KMT5C

Summary

KMT5C (lysine methyltransferase 5C, HGNC:28405) is a protein-coding gene on chromosome 19q13.42, encoding Histone-lysine N-methyltransferase KMT5C (Q86Y97). 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….

SUV420H2 and the related enzyme SUV420H1 (MIM 610881) function as histone methyltransferases that specifically trimethylate nucleosomal histone H4 (see MIM 602822) on lysine-20 (K20) (Schotta et al., 2004 [PubMed 15145825]).

Source: NCBI Gene 84787 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 19 total
• Druggable target: yes
• MANE Select transcript: NM_032701

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28405
Approved symbol	KMT5C
Name	lysine methyltransferase 5C
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Aliases	MGC2705
Ensembl gene	ENSG00000133247
Ensembl biotype	protein_coding
OMIM	613198
Entrez	84787

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 14 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000255613, ENST00000402499, ENST00000445196, ENST00000460956, ENST00000464185, ENST00000468951, ENST00000474492, ENST00000498738, ENST00000587442, ENST00000589338, ENST00000592631, ENST00000630497, ENST00000885238, ENST00000885239, ENST00000885240, ENST00000885241, ENST00000885242, ENST00000918566, ENST00000918567, ENST00000918568, ENST00000918569, ENST00000918570, ENST00000918571, ENST00000943506

RefSeq mRNA: 1 — MANE Select: NM_032701 NM_032701

CCDS: CCDS12922

Canonical transcript exons

ENST00000255613 — 9 exons

Exon	Start	End
ENSE00001846483	55339876	55339957
ENSE00003464730	55346213	55346349
ENSE00003476985	55346500	55346687
ENSE00003506447	55343978	55343997
ENSE00003523799	55342215	55342380
ENSE00003638279	55341794	55342046
ENSE00003680354	55342742	55342851
ENSE00003681344	55343680	55343843
ENSE00003846253	55346956	55348121

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 96.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.7989 / max 137.5056, expressed in 1686 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177606	9.7989	1686

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	96.96	gold quality
right uterine tube	UBERON:0001302	95.57	gold quality
kidney epithelium	UBERON:0004819	93.43	gold quality
upper arm skin	UBERON:0004263	92.87	gold quality
nasal cavity epithelium	UBERON:0005384	91.58	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.54	gold quality
cerebellar hemisphere	UBERON:0002245	91.22	gold quality
cerebellar cortex	UBERON:0002129	91.12	gold quality
vena cava	UBERON:0004087	90.86	gold quality
cerebellum	UBERON:0002037	90.29	gold quality
pituitary gland	UBERON:0000007	90.19	gold quality
epithelial cell of pancreas	CL:0000083	90.05	gold quality
body of tongue	UBERON:0011876	89.77	gold quality
adenohypophysis	UBERON:0002196	89.65	gold quality
left ventricle myocardium	UBERON:0006566	88.99	silver quality
parotid gland	UBERON:0001831	88.56	gold quality
lateral nuclear group of thalamus	UBERON:0002736	87.97	gold quality
skin of abdomen	UBERON:0001416	87.68	gold quality
apex of heart	UBERON:0002098	87.57	gold quality
pericardium	UBERON:0002407	87.54	gold quality
cardiac muscle of right atrium	UBERON:0003379	87.41	silver quality
sural nerve	UBERON:0015488	87.05	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.91	gold quality
subthalamic nucleus	UBERON:0001906	86.86	gold quality
dorsal plus ventral thalamus	UBERON:0001897	86.81	gold quality
pons	UBERON:0000988	86.68	gold quality
tongue	UBERON:0001723	86.65	gold quality
spinal cord	UBERON:0002240	86.55	gold quality
inferior vagus X ganglion	UBERON:0005363	86.50	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	86.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.70

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB, RELA

miRNA regulators (miRDB)

53 targeting KMT5C, 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-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-3163	100.00	77.23	8605
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-6871-3P	99.43	68.85	741
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662

Literature-anchored findings (GeneRIF, showing 18)

• The decrease in trimethylation of lysine 20 of histone H4 in breast cancer cells was accompanied by diminished expression of Suv4-20h2 histone methyltransferase. (PMID:16322686)
• occurrence of an unusual TG 3’ splice site in intron 5 (PMID:17672918)
• 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)
• SUV420H1 and SUV420H2 isoforms have different in their cellular localization and effects on myogenic differentiation (PMID:21206904)
• data indicate that H4K20me3 invokes gene repression by antagonizing hMOF-mediated H4K16Ac (PMID:21321083)
• The crystal structure of SUV420H2 was used to characterize substrate selectivity and product specificity. (PMID:24396869)
• One of the most downregulated genes in response to SUV420H2 expression was the Src substrate, tensin-3, a focal adhesion protein that contributes to cancer cell migration. (PMID:25814362)
• Upregulation of long non-coding RNA PAPAS in response to hypoosmotic stress does not increase H4K20me3 because of Nedd4-dependent ubiquitinylation and proteasomal degradation of Suv4-20h2. (PMID:26904956)
• The sequences surrounding both methylation sites do not fit to the specificity profile of SUV4-20H1. (PMID:27105552)
• Study provides evidence that Suv420h2 controls the H4K20 methylome of osteoblasts and is critical for normal progression of osteoblastogenesis. (PMID:27862226)
• 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)
• The analysis of human pancreatic cancer biopsies was concordant with these findings, because high levels of SUV420H2 correlated with a loss of epithelial characteristics in progressively invasive cancer. Together, these data indicate that SUV420H2 is an upstream epigenetic regulator of epithelial/mesenchymal state control. (PMID:29229751)
• H4K20me3 methyltransferase SUV420H2 shapes the chromatin landscape of pluripotent embryonic stem cells. (PMID:33144397)
• Loss of KMT5C Promotes EGFR Inhibitor Resistance in NSCLC via LINC01510-Mediated Upregulation of MET. (PMID:35404406)
• Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression. (PMID:36402192)
• Epigenetic regulation of DHRS2 by SUV420H2 inhibits cell apoptosis in renal cell carcinoma. (PMID:37119764)
• Lysine methyltransferase 5C increases the proliferation and metastatic abilities of clear cell renal cell carcinoma via aerobic glycolysis. (PMID:38426605)
• Impact of Histone Lysine Methyltransferase SUV4-20H2 on Cancer Onset and Progression with Therapeutic Potential. (PMID:38473745)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kmt5c	ENSDARG00000075461
mus_musculus	Kmt5c	ENSMUSG00000059851
rattus_norvegicus	Kmt5c	ENSRNOG00000017508

Paralogs (1): KMT5B (ENSG00000110066)

Protein

Protein identifiers

Histone-lysine N-methyltransferase KMT5C — Q86Y97 (reviewed: Q86Y97)

Alternative names: Lysine N-methyltransferase 5C, Lysine-specific methyltransferase 5C, Suppressor of variegation 4-20 homolog 2, [histone H4]-N-methyl-L-lysine20 N-methyltransferase KMT5B, [histone H4]-lysine20 N-methyltransferase KMT5B

All UniProt accessions (2): A0A0D9SF94, Q86Y97

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. KMT5C is targeted to histone H3 via its interaction with RB1 family proteins (RB1, RBL1 and RBL2). 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. Interacts with HP1 proteins CBX1, CBX3 and CBX5. Interacts with RB1 family proteins RB1, RBL1 and RBL2.

Subcellular location. Nucleus. Chromosome.

Activity regulation. Inhibited by 6,7-Dichloro-N-cyclopentyl-4-(pyridin-4-yl)phthalazin-1-amine (A-196) with an IC(50) of 144 nM.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q86Y97-1	1	yes
Q86Y97-2	2

RefSeq proteins (1): NP_116090* (*=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
IPR044425	KMT5C_SET	Domain
IPR046341	SET_dom_sf	Homologous_superfamily

Pfam: PF00856

Enzyme classification (BRENDA):

• EC 2.1.1.361 — [histone H4]-lysine20 N-methyltransferase (BRENDA: 4 organisms, 17 substrates, 2 inhibitors, 0 Km, 0 kcat entries)

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 (42 total): binding site 11, helix 10, strand 8, turn 4, modified residue 2, splice variant 2, region of interest 2, chain 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3RQ4	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86Y97-F1	68.36	0.39

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 (11): 182–183; 185; 229; 230; 231; 234; 32; 114–117; 121; 160; 169

Post-translational modifications (2): 416, 422

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: 181 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_B_CELL_ACTIVATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, PEREZ_TP63_TARGETS, AAGCCAT_MIR135A_MIR135B, GOBP_POSITIVE_REGULATION_OF_B_CELL_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_REGULATION_OF_IMMUNOGLOBULIN_PRODUCTION

GO Biological Process (6): DNA repair (GO:0006281), 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 (11): chromatin binding (GO:0003682), histone binding (GO:0042393), 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), transferase activity (GO:0016740)

GO Cellular Component (6): condensed chromosome, centromeric region (GO:0000779), heterochromatin (GO:0000792), nucleus (GO:0005634), nucleoplasm (GO:0005654), pericentric heterochromatin (GO:0005721), 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
binding	2
cation binding	2
histone H4K20 methyltransferase activity	2
chromosome, centromeric region	2
DNA metabolic process	1
DNA damage response	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
protein binding	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
catalytic activity	1
condensed chromosome	1
chromatin	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
heterochromatin	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

776 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KMT5C	SUV39H1	O43463	817
KMT5C	DNMT1	P26358	813
KMT5C	KMT5A	Q9NQR1	811
KMT5C	SETDB1	Q15047	809
KMT5C	H4C7	Q99525	785
KMT5C	H4C16	P02304	779
KMT5C	BRSK1	Q8TDC3	775
KMT5C	CBX5	P45973	746
KMT5C	CBX1	P23197	731
KMT5C	SUV39H2	Q9H5I1	726
KMT5C	EHMT2	Q96KQ7	719
KMT5C	CBX3	Q13185	700
KMT5C	DNMT3A	Q9Y6K1	668
KMT5C	MECP2	P51608	643
KMT5C	DNMT3B	Q9UBC3	638

IntAct

14 interactions, top by confidence:

A	B	Type	Score
CBX3	KMT5C	psi-mi:“MI:0915”(physical association)	0.660
CBX3	KMT5C	psi-mi:“MI:0407”(direct interaction)	0.660
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
KMT5C	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
CBX5	KMT5C	psi-mi:“MI:0915”(physical association)	0.400
KMT5C	CBX1	psi-mi:“MI:0915”(physical association)	0.400
KMT5C	CBX4	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
PIPSL	C1orf226	psi-mi:“MI:0914”(association)	0.350
FTL	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
FTL		psi-mi:“MI:0914”(association)	0.350
HTR7	WBP4	psi-mi:“MI:0914”(association)	0.350
NSUN2	RPSA2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (48): PSTPIP1 (Affinity Capture-RNA), NEDD4 (Affinity Capture-Western), SUV420H2 (Affinity Capture-MS), SPRR1B (Affinity Capture-MS), NONO (Affinity Capture-MS), FAM76B (Affinity Capture-MS), RPL23A (Affinity Capture-MS), SAP30BP (Affinity Capture-MS), SUV420H2 (Affinity Capture-MS), CBX3 (Affinity Capture-MS), POC1B (Affinity Capture-MS), MEPCE (Affinity Capture-MS), WDR82 (Affinity Capture-MS), FAM76A (Affinity Capture-MS), TOP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RR11, A0A0U1RRI6, A6NCS6, A6NJG2, B0BN44, D3YXK1, E9PY61, E9Q0B3, F5H4A9, O00220, O00221, P09038, P0DPI3, P22083, P98077, Q08AU9, Q2M2W7, Q2M3V2, Q2TBI2, Q5F267, Q5FW56, Q5IS69, Q5R866, Q5T4W7, Q5TM52, Q5U4P2, Q5VTJ3, Q659K9, Q673H1, Q69ZB3, Q6AYE8, Q6IPT2, Q6PJ61, Q7RTU4, Q7TSX9, Q7YR31, Q80SU3, Q86SH2, Q86Y97, Q8NBR0

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, Q8IE95

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
KMT5C	“down-regulates activity”	H4C1	methylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1765 predictions. Top by Δscore:

Variant	Effect	Δscore
19:55339946:G:GT	donor_gain	1.0000
19:55339954:GCGG:G	donor_gain	1.0000
19:55342042:GTCAG:G	donor_gain	1.0000
19:55342044:CAG:C	donor_loss	1.0000
19:55342045:AGG:A	donor_loss	1.0000
19:55342046:GGTGA:G	donor_loss	1.0000
19:55342047:G:GA	donor_loss	1.0000
19:55342047:G:GC	donor_loss	1.0000
19:55342381:G:GG	donor_gain	1.0000
19:55343960:T:TA	acceptor_gain	1.0000
19:55343966:A:AG	acceptor_gain	1.0000
19:55343967:A:G	acceptor_gain	1.0000
19:55346211:AGTTT:A	acceptor_gain	1.0000
19:55346212:GTTT:G	acceptor_gain	1.0000
19:55346212:GTTTG:G	acceptor_gain	1.0000
19:55346323:GCACT:G	donor_gain	1.0000
19:55346347:GAG:G	donor_gain	1.0000
19:55346465:ACCC:A	acceptor_gain	1.0000
19:55346465:ACCCG:A	acceptor_gain	1.0000
19:55346486:ACCC:A	acceptor_gain	1.0000
19:55346489:C:A	acceptor_gain	1.0000
19:55346685:GCG:G	donor_gain	1.0000
19:55339897:G:GT	donor_gain	0.9900
19:55339907:G:GT	donor_gain	0.9900
19:55339940:G:GT	donor_gain	0.9900
19:55339943:G:GT	donor_gain	0.9900
19:55339955:CGGGT:C	donor_loss	0.9900
19:55339956:GGGT:G	donor_loss	0.9900
19:55339959:T:A	donor_loss	0.9900
19:55341789:TGCAG:T	acceptor_loss	0.9900

AlphaMissense

2924 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:55343771:T:C	F160L	1.000
19:55343773:C:A	F160L	1.000
19:55343773:C:G	F160L	1.000
19:55343839:C:A	N182K	1.000
19:55343839:C:G	N182K	1.000
19:55343840:C:G	H183D	1.000
19:55343842:T:A	H183Q	1.000
19:55343842:T:G	H183Q	1.000
19:55343994:C:G	C189W	1.000
19:55346303:T:C	F221L	1.000
19:55346305:C:A	F221L	1.000
19:55346305:C:G	F221L	1.000
19:55346306:T:C	F222L	1.000
19:55346308:C:A	F222L	1.000
19:55346308:C:G	F222L	1.000
19:55342021:T:C	F29L	0.999
19:55342023:C:A	F29L	0.999
19:55342023:C:G	F29L	0.999
19:55342035:G:C	K33N	0.999
19:55342035:G:T	K33N	0.999
19:55342797:G:A	C111Y	0.999
19:55342798:C:G	C111W	0.999
19:55342805:T:C	Y114H	0.999
19:55342827:C:A	A121D	0.999
19:55343774:A:C	S161R	0.999
19:55343775:G:A	S161N	0.999
19:55343776:C:A	S161R	0.999
19:55343776:C:G	S161R	0.999
19:55343813:T:A	W174R	0.999
19:55343813:T:C	W174R	0.999

dbSNP variants (sampled 300 via entrez): RS1000074924 (19:55345754 C>G,T), RS1000162168 (19:55338625 G>C), RS1000236246 (19:55338917 GAAAC>G), RS1000334378 (19:55347643 A>C), RS1000341786 (19:55339258 T>C), RS1000394691 (19:55343893 C>A), RS1000700230 (19:55347538 G>A), RS1000955666 (19:55346549 C>T), RS1001622137 (19:55348485 GGA>G), RS1001649064 (19:55344636 G>A), RS1001878662 (19:55339959 T>G), RS1002024787 (19:55348609 T>A,C), RS1002111972 (19:55338418 G>C), RS1002164863 (19:55339529 C>A,T), RS1002484058 (19:55337894 G>A,C)

Disease associations

OMIM: gene MIM:613198 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000401_6	Menopause (age at onset)	6.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2321644 (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	6.84	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

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

pChembl	Type	Value	Unit	Molecule
6.84	IC50	144	nM	CHEMBL4521971
6.58	EC50	262	nM	CHEMBL4521971
5.92	IC50	1200	nM	CHEMBL5653590
5.32	IC50	4800	nM	CHEMBL1288796
5.00	IC50	1e+04	nM	S-ADENOSYLHOMOCYSTEINE

PubChem BioAssay actives

8 with measured affinity, of 83 total; 4 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	0.1440	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	1.2000	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	4.8000	uM
(2S)-2-amino-4-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]butanoic acid	1192335: Inhibition of SUV420H2 (unknown origin) by HMT assay	ic50	10.0000	uM

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases expression, affects expression, increases abundance	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
Estradiol	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
sulforaphane	decreases expression	1
CGP 52608	affects binding, increases reaction	1
(+)-JQ1 compound	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Cisplatin	increases expression	1
Ozone	increases abundance, affects expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1

ChEMBL screening assays

65 unique, capped per target: 65 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2330198	Binding	Inhibition of SUV420H2 (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)

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