H4C3

Summary

H4C3 (H4 clustered histone 3, HGNC:4787) is a protein-coding gene on chromosome 6p22.2, encoding Histone H4 (P62805). Core component of nucleosome.

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H4 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6.

Source: NCBI Gene 8364 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Tessadori-van Haaften neurodevelopmental syndrome 1 (Strong, GenCC)
• GWAS associations: 34
• Clinical variants (ClinVar): 57 total — 4 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 39
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003542

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4787
Approved symbol	H4C3
Name	H4 clustered histone 3
Location	6p22.2
Locus type	gene with protein product
Status	Approved
Aliases	H4/g, dJ221C16.1
Ensembl gene	ENSG00000197061
Ensembl biotype	protein_coding
OMIM	602827
Entrez	8364

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000377803

RefSeq mRNA: 1 — MANE Select: NM_003542 NM_003542

CCDS: CCDS4583

Canonical transcript exons

ENST00000377803 — 1 exons

Exon	Start	End
ENSE00001475159	26103933	26104337

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 99.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1455.1963 / max 27559.0242, expressed in 1822 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66475	1455.1963	1822

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.59	silver quality
trabecular bone tissue	UBERON:0002483	99.40	silver quality
cervix squamous epithelium	UBERON:0006922	99.38	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	99.05	gold quality
esophagus squamous epithelium	UBERON:0006920	98.80	silver quality
bone marrow cell	CL:0002092	98.61	gold quality
parotid gland	UBERON:0001831	98.61	silver quality
adrenal tissue	UBERON:0018303	98.41	gold quality
squamous epithelium	UBERON:0006914	97.92	silver quality
periodontal ligament	UBERON:0008266	97.89	silver quality
seminal vesicle	UBERON:0000998	97.71	silver quality
gingival epithelium	UBERON:0001949	97.25	silver quality
cerebellar vermis	UBERON:0004720	97.24	gold quality
pigmented layer of retina	UBERON:0001782	97.18	silver quality
blood vessel layer	UBERON:0004797	97.16	silver quality
Brodmann (1909) area 23	UBERON:0013554	96.90	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.82	gold quality
parietal pleura	UBERON:0002400	96.80	silver quality
lateral nuclear group of thalamus	UBERON:0002736	96.68	gold quality
colonic epithelium	UBERON:0000397	96.56	gold quality
epithelium of esophagus	UBERON:0001976	96.45	silver quality
lateral globus pallidus	UBERON:0002476	96.28	silver quality
renal medulla	UBERON:0000362	96.26	silver quality
middle temporal gyrus	UBERON:0002771	96.18	silver quality
palpebral conjunctiva	UBERON:0001812	96.03	silver quality
paraflocculus	UBERON:0005351	95.95	gold quality
visceral pleura	UBERON:0002401	95.92	silver quality
pleura	UBERON:0000977	95.84	silver quality
calcaneal tendon	UBERON:0003701	95.64	gold quality
gingiva	UBERON:0001828	95.63	silver quality

Single-cell (SCXA)

Detected in 53 experiment(s), a significant marker in 44.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	20034.96
E-CURD-79	yes	12095.96
E-MTAB-9435	yes	10380.22
E-MTAB-10432	yes	9996.65
E-MTAB-6505	yes	9047.94
E-MTAB-6911	yes	7881.16
E-MTAB-8271	yes	7763.42
E-MTAB-10662	yes	7396.12
E-CURD-112	yes	7249.12
E-HCAD-6	yes	6321.78
E-MTAB-8894	yes	5213.78
E-HCAD-23	yes	3950.53
E-MTAB-8495	yes	3610.51
E-GEOD-124263	yes	3446.88
E-CURD-114	yes	3388.95

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• Germline mutations affecting the histone H4 core cause a developmental syndrome by altering DNA damage response and cell cycle control. (PMID:28920961)

Cross-species orthologs

0 orthologs

Paralogs (14): H4C8 (ENSG00000158406), H4C11 (ENSG00000197238), H4C16 (ENSG00000197837), H4C15 (ENSG00000270276), H4C14 (ENSG00000270882), H4C12 (ENSG00000273542), H4C6 (ENSG00000274618), H4C13 (ENSG00000275126), H4C7 (ENSG00000275663), H4C9 (ENSG00000276180), H4C5 (ENSG00000276966), H4C4 (ENSG00000277157), H4C1 (ENSG00000278637), H4C2 (ENSG00000278705)

Protein

Protein identifiers

Histone H4 — P62805 (reviewed: P62805)

All UniProt accessions (2): B2R4R0, P62805

UniProt curated annotations — full annotation on UniProt →

Function. Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.

Subunit / interactions. The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Found in a co-chaperone complex with DNJC9, MCM2 and histone H3.3-H4 dimers. Within the complex, interacts with DNJC9 (via C-terminus); the interaction is direct. Interacts with NASP; NASP is a histone chaperone that stabilizes and maintains a soluble pool of Histone H3-H4 dimers.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Acetylation at Lys-6 (H4K5ac), Lys-9 (H4K8ac), Lys-13 (H4K12ac) and Lys-17 (H4K16ac) occurs in coding regions of the genome but not in heterochromatin. Acetylated as part of spermatogenesis progression prior to histone-to-protamine exchange. Citrullination at Arg-4 (H4R3ci) by PADI4 impairs methylation. Monomethylation and asymmetric dimethylation at Arg-4 (H4R3me1 and H4R3me2a, respectively) by PRMT1 favors acetylation at Lys-9 (H4K8ac) and Lys-13 (H4K12ac). Demethylation is performed by JMJD6. Symmetric dimethylation on Arg-4 (H4R3me2s) by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage. Monomethylated, dimethylated or trimethylated at Lys-21 (H4K20me1, H4K20me2, H4K20me3). Monomethylation is performed by KMT5A/SET8. Dimethylation and trimethylation is performed by KMT5B and KMT5C and induces gene silencing. Monomethylated at Lys-13 (H4K12me1) by N6AMT1; H4K12me1 modification is present at the promoters of numerous genes encoding cell cycle regulators. H4K20me2 and H4K20me3 are demethylated into monomethyl (H4K20me1) by RSBN1. H4K20me1, H4K20me2 and H4K20me3 are demethylated by RAD23A and RAD23B. H4K20me1 is demethylated by PHF8. Acetyl-methylated at Lys-6 and Lys-13 (H4K5acme and H4K12acme, respectively), acetyl-methylation is an epigenetic mark of active chromatin associated with increased transcriptional initiation. Acetyl-methylation is formed by acetylation by EP300/p300 of lysine residues that are already monomethylated on the same side chain. H4K5acme and H4K12acme marks specifically bind BRD2. Phosphorylated by PAK2 at Ser-48 (H4S47ph). This phosphorylation increases the association of H3.3-H4 with the histone chaperone HIRA, thus promoting nucleosome assembly of H3.3-H4 and inhibiting nucleosome assembly of H3.1-H4. Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins. Monoubiquitinated at Lys-92 of histone H4 (H4K91ub1) in response to DNA damage. The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 Lys-21 methylation (H4K20me). Ubiquitinated; by PHF7. Ufmylated; monofmylated by UFL1 at Lys-32 (H4K31Ufm1) in response to DNA damage. Sumoylated, which is associated with transcriptional repression. Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes. Butyrylation of histones marks active promoters and competes with histone acetylation. Glutarylation at Lys-92 (H4K91glu) destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes. Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription. Delactylated by SIRT3 at Lys-17 (H4K16la).

Disease relevance. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 1 (TEBIVANED1) [MIM:619758] An autosomal dominant disorder with onset in infancy, characterized by poor overall growth, microcephaly, hypotonia, profound global developmental delay, impaired intellectual development, poor or absent speech, and characteristic dysmorphic facial features, including hypertelorism and abnormal nose. Other variable neurologic and systemic features may also occur. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED1 is caused by variants in H4C3. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 2 (TEBIVANED2) [MIM:619759] An autosomal dominant disorder characterized by poor overall growth, microcephaly, hypotonia, profound global developmental delay, impaired intellectual development, absent speech, and characteristic dysmorphic facial features, including hypertelorism, abnormal nose, and wide mouth. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED2 is caused by variants in H4C11. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 3 (TEBIVANED3) [MIM:619950] An autosomal dominant disorder characterized by global developmental delay with poor overall growth, impaired intellectual development, and speech difficulties. More variable features include hypotonia, microcephaly, and dysmorphic facies. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED3 is caused by variants in H4C5. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 4 (TEBIVANED4) [MIM:619951] An autosomal dominant disorder characterized by global developmental delay with poor overall growth, variably impaired intellectual development, learning difficulties, distal skeletal anomalies, and dysmorphic facies. Some patients have visual or hearing deficits. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED4 is caused by variants in H4C9. Chromosomal aberrations involving HISTONE H4 is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;6)(q27;p21), with BCL6.

Similarity. Belongs to the histone H4 family.

RefSeq proteins (1): NP_003533* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001951	Histone_H4	Family
IPR004823	TAF_TATA-bd_Histone-like_dom	Domain
IPR009072	Histone-fold	Homologous_superfamily
IPR019809	Histone_H4_CS	Conserved_site
IPR035425	CENP-T/H4_C	Domain

Pfam: PF15511

UniProt features (138 total): modified residue 94, sequence variant 17, cross-link 8, strand 4, helix 4, mutagenesis site 2, sequence conflict 2, turn 2, initiator methionine 1, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

626 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3F9X	X-RAY DIFFRACTION	1.25
8PEF	X-RAY DIFFRACTION	1.28
5TEG	X-RAY DIFFRACTION	1.3
3UVW	X-RAY DIFFRACTION	1.37
8UK5	X-RAY DIFFRACTION	1.4
1ZKK	X-RAY DIFFRACTION	1.45
4YY6	X-RAY DIFFRACTION	1.45
3F9Y	X-RAY DIFFRACTION	1.5
3QZT	X-RAY DIFFRACTION	1.5
4YYI	X-RAY DIFFRACTION	1.5
4YYM	X-RAY DIFFRACTION	1.5
5FFW	X-RAY DIFFRACTION	1.5
2BQZ	X-RAY DIFFRACTION	1.5
4YYD	X-RAY DIFFRACTION	1.52
8B5C	X-RAY DIFFRACTION	1.58
6RXS	X-RAY DIFFRACTION	1.6
3F9W	X-RAY DIFFRACTION	1.6
3F9Z	X-RAY DIFFRACTION	1.6
6VO5	X-RAY DIFFRACTION	1.6
7M98	X-RAY DIFFRACTION	1.6
2IG0	X-RAY DIFFRACTION	1.7
3O36	X-RAY DIFFRACTION	1.7
4QUT	X-RAY DIFFRACTION	1.7
5YE3	X-RAY DIFFRACTION	1.7
4YYH	X-RAY DIFFRACTION	1.74
8TGP	X-RAY DIFFRACTION	1.76
4YYK	X-RAY DIFFRACTION	1.79
5YE4	X-RAY DIFFRACTION	1.8
3QZS	X-RAY DIFFRACTION	1.8
4QUU	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62805-F1	90.90	0.75

Antibody-complex structures (SAbDab): 21 — 5YE3, 5YE4, 6E0C, 6E0P, 7K5X, 7K5Y, 7K60, 7K61, 7K63, 7U0G, 7U0I, 7U0J, 8DK5, 8EVG, 8EVH, 8EVI, 8EVJ, 8SPS, 8SPU, 8SYP, 8VFX

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (102): 4, 21, 32, 32, 60, 80, 92, 92, 6, 6, 6, 6, 6, 6, 6, 6, 9, 9, 9, 9 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
13	impaired methylation by n6amt1.
32	abolished ufmylation.

Function

Pathways and Gene Ontology

Reactome pathways

60 pathways

ID	Pathway
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine
R-HSA-110329	Cleavage of the damaged pyrimidine
R-HSA-110330	Recognition and association of DNA glycosylase with site containing an affected purine
R-HSA-110331	Cleavage of the damaged purine
R-HSA-1221632	Meiotic synapsis
R-HSA-171306	Packaging Of Telomere Ends
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-212300	PRC2 methylates histones and DNA
R-HSA-2299718	Condensation of Prophase Chromosomes
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-3214815	HDACs deacetylate histones
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-3214842	HDMs demethylate histones
R-HSA-3214847	HATs acetylate histones
R-HSA-3214858	RMTs methylate histone arginines
R-HSA-427359	SIRT1 negatively regulates rRNA expression
R-HSA-427389	ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression
R-HSA-427413	NoRC negatively regulates rRNA expression
R-HSA-4551638	SUMOylation of chromatin organization proteins
R-HSA-5250924	B-WICH complex positively regulates rRNA expression
R-HSA-5334118	DNA methylation
R-HSA-5578749	Transcriptional regulation by small RNAs
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-5625886	Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693607	Processing of DNA double-strand break ends

MSigDB gene sets: 482 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, MODULE_52, MULLIGHAN_NPM1_SIGNATURE_3_UP, HORIUCHI_WTAP_TARGETS_DN, JI_RESPONSE_TO_FSH_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_MEIOTIC_SYNAPSIS, RORA1_01, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_TELOMERE_ORGANIZATION

GO Biological Process (5): chromatin organization (GO:0006325), nucleosome assembly (GO:0006334), telomere organization (GO:0032200), negative regulation of megakaryocyte differentiation (GO:0045653), protein localization to CENP-A containing chromatin (GO:0061644)

GO Molecular Function (5): DNA binding (GO:0003677), RNA binding (GO:0003723), structural constituent of chromatin (GO:0030527), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (10): chromosome, telomeric region (GO:0000781), nucleosome (GO:0000786), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), membrane (GO:0016020), protein-containing complex (GO:0032991), CENP-A containing nucleosome (GO:0043505), extracellular exosome (GO:0070062), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Chromatin modifying enzymes	5
Cellular Senescence	3
Depyrimidination	2
Depurination	2
Meiosis	1
Telomere Maintenance	1
Pre-NOTCH Expression and Processing	1
TCF dependent signaling in response to WNT	1
Epigenetic regulation of gene expression	1
Mitotic Prophase	1
Negative epigenetic regulation of rRNA expression	1
Positive epigenetic regulation of rRNA expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
nucleic acid binding	2
chromatin	2
cellular component organization	1
chromatin organization	1
nucleosome organization	1
protein-DNA complex assembly	1
chromosome organization	1
megakaryocyte differentiation	1
negative regulation of myeloid cell differentiation	1
regulation of megakaryocyte differentiation	1
protein localization to chromatin	1
protein localization to chromosome, centromeric region	1
structural molecule activity	1
protein dimerization activity	1
binding	1
chromosomal region	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular_component	1
nucleosome	1
CENP-A containing chromatin	1
extracellular vesicle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

672 interactions, top by confidence:

A	B	Type	Score
ASF1A	H4C16	psi-mi:“MI:0915”(physical association)	0.950
H4C16	ASF1A	psi-mi:“MI:0915”(physical association)	0.950
ASF1A	H4C16	psi-mi:“MI:0914”(association)	0.950
H3C1	H4C16	psi-mi:“MI:0915”(physical association)	0.890
H4C16	H3C1	psi-mi:“MI:0407”(direct interaction)	0.890
ASF1A	MCM2	psi-mi:“MI:0915”(physical association)	0.890
ASF1A	MCM2	psi-mi:“MI:0914”(association)	0.890
TP53BP1	H4C16	psi-mi:“MI:0407”(direct interaction)	0.870
H3-3A	H4C16	psi-mi:“MI:0915”(physical association)	0.860
H3-3A	H4C16	psi-mi:“MI:0914”(association)	0.860
H3-3A	H4C16	psi-mi:“MI:0407”(direct interaction)	0.860
H2AC4	H2BC11	psi-mi:“MI:0915”(physical association)	0.850

BioGRID (3544): RBBP4 (Affinity Capture-Western), HIST1H4A (Affinity Capture-Western), HIST4H4 (Biochemical Activity), HIST4H4 (Affinity Capture-MS), HIST2H4B (Affinity Capture-MS), HIST4H4 (Two-hybrid), ASF1A (Two-hybrid), HIST4H4 (Biochemical Activity), HIST4H4 (Biochemical Activity), HIST1H4I (Affinity Capture-RNA), HIST1H4E (Affinity Capture-RNA), HIST1H4I (Affinity Capture-RNA), HIST1H4E (Affinity Capture-RNA), HIST1H4E (Affinity Capture-RNA), HIST1H4A (Biochemical Activity)

ESM2 similar proteins: P02309, P08436, P09322, P0CG89, P23750, P23751, P27996, P35057, P35059, P50566, P59259, P62785, P62786, P62787, P62788, P62794, P62797, P62798, P62799, P62800, P62801, P62802, P62803, P62805, P62806, P62887, Q27443, Q27765, Q43083, Q4R362, Q5RCS7, Q6LAF1, Q6LAF3, Q6PMI5, Q6V9I2, Q6WV72, Q6WV73, Q6WV90, Q6WZ83, Q71V09

Diamond homologs: P02309, P04914, P04915, P08436, P09322, P0CG89, P23750, P23751, P27996, P35057, P35059, P50566, P59259, P62776, P62777, P62778, P62779, P62780, P62781, P62782, P62783, P62784, P62785, P62786, P62787, P62788, P62790, P62791, P62792, P62793, P62794, P62795, P62796, P62797, P62798, P62799, P62800, P62801, P62802, P62803

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
TP53BP1	unknown	H4C1	binding
MAML1	“down-regulates activity”	H4C1	acetylation
“Integrator complex”	“down-regulates quantity by repression”	H4C1	“transcriptional regulation”
KAT5	“down-regulates activity”	H4C1	acetylation
H4C1	“up-regulates activity”	BRD2	relocalization
H4C1	“up-regulates activity”	BRD4	relocalization
H4C1	“up-regulates activity”	BRDT	relocalization
H4C1	“form complex”	“Nucleosome_H3.3 variant”	binding
“MSL acetyltransferase”	“down-regulates activity”	H4C1	acetylation
UFL1	“up-regulates activity”	H4C1	ubiquitination
SLBP	“up-regulates quantity by expression”	H4C1	“translation regulation”
“NSL histone acetyltransferase”	“down-regulates activity”	H4C1	acetylation
“NuA4 complex”	“down-regulates activity”	H4C1	acetylation
DTX3L	“down-regulates activity”	H4C1	monoubiquitination
“BRCA1-BARD1 complex”	“up-regulates activity”	H4C1	ubiquitination
H4C1	“form complex”	“CENP-A nucleosome”	binding
H4C1	“form complex”	“Nucleosome_H2A.Z.2 variant”	binding
H4C1	“form complex”	“Nucleosome_H2A.Z.1 variant”	binding
H4C1	“form complex”	“Nucleosome_H3.1 variant”	binding
H4C1	“form complex”	“Nucleosome_H3.1t variant”	binding
HAT1	“down-regulates activity”	H4C1	acetylation
H4C1	“form complex”	Nucleosome	binding
KMT5C	“down-regulates activity”	H4C1	methylation
KMT5B	“down-regulates activity”	H4C1	methylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	5	40.5×	1e-06
Notch-HLH transcription pathway	6	29.5×	6e-07
NOTCH1 Intracellular Domain Regulates Transcription	8	22.9×	3e-08
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	12	22.0×	3e-11
Packaging Of Telomere Ends	8	21.2×	7e-08
FXIIa activates plasma kallikrein-kinin system	10	20.9×	2e-09
Condensation of Prophase Chromosomes	11	20.7×	3e-10
NuRD complex assembly	12	20.4×	7e-11

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of gene expression, epigenetic	6	25.3×	2e-05
nucleosome assembly	16	23.6×	5e-15
heterochromatin formation	8	21.5×	1e-06
epigenetic regulation of gene expression	5	20.2×	3e-04
chromatin organization	12	12.5×	9e-08
antimicrobial humoral immune response mediated by antimicrobial peptide	5	8.5×	1e-02
chromatin remodeling	11	8.4×	1e-05
DNA damage response	10	5.6×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	5
Uncertain significance	36
Likely benign	6
Benign	6

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1699322	NM_003542.4(H4C3):c.274A>G (p.Lys92Glu)	Pathogenic
2443367	NM_003542.4(H4C3):c.98C>T (p.Pro33Leu)	Pathogenic
3572931	NM_003542.4(H4C3):c.74del (p.Asp25fs)	Pathogenic
976699	NM_003542.4(H4C3):c.274A>C (p.Lys92Gln)	Pathogenic
1342161	NM_003542.4(H4C3):c.275A>G (p.Lys92Arg)	Likely pathogenic
2443379	NM_003542.4(H4C3):c.305G>A (p.Gly102Asp)	Likely pathogenic
2443610	NM_003542.4(H4C3):c.98C>G (p.Pro33Arg)	Likely pathogenic
2597503	NM_003542.4(H4C3):c.136C>A (p.Arg46Ser)	Likely pathogenic
3030693	NM_003542.4(H4C3):c.297T>G (p.Tyr99Ter)	Likely pathogenic

SpliceAI

95 predictions. Top by Δscore:

Variant	Effect	Δscore
6:26103990:G:GA	donor_gain	0.8100
6:26103989:T:TA	donor_gain	0.7600
6:26104032:GGCAT:G	donor_gain	0.7200
6:26103943:G:GT	donor_gain	0.6900
6:26104207:T:TA	donor_gain	0.6900
6:26104208:A:AA	donor_gain	0.6900
6:26103983:G:GT	donor_gain	0.6800
6:26104006:G:GG	donor_gain	0.6600
6:26103956:T:TA	donor_gain	0.6500
6:26104074:G:GA	donor_gain	0.6500
6:26104129:T:TA	donor_gain	0.6400
6:26103983:G:T	donor_gain	0.6300
6:26104107:G:GT	donor_gain	0.6300
6:26104130:T:A	donor_gain	0.6300
6:26104131:T:TG	donor_gain	0.6300
6:26104005:C:G	donor_gain	0.6100
6:26104073:T:TA	donor_gain	0.6100
6:26104014:C:CG	donor_gain	0.6000
6:26104108:A:T	donor_gain	0.6000
6:26104078:TC:T	donor_gain	0.5900
6:26104009:AG:A	donor_gain	0.5800
6:26104010:G:GT	donor_gain	0.5800
6:26104011:G:T	donor_gain	0.5700
6:26104094:T:TA	donor_gain	0.5700
6:26104112:TCGAG:T	donor_loss	0.5600
6:26104113:CGAGG:C	donor_loss	0.5600
6:26104114:GAG:G	donor_loss	0.5600
6:26104115:AGGTG:A	donor_loss	0.5600
6:26104116:GG:G	donor_loss	0.5600
6:26104117:G:C	donor_loss	0.5600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000465875 (6:26102150 C>G,T), RS1001321460 (6:26103228 G>GAAGAGT), RS1001469277 (6:26103639 C>G,T), RS1001605230 (6:26103891 G>A,C), RS1002513130 (6:26104364 G>A,T), RS1002544243 (6:26104475 C>T), RS1002934655 (6:26104387 C>T), RS1002985539 (6:26104264 A>G), RS1004578016 (6:26104373 A>G), RS1004783008 (6:26104342 G>A,C), RS1005175515 (6:26103613 A>G), RS1005472364 (6:26103181 C>G), RS1006010932 (6:26104831 A>G), RS1007234225 (6:26103053 T>C), RS1007513913 (6:26102667 A>G)

Disease associations

OMIM: gene MIM:602827 | disease phenotypes: MIM:619758

GenCC curated gene-disease

Disease	Classification	Inheritance
Tessadori-van Haaften neurodevelopmental syndrome 1	Strong	Autosomal dominant

Mondo (1): Tessadori-van Haaften neurodevelopmental syndrome 1 (MONDO:0030729)

Orphanet (0):

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000089	Renal hypoplasia
HP:0000154	Wide mouth
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000384	Preauricular skin tag
HP:0000403	Recurrent otitis media
HP:0000455	Broad nasal tip
HP:0000456	Bifid nasal tip
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000582	Upslanted palpebral fissure
HP:0000629	Periorbital fullness
HP:0000646	Amblyopia
HP:0000709	Psychosis
HP:0000822	Hypertension
HP:0000965	Cutis marmorata
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001399	Hepatic failure
HP:0001510	Growth delay
HP:0001537	Umbilical hernia
HP:0001558	Decreased fetal movement
HP:0001684	Secundum atrial septal defect
HP:0001773	Short foot
HP:0002205	Recurrent respiratory infections
HP:0003577	Congenital onset

GWAS associations

34 associations (top):

Study	Trait	p-value
GCST000759_6	LDL cholesterol	6.000000e-10
GCST000760_30	Cholesterol, total	2.000000e-08
GCST004521_113	Autism spectrum disorder or schizophrenia	3.000000e-19
GCST004521_169	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_69	Autism spectrum disorder or schizophrenia	8.000000e-24
GCST004521_83	Autism spectrum disorder or schizophrenia	1.000000e-13
GCST004602_48	Mean corpuscular volume	2.000000e-229
GCST004612_9	High light scatter reticulocyte percentage of red cells	1.000000e-09
GCST004621_95	Red cell distribution width	3.000000e-161
GCST004630_84	Mean corpuscular hemoglobin	0.000000e+00
GCST006166_59	Diastolic blood pressure x alcohol consumption interaction (2df test)	3.000000e-33
GCST006169_15	Diastolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	1.000000e-16
GCST006172_35	Mean arterial pressure x alcohol consumption (light vs heavy) interaction (2df test)	7.000000e-15
GCST006979_496	Heel bone mineral density	1.000000e-10
GCST007267_212	Systolic blood pressure	3.000000e-13
GCST007928_68	Medication use (diuretics)	1.000000e-09
GCST008163_61	Height	5.000000e-06
GCST008971_133	Urate levels	6.000000e-13
GCST010002_50	Refractive error	4.000000e-34
GCST010142_16	Fish- and plant-related diet	2.000000e-10
GCST010142_19	Fish- and plant-related diet	4.000000e-10
GCST010142_34	Fish- and plant-related diet	7.000000e-09
GCST010142_35	Fish- and plant-related diet	8.000000e-09
GCST010142_42	Fish- and plant-related diet	1.000000e-08
GCST010142_7	Fish- and plant-related diet	3.000000e-12
GCST90002383_405	Hematocrit	3.000000e-178
GCST90002384_81	Hemoglobin	0.000000e+00
GCST90002385_363	High light scatter reticulocyte count	3.000000e-69
GCST90002386_129	High light scatter reticulocyte percentage of red cells	4.000000e-83
GCST90002390_570	Mean corpuscular hemoglobin	0.000000e+00

EFO canonical traits (16, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0004329	alcohol drinking
EFO:0006336	diastolic blood pressure
EFO:0006340	mean arterial pressure
EFO:0009270	heel bone mineral density
EFO:0006335	systolic blood pressure
EFO:0009928	Diuretic use measurement
EFO:0004531	urate measurement
EFO:0008111	diet measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007984	platelet component distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5876 (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: 312 (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
CHEMBL3919831	AMREDOBRESIB	2	312

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

Binding affinities (BindingDB)

78 measured of 78 human assays (78 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-[1-[(5-fluoro-2-pyridinyl)methyl]-6-morpholin-4-ylimidazo[4,5-c]pyridin-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	1 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-[1-benzyl-2-[8-[[1-(2-methoxyethyl)piperidin-4-yl]amino]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzimidazol-5-yl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one	IC50	3 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	3 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	3 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-5-methyl-4-phenylimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	4 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	4 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-[1-benzyl-2-[3-methyl-8-(methylamino)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzimidazol-5-yl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one	IC50	5 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	5 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-3-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	5 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzylbenzimidazol-2-yl)-3-methyl-N-(1-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	7 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-6-morpholin-4-ylbenzimidazol-2-yl)-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	7 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[6-(dimethylamino)-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	7 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1,5-dimethyl-4-phenoxypyrazol-3-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzylbenzimidazol-2-yl)-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-3-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-[(4-fluorophenyl)methyl]benzimidazol-2-yl]-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-[(3,4-difluorophenyl)methyl]benzimidazol-2-yl]-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[9-benzyl-2-(4-methylpiperazin-1-yl)purin-8-yl]-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)benzimidazol-2-yl]-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-[(3R)-3-methylmorpholin-4-yl]-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-[(3S)-3-methylmorpholin-4-yl]-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-6-morpholin-4-ylbenzimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	10 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	10 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[5-(oxan-4-yl)-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	11 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	12 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-4-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	12 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-methoxyacetamide	IC50	12.8 nM	US-9125915: Antitumor agent
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	13 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[6-(dimethylamino)-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	13 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-[(3R)-oxolan-3-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	13 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyrazine	IC50	14 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-N-propan-2-yl-6-[1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	14 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-4,5-dimethylimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	15 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-methyl-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	15 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-N-ethyl-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	17 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[1-[(6-methyl-2-pyridinyl)methyl]-6-morpholin-4-ylimidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	17 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-methylacetamide	IC50	17.3 nM	US-9125915: Antitumor agent
6-(4-benzyl-1,5-dimethylpyrazol-3-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	18 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(3-benzylimidazo[4,5-b]pyridin-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	18 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-N-propan-2-yl-6-[6-propan-2-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	18 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
methyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate	IC50	18.2 nM	US-9125915: Antitumor agent
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-[(3R)-oxolan-3-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	20 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-N-propan-2-yl-6-[1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	20 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2-hydroxyethyl)acetamide	IC50	21 nM	US-9125915: Antitumor agent
6-(1-benzylbenzimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	22 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	26 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-methyl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	28 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-4,5-dimethylimidazol-2-yl)-3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyrazine	IC50	31 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors

ChEMBL bioactivities

65 potent at pChembl≥5 of 66 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL3930178
8.52	IC50	3	nM	CHEMBL3938152
8.52	IC50	3	nM	CHEMBL3953268
8.52	IC50	3	nM	CHEMBL3916639
8.40	IC50	4	nM	CHEMBL3979803
8.40	IC50	4	nM	CHEMBL3959499
8.30	IC50	5	nM	CHEMBL3913643
8.30	IC50	5	nM	CHEMBL3939182
8.30	IC50	5	nM	CHEMBL3935504
8.15	IC50	7	nM	CHEMBL3983932
8.15	IC50	7	nM	CHEMBL3920322
8.15	IC50	7	nM	CHEMBL3923899
8.10	IC50	8	nM	CHEMBL3929450
8.10	IC50	8	nM	CHEMBL3923105
8.10	IC50	8	nM	CHEMBL3929086
8.10	IC50	8	nM	CHEMBL3927028
8.05	IC50	9	nM	CHEMBL3941148
8.05	IC50	9	nM	CHEMBL3970690
8.05	IC50	9	nM	CHEMBL3908717
8.05	IC50	9	nM	CHEMBL3951550
8.05	IC50	9	nM	AMREDOBRESIB
8.05	IC50	9	nM	CHEMBL4112988
8.05	IC50	9	nM	CHEMBL3893231
8.01	Kd	9.891	nM	CHEMBL5653589
8.01	ED50	9.891	nM	CHEMBL5653589
8.00	IC50	10	nM	CHEMBL3914807
8.00	IC50	10	nM	CHEMBL3902208
7.96	IC50	11	nM	CHEMBL3907651
7.92	IC50	12	nM	CHEMBL3973914
7.92	IC50	12	nM	CHEMBL3966649
7.89	IC50	13	nM	CHEMBL3928047
7.89	IC50	13	nM	CHEMBL3951605
7.89	IC50	13	nM	CHEMBL4114198
7.85	IC50	14	nM	CHEMBL3919702
7.85	IC50	14	nM	CHEMBL3946335
7.82	IC50	15	nM	CHEMBL3916156
7.82	IC50	15	nM	CHEMBL3937464
7.77	IC50	17	nM	CHEMBL3956797
7.77	IC50	17	nM	CHEMBL3914869
7.75	IC50	18	nM	CHEMBL3891629
7.75	IC50	18	nM	CHEMBL3947502
7.75	IC50	18	nM	CHEMBL3956941
7.70	IC50	20	nM	CHEMBL4115491
7.70	IC50	20	nM	CHEMBL3960315
7.66	IC50	22	nM	CHEMBL3946480
7.58	IC50	26	nM	CHEMBL3929241
7.55	IC50	28	nM	CHEMBL3909523
7.51	IC50	31	nM	CHEMBL3985926
7.51	IC50	31	nM	CHEMBL4107079
7.50	IC50	32	nM	CHEMBL3916033

PubChem BioAssay actives

2 with measured affinity, of 108 total; 2 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148510: Binding affinity to human HIST1H4A incubated for 45 mins by Kinobead based pull down assay	kd	0.0099	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148510: Binding affinity to human HIST1H4A incubated for 45 mins by Kinobead based pull down assay	kd	4.0927	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	4
bisphenol A	decreases expression, decreases methylation	3
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression	2
Arsenic Trioxide	increases expression, decreases expression	2
Chlorambucil	decreases expression	2
Cisplatin	affects cotreatment, decreases expression, decreases reaction	2
Fluorouracil	decreases expression	2
Dronabinol	decreases expression	2
Tretinoin	affects expression, decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Copper Sulfate	decreases expression, increases expression	2
tert-Butylhydroperoxide	decreases expression	2
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
lead acetate	increases expression	1
thallium sulfate	decreases expression	1
methylparaben	decreases expression	1
cobaltous chloride	decreases expression	1
nickel chloride	increases expression	1
benzo(e)pyrene	decreases methylation	1
versicolorin A	decreases expression	1
cupric chloride	increases expression	1
hydroquinone	decreases expression	1
perfluorodecanoic acid	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, affects response to substance, increases expression	1
beta-methylcholine	affects expression	1
dinophysistoxin 1	decreases expression	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2175621	Binding	Binding affinity to fluorescein-labeled Histone H4(1-20) by spectrofluorometry	Pharmacophore-based virtual screening and biological evaluation of small molecule inhibitors for protein arginine methylation. — J Med Chem

Clinical trials (associated diseases)

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