAAAC:C	acceptor_gain	1.0000
11:68171149:AAA:A	acceptor_gain	1.0000
11:68171149:AAACT:A	acceptor_loss	1.0000
11:68171150:AA:A	acceptor_gain	1.0000
11:68171152:C:CC	acceptor_gain	1.0000
11:68171153:T:C	acceptor_loss	1.0000
11:68173803:CCA:C	donor_gain	1.0000
11:68173803:CCACT:C	donor_gain	1.0000
11:68175011:AACTT:A	donor_loss	1.0000
11:68175012:ACTTA:A	donor_loss	1.0000

AlphaMissense

5871 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:68157734:A:T	I871N	1.000
11:68157740:A:C	I869S	1.000
11:68157740:A:T	I869N	1.000
11:68157767:A:G	L860S	1.000
11:68157773:A:C	L858W	1.000
11:68157773:A:G	L858S	1.000
11:68158187:A:G	L720P	1.000
11:68158187:A:T	L720H	1.000
11:68158193:A:G	L718S	1.000
11:68158226:A:G	L707S	1.000
11:68167087:G:T	R357S	1.000
11:68167100:T:A	R352S	1.000
11:68167100:T:G	R352S	1.000
11:68167160:A:C	F332L	1.000
11:68167160:A:T	F332L	1.000
11:68167162:A:G	F332L	1.000
11:68171020:G:C	C324W	1.000
11:68171021:C:A	C324F	1.000
11:68171021:C:G	C324S	1.000
11:68171021:C:T	C324Y	1.000
11:68171022:A:G	C324R	1.000
11:68171022:A:T	C324S	1.000
11:68171029:A:C	C321W	1.000
11:68171030:C:A	C321F	1.000
11:68171030:C:G	C321S	1.000
11:68171030:C:T	C321Y	1.000
11:68171031:A:G	C321R	1.000
11:68171031:A:T	C321S	1.000
11:68171035:G:C	C319W	1.000
11:68171036:C:A	C319F	1.000

dbSNP variants (sampled 300 via entrez): RS1000011031 (11:68211383 A>G), RS1000115536 (11:68201111 T>C), RS1000130543 (11:68164595 CAG>C), RS1000130963 (11:68174317 G>C), RS1000162806 (11:68213373 C>A,G,T), RS1000350954 (11:68189037 C>T), RS1000403833 (11:68200709 A>G), RS1000430769 (11:68208485 A>G), RS1000450729 (11:68167293 A>C,T), RS1000464166 (11:68172789 T>A,C), RS1000557227 (11:68172565 G>A), RS1000590558 (11:68176151 C>T), RS1000732993 (11:68207317 G>T), RS1000737376 (11:68166031 G>T), RS1000760663 (11:68210012 T>C)

Disease associations

OMIM: gene MIM:610881 | disease phenotypes: MIM:617788, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	Autosomal dominant
intellectual disability, autosomal dominant 51	Definitive	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 (6): intellectual disability, autosomal dominant 51 (MONDO:0030917), intellectual disability (MONDO:0001071), schizophrenia (MONDO:0005090), autism spectrum disorder (MONDO:0005258), neural tube defect (MONDO:0018075), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (7): Intellectual disability-hypotonia-facial dysmorphism-macrocephaly syndrome (Orphanet:684226), Neural tube defect (Orphanet:3388), Spina bifida and other spinal dysraphisms (Orphanet:823), Rare genetic intellectual disability (Orphanet:183757), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000348	High forehead
HP:0000403	Recurrent otitis media
HP:0000431	Wide nasal bridge
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0001762	Talipes equinovarus
HP:0001833	Long foot
HP:0002028	Chronic diarrhea
HP:0002033	Poor suck
HP:0002119	Ventriculomegaly
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0003593	Infantile onset
HP:0005338	Sparse lateral eyebrow
HP:0007018	Attention deficit hyperactivity disorder
HP:0009765	Low hanging columella
HP:0010511	Long toe
HP:0011968	Feeding difficulties
HP:0012450	Chronic constipation
HP:0012520	Dilation of Virchow-Robin spaces
HP:0012741	Unilateral cryptorchidism
HP:0012810	Wide nasal base

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001848_382	IgG glycosylation	1.000000e-08
GCST001848_598	IgG glycosylation	9.000000e-10
GCST005111_3	Breast cancer in childhood cancer survivors	3.000000e-07
GCST008972_67	Urate levels	5.000000e-29
GCST012020_220	Serum metabolite levels	3.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005193	serum IgG glycosylation measurement
EFO:0004531	urate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009436	Neural Tube Defects	C10.500.680; C16.131.666.680

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2321645 (SINGLE PROTEIN), CHEMBL6066855 (PROTEIN FAMILY)

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)

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
A-196	Inhibition	7.6	pIC50

Binding affinities (BindingDB)

1 measured of 4 human assays (4 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
6,7-Dichloro-N-cyclopentyl-4-(pyridin-4-yl)phthalazin-1-amine	IC50	25 nM

ChEMBL bioactivities

6 potent at pChembl≥5 of 6 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.60	IC50	25	nM	CHEMBL4521971
6.58	EC50	262	nM	CHEMBL4521971
6.23	IC50	590	nM	CHEMBL5653590
5.23	IC50	5900	nM	CHEMBL1288796

PubChem BioAssay actives

7 with measured affinity, of 91 total; 3 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
6,7-dichloro-N-cyclopentyl-4-pyridin-4-ylphthalazin-1-amine	1802688: Scintillation Proximity Assay (SPA) from Article 10.1038/nchembio.2282: “The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity.”	ic50	0.0250	uM
6,7-dichloro-N-cyclopentylquinolin-4-amine	1802688: Scintillation Proximity Assay (SPA) from Article 10.1038/nchembio.2282: “The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity.”	ic50	0.5900	uM
7-chloro-N-cyclopentylquinolin-4-amine	1802688: Scintillation Proximity Assay (SPA) from Article 10.1038/nchembio.2282: “The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity.”	ic50	5.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	8
sodium arsenite	decreases expression, increases expression	4
methylmercuric chloride	decreases expression, increases expression	2
bisphenol A	decreases expression, decreases methylation	2
trichostatin A	affects expression, decreases expression	2
Estradiol	decreases expression, affects cotreatment	2
Formaldehyde	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	increases phosphorylation	1
A-196 compound	affects binding	1
dicrotophos	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
pentanal	decreases expression	1
4-phenylbutyric acid	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases methylation	1
jinfukang	decreases expression	1
NSC 689534	affects binding, increases expression	1
(+)-JQ1 compound	decreases expression	1

ChEMBL screening assays

72 unique, capped per target: 72 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2330199	Binding	Inhibition of SUV420H1 (unknown origin) using histone H4 (1 to 24)K20Me1 as substrate after 1 hr by scintillation proximity assay in presence of [3H]-S-adenosylmethionine	Exploiting an allosteric binding site of PRMT3 yields potent and selective inhibitors. — J Med Chem

Clinical trials (associated diseases)

199 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)
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
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
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1