HDAC9
protein-codinghistone deacetylase 9, the group of Histone deacetylases, class IIA
Gene summary
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene has sequence homology to members of the histone deacetylase family. This gene is orthologous to the Xenopus and mouse MITR genes. The MITR protein lacks the histone deacetylase catalytic domain. It represses MEF2 activity through recruitment of multicomponent corepressor complexes that include CtBP and HDACs. This encoded protein may play a role in hematopoiesis. Multiple alternatively spliced transcripts have been described for this gene but the full-length nature of some of them has not been determined. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~915.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0000107
Submitter: ClinGen
HDAC9 was first reported in relation to autosomal dominant auriculocondylar syndrome in 2022 (Romanelli Tavares et al., PMID: 34750192). This condition is characterized by malformation of the ears, rounding of the race, puffy cheeks, micrognathia, microstomia, dental malocclusion, and atypical mandibular condyles with temporomandibular joint anomalies. Probands can additionally have conductive hearing loss. However, the expert panel also evaluated individuals with craniosynostosis since that phenotype falls within the expertise of the GCEP. 7 variants (large deletion, large duplication, translocation, frameshift) that have been reported in 7 probands in 3 publications (PMIDs: 34750192, 35710300, 38318288) are included in this curation. None of the cases were scored due to impacting genomic regions/genes beyond HDAC9; implicating the locus HDAC9 is at, namely TWIST1, rather than HDAC9 itself; or lack of phenotype specificity. One type of experimental evidence, a mouse model (PMID: 35710300) was evaluated, but it was not scored due to implicating the locus the gene is at, specifically TWIST1, rather than HDAC9 itself. In summary, the evidence supporting the relationship between HDAC9 and auriculocondylar syndrome has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role HDAC9 plays in this disease. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 11/20/2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0957543
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Craniofacial
Intervention: Audiologic/Otolaryngologic
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HDAC9 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_178425.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 4 | 2 | 9 | ||
| missense | 105 | 3 | 2 | 110 | ||
| nonsense | 1 | 1 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 6 | 6 | ||||
| Total | 0 | 0 | 117 | 7 | 4 | 128 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_848512.1 | 25 | MANE Select | |
| Ensembl | ENSP00000509161.1 | 25 | MANE Select | |
| RefSeq | NP_001191073.1 | 12 | Standard | |
| RefSeq | NP_001191074.1 | 10 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| hdac9b | Danio rerio | Structure: vascular lymphangioblast Quality: malformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Viral carcinogenesis - Homo sapiens (human)
- Alcoholism - Homo sapiens (human)
- Human papillomavirus infection - Homo sapiens (human)
- Valproic Acid Pathway, Pharmacodynamics
- Pathway_PA165964473
Biological Process
- negative regulation of transcription by RNA polymerase II
- response to amphetamine
- inflammatory response
- heart development
- histone deacetylation
Molecular Function
- transcription corepressor activity
- histone deacetylase activity
- protein kinase C binding
- protein binding
- transcription factor binding
Cellular Component
- histone deacetylase complex
- nucleus
- nucleoplasm
- transcription factor complex
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000441542
- Coding exons
- 25
- Length
- 915468
- Individuals with no LoFs
- 124662
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 26
- Defined
- 124688
- p
- 0.000104
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.06 | 422 | 559 | 0.755 | 0.0000289 | 6906 |
| Missense (PolyPhen) | 121 | 239.67 | 0.50485 | 3034 | ||
| Synonymous | -0.0164 | 211 | 211 | 1.00 | 0.0000112 | 2057 |
| Loss of Function | 6.32 | 9 | 63.2 | 0.142 | 0.00000354 | 702 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00013 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Represses MEF2-dependent transcription.;
- Disease
- DISEASE: Note=A chromosomal aberration involving HDAC9 is found in a family with Peters anomaly. Translocation t(1;7)(q41;p21) with TGFB2 resulting in lack of HDAC9 protein. {ECO:0000269|PubMed:12706107}.;
Recessive Scores
- pRec
- 0.715
Intolerance Scores
- LoFtool
- 0.306
- RVIS EVS
- -1.06
- RVIS percentile EVS
- 7.52
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- H
- Indispensability pred.
- E
- Indispensability score
- 0.555
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |