H3-3A

Summary

H3-3A (H3.3 histone A, HGNC:4764) is a protein-coding gene on chromosome 1q42.12, encoding Histone H3.3 (P84243). Variant histone H3 which replaces conventional H3 in a wide range of nucleosomes in active genes. In precision oncology, H3-3A K28M confers sensitivity to Dordaviprone in Diffuse Midline Glioma, H3 K27-altered (CIViC Level A); 1 further curated variant–drug associations are listed below. It is a common-essential gene (DepMap: required in 99.8% of cancer cell lines).

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 contains introns and its mRNA is polyadenylated, unlike most histone genes. The protein encoded is a replication-independent member of the histone H3 family.

Source: NCBI Gene 3020 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Bryant-Li-Bhoj neurodevelopmental syndrome 1 (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 62 total — 5 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 67
• Druggable target: yes
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Cancer dependency (DepMap): dependent in 99.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_002107

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4764
Approved symbol	H3-3A
Name	H3.3 histone A
Location	1q42.12
Locus type	gene with protein product
Status	Approved
Aliases	H3.3A
Ensembl gene	ENSG00000163041
Ensembl biotype	protein_coding
OMIM	601128
Entrez	3020

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 46 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000366813, ENST00000366814, ENST00000366815, ENST00000366816, ENST00000653960, ENST00000655399, ENST00000656829, ENST00000661429, ENST00000666609, ENST00000667897, ENST00000904835, ENST00000904836, ENST00000904837, ENST00000904838, ENST00000904839, ENST00000904840, ENST00000904841, ENST00000904842, ENST00000921919, ENST00000921920, ENST00000921921, ENST00000921922, ENST00000921923, ENST00000921924, ENST00000921925, ENST00000921926, ENST00000921927, ENST00000921928, ENST00000921929, ENST00000921930, ENST00000921931, ENST00000921932, ENST00000921933, ENST00000921934, ENST00000921935, ENST00000921936, ENST00000921937, ENST00000921938, ENST00000921939, ENST00000921940, ENST00000921941, ENST00000921942, ENST00000921943, ENST00000921944, ENST00000953111, ENST00000953112, ENST00000953113, ENST00000953114

RefSeq mRNA: 5 — MANE Select: NM_002107 NM_001379043, NM_001379045, NM_001379046, NM_001379047, NM_002107

CCDS: CCDS1550

Canonical transcript exons

ENST00000366815 — 4 exons

Exon	Start	End
ENSE00001428176	226064329	226064479
ENSE00001442671	226062716	226062811
ENSE00001442672	226071351	226072019
ENSE00002355903	226065656	226065809

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 73.0201 / max 500.0297, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8850	72.0877	1825
8851	0.6875	326
8852	0.2449	95

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	99.89	gold quality
monocyte	CL:0000576	99.88	gold quality
ventricular zone	UBERON:0003053	99.88	gold quality
leukocyte	CL:0000738	99.87	gold quality
cortical plate	UBERON:0005343	99.83	gold quality
blood	UBERON:0000178	99.82	gold quality
endometrium	UBERON:0001295	99.71	gold quality
rectum	UBERON:0001052	99.69	gold quality
corpus callosum	UBERON:0002336	99.68	gold quality
granulocyte	CL:0000094	99.65	gold quality
vermiform appendix	UBERON:0001154	99.65	gold quality
lymph node	UBERON:0000029	99.63	gold quality
gall bladder	UBERON:0002110	99.63	gold quality
calcaneal tendon	UBERON:0003701	99.62	gold quality
smooth muscle tissue	UBERON:0001135	99.61	gold quality
right lung	UBERON:0002167	99.59	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.59	gold quality
bone marrow	UBERON:0002371	99.58	gold quality
islet of Langerhans	UBERON:0000006	99.57	gold quality
duodenum	UBERON:0002114	99.57	gold quality
fallopian tube	UBERON:0003889	99.56	gold quality
mucosa of transverse colon	UBERON:0004991	99.56	gold quality
spleen	UBERON:0002106	99.53	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	99.52	gold quality
transverse colon	UBERON:0001157	99.52	gold quality
placenta	UBERON:0001987	99.52	gold quality
esophagus mucosa	UBERON:0002469	99.52	gold quality
right uterine tube	UBERON:0001302	99.51	gold quality
skin of abdomen	UBERON:0001416	99.51	gold quality
zone of skin	UBERON:0000014	99.50	gold quality

Single-cell (SCXA)

Detected in 29 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-GEOD-149689	yes	21808.05
E-MTAB-6505	yes	17318.82
E-MTAB-7407	yes	7736.61
E-GEOD-135922	yes	5149.07
E-CURD-46	yes	3168.14
E-HCAD-4	yes	266.51
E-MTAB-8142	yes	134.48
E-HCAD-1	yes	95.15
E-CURD-122	yes	78.45
E-MTAB-10553	yes	41.86
E-MTAB-9221	yes	36.12
E-MTAB-9467	yes	29.45
E-MTAB-6678	yes	25.54
E-HCAD-9	yes	24.49
E-CURD-88	yes	20.12

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
GLI1	Activation

Upstream regulators (CollecTRI, top): ATRX, SP1

miRNA regulators (miRDB)

30 targeting H3-3A, 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-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-548L	99.06	70.90	2560
HSA-MIR-935	98.82	69.36	1072
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-198	98.70	67.32	920
HSA-MIR-9851-5P	97.57	67.49	1067
HSA-MIR-6501-5P	97.41	68.24	712
HSA-MIR-6859-3P	97.26	64.69	428
HSA-MIR-6846-3P	94.80	65.19	389

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Histone H3 lysine 4 methylation disrupts binding of nucleosome remodeling and deacetylase (NuRD) repressor complex (PMID:11850414)
• analysis of histone posttranslational modifications on H3.1 and H3.3 (PMID:17052464)
• Data reveal that TPA activates transcription of TBX2 through activating MSK1, which leads to an increase in phosphorylated histone H3 and the recruitment of Sp1 to the TBX2 gene. (PMID:19633291)
• Studies indicate that H3.3 accomplishes a surprising variety of cellular and developmental processes. (PMID:20153629)
• Part of multiple H3.3-specific histone chaperone complexes (PMID:21047901)
• discussion of the importance of H3.3 deposition as a salvage pathway to maintain chromatin integrity (PMID:22195966)
• recurrent mutations in a regulatory histone in humans; data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis (PMID:22286061)
• K27M mutation in H3.3 is universally associated with short survival in diffuse intrinsic pontine gliomas, while patients wild-type for H3.3 show improved survival. (PMID:22661320)
• demonstrate that the two H3F3A mutations give rise to glioblastomas in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins (PMID:23079654)
• Somatic mutation of H3F3A, a chromatin remodeling gene, is rare in acute leukemias and non-Hodgkin lymphoma. (PMID:23116151)
• This study suggested that none of H3.3 G34R mutated tumors presented primitive neuroectodermal tumors of central nervous system and pediatric glioblastomas. (PMID:23354654)
• The results of this study indicate that H3F3A K27M mutant GBMs show decreased H3K27me3 that may be of both diagnostic and biological relevance. (PMID:23414300)
• H3F3A K27M mutations occur exclusively in pediatric diffuse high-grade astrocytomas (PMID:23429371)
• diffuse intrinsic pontine gliomas containing K27M mutation display lower overall amounts of H3 with trimethylated lysine 27(H3K27me3);H3K27M inhibits enzymatic activity of Polycomb repressive complex 2 through interaction with the EZH2 subunit; propose a model where aberrant epigenetic silencing through H3K27M-mediated inhibition of PRC2 activity promotes gliomagenesis (PMID:23539183)
• indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis (PMID:23603901)
• Low frequency of H3.3 mutations in myelodysplastic syndromes patients. (PMID:23660862)
• H3F3A exon 2 mutation analyzed in solid tumors from 1351 South Korean patients (PMID:23758177)
• A remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions. (PMID:24162739)
• Reduced H3K27me3 and/or DNA hypomethylation are the major driving forces of activated gene expression in K27M mutant pediatric high-grade gliomas. (PMID:24183680)
• Loss of H3.3 from pericentromeric heterochromatin upon DAXX or PML depletion suggests that the targeting of H3.3 to PML-NBs is implicated in pericentromeric heterochromatin organization. (PMID:24200965)
• All reported H3.3 mutations identified in human tumors have been in the H3F3A gene leading to single codon changes within the N-terminal tail of the H3.3 protein. [Review] (PMID:24229707)
• These data suggest that adult brainstem gliomas differ from adult supratentorial gliomas. In particular, histone genes HIST1H3B (K27M) ) mutations are frequent in adult brainstem gliomas. (PMID:24242757)
• H3F3A K27M mutation is associated with thalamic gliomas. (PMID:24285547)
• The mutually exclusive associations of HDAC1/p300, p300/histone, and HDAC1/histone on chromatin contribute to the dynamic regulation of histone acetylation. (PMID:24722339)
• These results suggest that immunohistochemical detection of H3.3 K27M is a sensitive and specific surrogate for the H3F3A K27M mutation and defines a prognostically poor subset of pediatric glioblastomas. (PMID:25200322)
• this study identifies an H3.3K36me3-specific reader and a regulator of intron retention and reveals that BS69 connects histone H3.3K36me3 to regulated RNA splicing, providing significant, important insights into chromatin regulation of pre-mRNA processing. (PMID:25263594)
• we describe three interesting cases of paediatric glial and glioneuronal tumours harbouring both BRAF V600E and H3F3A K27M mutations. (PMID:25389051)
• The CENP-A/histone H3.3 nucleosome forms an unexpectedly stable structure and allows the binding of the essential centromeric protein, CENP-C, which is ectopically mislocalized in the chromosomes of CENP-A overexpressing tumor cells. (PMID:25408271)
• On the basis of our findings, H3F3A p.Gly34 Trp or p.Gly34 Leu mutations are not a frequent event in CGCL. (PMID:25442495)
• our observations further extend the knowledge of H3F3A mutation and its location in pediatric glioblastomas (PMID:25479829)
• study found spinal high-grade gliomas in children and adults frequently harbor H3F3A (K27M) mutations (PMID:26231952)
• Study examined the relationship of K27M mutations in the distinct histone H3 variants (i.e. HIST1H3B and H3F3A) with specific pontine glioma biology (PMID:26399631)
• H3F3A and H3F3B mutation analysis appears to be a highly specific, although less sensitive, diagnostic tool for the distinction of GCTB and chondroblastoma from other giant cell-containing tumors. (PMID:26457357)
• This study showed that heterozygous K27M mutations in H3F3A (n = 4) or HIST1H3B (n = 3) across all primary, contiguous, and metastatic tumor sites in all Diffuse intrinsic pontine glioma. (PMID:26727948)
• we describe the presence of the mutation p.K27M of H3F3A (H3.3K27M) in two tumours of young patients with classical histopathology of ganglioglioma (PMID:27219822)
• overexpression of H3F3A, encoding H3.3, is associated with lung cancer progression and promotes lung cancer cell migration by activating metastasis-related genes (PMID:27694942)
• H3F3 mutations are sensitive and specific markers of giant cell tumors of the bone and chondroblastomas (PMID:28059095)
• The kinase activity of Aurora B on serine 31 of histone H3.3 was biochemically confirmed with nucleosomal substrates in vitro. (PMID:28137420)
• We determined the incidence of H3.3 G34 mutations in primary malignant bone tumors as assessed by genotype and H3.3 G34W immunostaining (PMID:28505000)
• H3F3A is the most frequently mutated giant cell tumor of bone driver gene. H3F3A mutations are not present in atypical giant cell tumor of bone. (PMID:28545165)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
caenorhabditis_elegans		WBGENE00001945

Paralogs (20): CENPA (ENSG00000115163), H3-3B (ENSG00000132475), H3-4 (ENSG00000168148), H3C13 (ENSG00000183598), H3-5 (ENSG00000188375), H3C12 (ENSG00000197153), H3C4 (ENSG00000197409), H3C14 (ENSG00000203811), H3C15 (ENSG00000203852), H3Y2 (ENSG00000268799), H3Y1 (ENSG00000269466), H3-7 (ENSG00000273213), H3C8 (ENSG00000273983), H3C6 (ENSG00000274750), H3C11 (ENSG00000275379), H3C1 (ENSG00000275714), H3C7 (ENSG00000277775), H3C10 (ENSG00000278828), H3C2 (ENSG00000286522), H3C3 (ENSG00000287080)

Protein

Protein identifiers

Histone H3.3 — P84243 (reviewed: P84243)

All UniProt accessions (4): A0A590UJJ6, B2R4P9, B4DEB1, P84243

UniProt curated annotations — full annotation on UniProt →

Function. Variant histone H3 which replaces conventional H3 in a wide range of nucleosomes in active genes. Constitutes the predominant form of histone H3 in non-dividing cells and is incorporated into chromatin independently of DNA synthesis. Deposited at sites of nucleosomal displacement throughout transcribed genes, suggesting that it represents an epigenetic imprint of transcriptionally active chromatin. 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. Interacts with HIRA, a chaperone required for its incorporation into nucleosomes. Interacts with ZMYND11; when trimethylated at ‘Lys-36’ (H3.3K36me3). 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 ASF1A, MCM2, NASP and SPT2. Interacts with DAXX; 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 is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability. Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription. Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3’ of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters. Specifically enriched in modifications associated with active chromatin such as methylation at Lys-5 (H3K4me), Lys-37 and Lys-80. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me), which are linked to gene repression, are underrepresented. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at ‘Lys-120’. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication. Phosphorylated at Thr-4 (H3T3ph) by VRK1. Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 or isoform M2 of PKM (PKM2) is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin. Phosphorylation on Ser-32 (H3S31ph) is specific to regions bordering centromeres in metaphase chromosomes. Monoubiquitinated at Lys-15 (H3K14ub), Lys-19 (H3K18ub) and Lys-24 (H3K23ub) by UHRF1 and HLTF at hemimethylated DNA sites following DNA replication, promoting recruitment of DNMT1 DNA methyltransferase and replication-coupled DNA methylation maintenance. Monoubiquitinated by RAG1 in lymphoid cells, monoubiquitination is required for V(D)J recombination. 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. Lysine deamination at Lys-5 (H3K4all) to form allysine is mediated by LOXL2. Allysine formation by LOXL2 only takes place on H3K4me3 and results in gene 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. It is present during late spermatogenesis. Succinylation at Lys-80 (H3K79succ) by KAT2A takes place with a maximum frequency around the transcription start sites of genes. It gives a specific tag for epigenetic transcription activation. Desuccinylation at Lys-123 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair. Serine ADP-ribosylation by PARP1 or PARP2 constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage. Serine ADP-ribosylation at Ser-11 (H3S10ADPr) promotes recruitment of CHD1L. H3S10ADPr is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac). Serotonylated by TGM2 at Gln-6 (H3Q5ser) during serotonergic neuron differentiation. H3Q5ser is associated with trimethylation of Lys-5 (H3K4me3) and enhances general transcription factor IID (TFIID) complex-binding to H3K4me3, thereby facilitating transcription. Dopaminylated by TGM2 at Gln-6 (H3Q5dop) in ventral tegmental area (VTA) neurons. H3Q5dop mediates neurotransmission-independent role of nuclear dopamine by regulating relapse-related transcriptional plasticity in the reward system. Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.

Disease relevance. Glioma (GLM) [MIM:137800] Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. The gene represented in this entry is involved in disease pathogenesis. H3F3A mutations affecting residues involved in post-translational modifications of histone H3.3 are recurrent in malignant, aggressive gliomas including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG). The mechanism through which mutations lead to tumorigenesis involves altered histones methylation, impaired regulation of Polycomb repressive complex 2 (PRC2) activity, and aberrant epigenetic regulation of gene expression. Bryant-Li-Bhoj neurodevelopmental syndrome 1 (BRYLIB1) [MIM:619720] An autosomal dominant disorder predominantly characterized by global developmental delay, impaired intellectual development, poor or absent speech, and delayed motor milestones. Clinical manifestations are highly variable, including abnormal head shape, dysmorphic facial features, oculomotor abnormalities, feeding problems, and non-specific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects. The disease is caused by variants affecting the gene represented in this entry. BRYLIB1 is caused by variants in H3-3A. Bryant-Li-Bhoj neurodevelopmental syndrome 2 (BRYLIB2) [MIM:619721] An autosomal dominant disorder predominantly characterized by global developmental delay, impaired intellectual development, poor or absent speech, and delayed motor milestones. Clinical manifestations are highly variable, including abnormal head shape, dysmorphic facial features, oculomotor abnormalities, feeding problems, and non-specific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects. The disease is caused by variants affecting the gene represented in this entry. BRYLIB2 is caused by variants in H3-3B. H3F3A and H3F3B mutations affecting residues involved in post-translational modifications of histone H3.3 are implicated in the pathogenesis of some bone and cartilage neoplasms. Mutations have been found with high prevalence in chondroblastoma and giant cell tumors of bone, and with low frequency in osteosarcoma, conventional chondrosarcoma and clear cell chondrosarcoma. Chondroblastoma samples frequently carry a H3F3B mutation affecting residue Lys-37 (H3K36), although H3F3A is mutated in some cases. Most giant cell tumors of bone harbor H3F3A mutations affecting residue Gly-35 (H3G34).

Domain organisation. Specific interaction of trimethylated form at ‘Lys-36’ (H3.3K36me3) with ZMYND11 is mediated by the encapsulation of Ser-32 residue with a composite pocket formed by the tandem bromo-PWWP domains.

Similarity. Belongs to the histone H3 family.

RefSeq proteins (5): NP_001365972, NP_001365974, NP_001365975, NP_001365976, NP_002098* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000164	Histone_H3/CENP-A	Family
IPR007125	H2A/H2B/H3	Domain
IPR009072	Histone-fold	Homologous_superfamily

Pfam: PF00125

UniProt features (190 total): modified residue 121, sequence variant 44, strand 8, helix 5, cross-link 3, mutagenesis site 3, initiator methionine 1, chain 1, lipid moiety-binding region 1, sequence conflict 1, region of interest 1, site 1

Structure

Experimental structures (PDB)

103 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3QL9	X-RAY DIFFRACTION	0.93
3ASL	X-RAY DIFFRACTION	1.41
4GNE	X-RAY DIFFRACTION	1.47
4L58	X-RAY DIFFRACTION	1.48
5JLB	X-RAY DIFFRACTION	1.5
4GNF	X-RAY DIFFRACTION	1.55
3QLA	X-RAY DIFFRACTION	1.6
3MUL	X-RAY DIFFRACTION	1.65
9G4A	X-RAY DIFFRACTION	1.65
4GNG	X-RAY DIFFRACTION	1.73
3MUK	X-RAY DIFFRACTION	1.75
4QQ4	X-RAY DIFFRACTION	1.75
1PDQ	X-RAY DIFFRACTION	1.76
4O62	X-RAY DIFFRACTION	1.78
6J9J	X-RAY DIFFRACTION	1.78
3JVK	X-RAY DIFFRACTION	1.8
7CIZ	X-RAY DIFFRACTION	1.8
4H9N	X-RAY DIFFRACTION	1.95
4H9Q	X-RAY DIFFRACTION	1.95
4N4I	X-RAY DIFFRACTION	2
5DX0	X-RAY DIFFRACTION	2.05
4H9O	X-RAY DIFFRACTION	2.05
5JJY	X-RAY DIFFRACTION	2.05
7W5M	X-RAY DIFFRACTION	2.15
5X7X	X-RAY DIFFRACTION	2.18
8RZU	X-RAY DIFFRACTION	2.19
4H9R	X-RAY DIFFRACTION	2.2
4H9P	X-RAY DIFFRACTION	2.2
6U04	X-RAY DIFFRACTION	2.2
7OKP	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P84243-F1	86.79	0.71

Functional residue map

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

Catalytic / active sites (1): 32 (interaction with zmynd11)

Post-translational modifications (125): 5, 65, 80, 80, 80, 80, 80, 80, 80, 80, 80, 5, 80, 80, 81, 87, 108, 116, 116, 123 …

Mutagenesis-validated functional residues (3):

Position	Phenotype
6	abolished serotonylation by tgm2.
43	reduced binding of histone h1 to histone h3.3-containing nucleosomes.
106–107	loss of interaction with dnajc9, but not with other histone chaperones, such as asf1a, mccm2, nasp or spt2.

Function

Pathways and Gene Ontology

Reactome pathways

39 pathways

ID	Pathway
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-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-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-68616	Assembly of the ORC complex at the origin of replication
R-HSA-73728	RNA Polymerase I Promoter Opening
R-HSA-73772	RNA Polymerase I Promoter Escape
R-HSA-8936459	RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function
R-HSA-8939236	RUNX1 regulates transcription of genes involved in differentiation of HSCs
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-912446	Meiotic recombination
R-HSA-9616222	Transcriptional regulation of granulopoiesis
R-HSA-9670095	Inhibition of DNA recombination at telomere
R-HSA-9710421	Defective pyroptosis
R-HSA-9764725	Negative Regulation of CDH1 Gene Transcription
R-HSA-977225	Amyloid fiber formation
R-HSA-9821002	Chromatin modifications during the maternal to zygotic transition (MZT)
R-HSA-9821993	Replacement of protamines by nucleosomes in the male pronucleus
R-HSA-983231	Factors involved in megakaryocyte development and platelet production
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis

MSigDB gene sets: 417 (showing top): REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, HORIUCHI_WTAP_TARGETS_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, TTTGTAG_MIR520D, GCM_NPM1, GOBP_CHROMOSOME_LOCALIZATION, MORF_UBE2I, GOBP_GROWTH, HSIAO_HOUSEKEEPING_GENES, GOBP_TELOMERE_ORGANIZATION, AAAYRNCTG_UNKNOWN, USF_C

GO Biological Process (19): oocyte maturation (GO:0001556), osteoblast differentiation (GO:0001649), nucleosome assembly (GO:0006334), nucleus organization (GO:0006997), spermatid development (GO:0007286), single fertilization (GO:0007338), embryo implantation (GO:0007566), cell population proliferation (GO:0008283), male gonad development (GO:0008584), positive regulation of cell growth (GO:0030307), pericentric heterochromatin formation (GO:0031508), subtelomeric heterochromatin formation (GO:0031509), telomere organization (GO:0032200), multicellular organism growth (GO:0035264), muscle cell differentiation (GO:0042692), negative regulation of chromosome condensation (GO:1902340), spermatogenesis (GO:0007283), oogenesis (GO:0048477), obsolete regulation of centromere complex assembly (GO:0090230)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), RNA polymerase II core promoter sequence-specific DNA binding (GO:0000979), structural constituent of chromatin (GO:0030527), nucleosomal DNA binding (GO:0031492), protein heterodimerization activity (GO:0046982), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (12): chromosome, telomeric region (GO:0000781), nucleosome (GO:0000786), inner kinetochore (GO:0000939), Barr body (GO:0001740), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), chromosome, centromeric region (GO:0000775), chromatin (GO:0000785), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Epigenetic regulation of gene expression	2
Cellular Senescence	2
Negative epigenetic regulation of rRNA expression	2
Positive epigenetic regulation of rRNA expression	2
RNA Polymerase I Promoter Clearance	2
Transcriptional regulation by RUNX1	2
Pre-NOTCH Expression and Processing	1
TCF dependent signaling in response to WNT	1
Mitotic Prophase	1
Gene Silencing by RNA	1
Activation of HOX genes during differentiation	1
RHO GTPases activate PKNs	1
Assembly of the pre-replicative complex	1
ESR-mediated signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
developmental process involved in reproduction	2
cell differentiation	2
germ cell development	2
constitutive heterochromatin formation	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
chromatin	2
chromosomal region	2
cell maturation	1
oocyte development	1
ossification	1
chromatin organization	1
nucleosome organization	1
protein-DNA complex assembly	1
organelle organization	1
spermatid differentiation	1
fertilization	1
multicellular organism development	1
female pregnancy	1
reproductive process	1
cellular process	1
gonad development	1
development of primary male sexual characteristics	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
chromosome, telomeric region	1
chromosome organization	1
multicellular organismal process	1
developmental growth	1
muscle structure development	1
chromosome condensation	1
regulation of chromosome condensation	1
negative regulation of chromosome organization	1
male gamete generation	1
female gamete generation	1
cis-regulatory region sequence-specific DNA binding	1
core promoter sequence-specific DNA binding	1
structural molecule activity	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

220 interactions, top by confidence:

A	B	Type	Score
ASF1A	H4C16	psi-mi:“MI:0914”(association)	0.950
IKI3	IKI1	psi-mi:“MI:0192”(acetylation reaction)	0.940
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
H3-3A	DAXX	psi-mi:“MI:0915”(physical association)	0.850
H3-3A	DAXX	psi-mi:“MI:0914”(association)	0.780
DAXX	H3-3A	psi-mi:“MI:0915”(physical association)	0.780
ASF1B	MCM2	psi-mi:“MI:0915”(physical association)	0.770
KIF3A	KIF3C	psi-mi:“MI:0914”(association)	0.730
H3-3A	ASF1B	psi-mi:“MI:0915”(physical association)	0.720
H3-3A	ASF1B	psi-mi:“MI:0914”(association)	0.720
Zmynd11	H3-3A	psi-mi:“MI:0407”(direct interaction)	0.690
Zmynd11	H3-3A	psi-mi:“MI:0915”(physical association)	0.690
H3-3A	Zmynd11	psi-mi:“MI:0915”(physical association)	0.690
CBX5	H3-3A	psi-mi:“MI:0407”(direct interaction)	0.670
H3-3A	MCM2	psi-mi:“MI:0915”(physical association)	0.660

BioGRID (1375): H3F3A (Affinity Capture-MS), H3F3B (Affinity Capture-MS), NASP (Two-hybrid), H3F3A (Affinity Capture-MS), H3F3A (Biochemical Activity), H3F3A (Reconstituted Complex), H3F3B (Reconstituted Complex), H3F3B (Affinity Capture-MS), H3F3B (Affinity Capture-MS), EHMT2 (Two-hybrid), H3F3A (Affinity Capture-MS), H3F3B (Affinity Capture-RNA), H3F3A (Affinity Capture-MS), H3F3A (Affinity Capture-MS), H3F3A (Affinity Capture-MS)

ESM2 similar proteins: A2Y533, C0HL66, C0HL67, P06352, P08437, P08903, P59226, P68427, P68428, P68429, P68430, P69071, P69072, P69073, P69074, P69075, P69076, P69077, P69078, P69079, P69246, P69248, P84231, P84243, P84244, P84245, P84246, P84247, P84248, P84250, Q10453, Q2RAD9, Q402E1, Q42681, Q4P7J7, Q5E9F8, Q5RCC9, Q6LBE3, Q6LBE8, Q6LCK1

Diamond homologs: A1CP80, A1D240, A2QRR5, A2Y533, A3GHN6, A3LXD5, A4RCX7, A5DFC5, A5DG57, A5DWE2, A5E094, C0HL66, C0HL67, P02299, P02301, P07041, P08903, P09988, P0CO04, P0CO05, P10651, P23753, P59226, P61830, P61831, P61832, P61833, P61834, P61835, P61836, P68427, P68428, P68429, P68430, P68431, P68432, P68433, P69071, P69072, P69073

SIGNOR signaling

69 interactions.

A	Effect	B	Mechanism
AURKB	“up-regulates activity”	H3-3A	phosphorylation
RPS6KA1	“down-regulates activity”	H3-3A	phosphorylation
RPS6KA3	“down-regulates activity”	H3-3A	phosphorylation
RPS6KA5	“down-regulates activity”	H3-3A	phosphorylation
FYN	“down-regulates activity”	H3-3A	phosphorylation
CHEK1	“down-regulates activity”	H3-3A	phosphorylation
UNII-XH2662798I	down-regulates	H3-3A
EP300	“down-regulates activity”	H3-3A	acetylation
RPS6KA5	“up-regulates activity”	H3-3A	phosphorylation
CBP/p300	“down-regulates activity”	H3-3A	acetylation
AKT	“down-regulates activity”	H3-3A	phosphorylation
RPS6K	“down-regulates activity”	H3-3A	phosphorylation
ERK1/2	“down-regulates activity”	H3-3A	phosphorylation
KDM4C	“down-regulates activity”	H3-3A	demethylation
H3-3A	“form complex”	“Nucleosome_H3.3 variant”	binding
SETDB2	“up-regulates activity”	H3-3A	methylation
KDM5A	“up-regulates activity”	H3-3A	demethylation
KDM5B	“up-regulates activity”	H3-3A	demethylation
P2RY2	“up-regulates activity”	H3-3A	demethylation
KDM5D	“up-regulates activity”	H3-3A	demethylation
“Set1-Ash2 HMT complex”	“down-regulates activity”	H3-3A	methylation
CBX5	“up-regulates activity”	H3-3A	binding
CBX1	“up-regulates activity”	H3-3A	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 138 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
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	5	16.2×	8e-04
SUMOylation of transcription cofactors	6	15.7×	4e-04
PTEN Regulation	6	14.7×	4e-04
Regulation of PTEN gene transcription	7	13.4×	3e-04
DNA methylation	6	11.5×	8e-04
Inhibition of DNA recombination at telomere	6	10.8×	1e-03
Intraflagellar transport	5	10.8×	3e-03
DNA Damage/Telomere Stress Induced Senescence	6	10.5×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of gene expression via chromosomal CpG island methylation	5	43.9×	4e-05
nucleosome assembly	15	17.6×	7e-12
heterochromatin formation	7	14.9×	6e-05
cellular response to UV	5	12.3×	5e-03
chromatin organization	10	8.3×	6e-05
chromatin remodeling	12	7.3×	4e-05
DNA damage response	13	5.8×	6e-05
DNA repair	10	5.3×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — HGGNOS, PAST.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	9
Uncertain significance	28
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1183980	NM_002107.7(H3-3A):c.363G>A (p.Met121Ile)	Pathogenic
1306413	NM_002107.7(H3-3A):c.335C>T (p.Ala112Val)	Pathogenic
1339283	NM_002107.7(H3-3A):c.52A>G (p.Arg18Gly)	Pathogenic
3376608	NM_002107.7(H3-3A):c.362T>C (p.Met121Thr)	Pathogenic
3573591	NM_002107.7(H3-3A):c.326A>T (p.Asn109Ile)	Pathogenic
1183978	NM_002107.7(H3-3A):c.166C>A (p.Gln56Lys)	Likely pathogenic
1306572	NM_002107.7(H3-3A):c.92C>T (p.Pro31Leu)	Likely pathogenic
3103884	NM_002107.7(H3-3A):c.25C>G (p.Arg9Gly)	Likely pathogenic
4291940	NM_002107.7(H3-3A):c.339C>G (p.Ile113Met)	Likely pathogenic
429971	NM_002107.7(H3-3A):c.88G>A (p.Ala30Thr)	Likely pathogenic
4755433	NM_002107.7(H3-3A):c.148C>T (p.Arg50Cys)	Likely pathogenic
983132	NM_002107.7(H3-3A):c.250C>G (p.Arg84Gly)	Likely pathogenic
985263	NM_002107.7(H3-3A):c.326A>G (p.Asn109Ser)	Likely pathogenic
985323	NM_002107.7(H3-3A):c.244G>C (p.Asp82His)	Likely pathogenic

SpliceAI

943 predictions. Top by Δscore:

Variant	Effect	Δscore
1:226062051:G:GT	donor_gain	1.0000
1:226062055:G:GT	donor_gain	1.0000
1:226062807:GGGGG:G	donor_gain	1.0000
1:226062808:GGGG:G	donor_gain	1.0000
1:226062808:GGGGG:G	donor_gain	1.0000
1:226062809:GGG:G	donor_gain	1.0000
1:226062809:GGGG:G	donor_gain	1.0000
1:226062809:GGGGT:G	donor_loss	1.0000
1:226062810:GG:G	donor_gain	1.0000
1:226062810:GGG:G	donor_gain	1.0000
1:226062810:GGGT:G	donor_loss	1.0000
1:226062811:GG:G	donor_gain	1.0000
1:226062811:GGT:G	donor_loss	1.0000
1:226062813:TAAGT:T	donor_loss	1.0000
1:226064323:T:A	acceptor_gain	1.0000
1:226064328:GGTAA:G	acceptor_gain	1.0000
1:226065652:A:AG	acceptor_gain	1.0000
1:226065652:AAAG:A	acceptor_gain	1.0000
1:226065653:A:G	acceptor_gain	1.0000
1:226065653:AAG:A	acceptor_gain	1.0000
1:226065653:AAGGC:A	acceptor_loss	1.0000
1:226065654:A:AG	acceptor_gain	1.0000
1:226065655:G:A	acceptor_gain	1.0000
1:226065655:G:GA	acceptor_gain	1.0000
1:226065655:GGC:G	acceptor_gain	1.0000
1:226065655:GGCC:G	acceptor_gain	1.0000
1:226065655:GGCCT:G	acceptor_gain	1.0000
1:226065807:CAGG:C	donor_loss	1.0000
1:226065808:AG:A	donor_loss	1.0000
1:226065809:GG:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000745370 (1:226071569 A>G,T), RS1000841676 (1:226067719 G>A), RS1000866150 (1:226071968 C>G,T), RS1001008990 (1:226066719 T>C), RS1001148352 (1:226072267 G>A,C), RS1001330905 (1:226061847 C>A), RS1001660364 (1:226063269 A>C), RS1001734844 (1:226063067 C>G,T), RS1002199691 (1:226066885 G>A), RS1002288684 (1:226072032 C>T), RS1002339263 (1:226062279 C>G), RS1002478055 (1:226067207 T>G), RS1002726161 (1:226072257 G>A), RS1002765413 (1:226061595 A>C), RS1002867475 (1:226064027 C>T)

Disease associations

OMIM: gene MIM:601128 | disease phenotypes: MIM:619720

GenCC curated gene-disease

Disease	Classification	Inheritance
Bryant-Li-Bhoj neurodevelopmental syndrome 1	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Bryant-Li-Bhoj neurodevelopmental syndrome 1	Definitive	AD

Mondo (4): intellectual disability (MONDO:0001071), Bryant-Li-Bhoj neurodevelopmental syndrome 1 (MONDO:0030606), glioblastoma (MONDO:0018177), neurodevelopmental disorder (MONDO:0700092)

Orphanet (2): Glioblastoma (Orphanet:360), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

67 total (30 of 67 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000194	Open mouth
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000289	Broad philtrum
HP:0000294	Low anterior hairline
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000430	Underdeveloped nasal alae
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000582	Upslanted palpebral fissure
HP:0000639	Nystagmus
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000954	Single transverse palmar crease

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003473_29	Aggressiveness in attention deficit hyperactivity disorder	6.000000e-06

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D005909	Glioblastoma	C04.557.465.625.600.380.080.335; C04.557.470.670.380.080.335; C04.557.580.625.600.380.080.335
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724667 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items; also 34 diagnostic, 2 prognostic, 1 oncogenic.

Variant	Therapy	Indication	Effect	Level	CIViC
H3-3A K28M	Dordaviprone	Diffuse Midline Glioma, H3 K27-altered	Sensitivity/Response	CIViC A	EID12695
H3-3A K28M	Dordaviprone	Glioma	Sensitivity/Response	CIViC B	EID7601

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases response to substance, affects binding, decreases reaction, increases reaction, decreases expression	3
Valproic Acid	increases methylation, affects cotreatment, increases expression, decreases expression	3
Acetaminophen	increases expression	2
bisphenol F	affects cotreatment, increases expression	1
bisphenol A	affects cotreatment, increases expression	1
arsenite	affects binding, increases reaction	1
3,3’-diindolylmethane	increases expression, increases reaction	1
butyraldehyde	decreases expression	1
chloropicrin	decreases expression	1
darinaparsin	increases reaction, affects reaction, increases response to substance, affects cotreatment, increases expression	1
olaparib	increases response to substance, increases expression, increases reaction	1
talazoparib	increases expression, increases reaction, increases response to substance, affects cotreatment	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Vehicle Emissions	decreases expression	1
Benzo(a)pyrene	increases expression	1
Berberine	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	increases expression	1
Estradiol	increases expression, increases reaction, decreases reaction	1
Formaldehyde	decreases reaction, affects binding	1
Hydralazine	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects expression	1
Indomethacin	affects cotreatment, increases expression	1
Phenobarbital	affects expression	1
Selenium	decreases expression	1
Tetrachlorodibenzodioxin	decreases reaction, increases expression	1
Dronabinol	increases expression	1
Tobacco Smoke Pollution	affects expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697225	Binding	Inhibition of H3F3A (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

60 cell lines: 55 cancer cell line, 3 embryonic stem cell, 2 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0378	KNS-42	Cancer cell line	Male
CVCL_A0SR	NCC-GCTB2-C1	Cancer cell line	Male
CVCL_A0SS	NCC-GCTB3-C1	Cancer cell line	Female
CVCL_A2L1	SEES3-1V human H3F3A, clone1	Embryonic stem cell	Male
CVCL_A2L2	SEES3-1V human H3F3A, clone2	Embryonic stem cell	Male
CVCL_A2L3	SEES3-1V human H3F3A, clone3	Embryonic stem cell	Male
CVCL_A9QC	NCC-GCTB1-C1	Cancer cell line	Male
CVCL_B3VJ	NCC-GCTB4-C1	Cancer cell line	Male
CVCL_C1GF	NCC-GCTB5-C1	Cancer cell line	Male
CVCL_C1MH	BCH869	Cancer cell line	Female

Clinical trials (associated diseases)

197 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)
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
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders