HDAC3

Chr 5

histone deacetylase 3

Also known as: HD3, KDAC3, RPD3, RPD3-2

NCBI Gene: 8841ENSG00000171720UniProt: O15379

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 belongs to the histone deacetylase/acuc/apha family. It has histone deacetylase activity and represses transcription when tethered to a promoter. It may participate in the regulation of transcription through its binding with the zinc-finger transcription factor YY1. This protein can also down-regulate p53 function and thus modulate cell growth and apoptosis. This gene is regarded as a potential tumor suppressor gene. [provided by RefSeq, Jul 2008]

48
ClinVar variants
13
Pathogenic / LP
0.57
pLI score
0
Active trials
Clinical Summary— HDAC3
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.57) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
13 Pathogenic / Likely Pathogenic· 28 VUS of 48 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.41LOEUF
pLI 0.567
Z-score 3.93
OE 0.21 (0.11–0.41)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.72Z-score
OE missense 0.35 (0.30–0.42)
92 obs / 260.9 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.21 (0.11–0.41)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.35 (0.30–0.42)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00
0≤1.21.6
LoF obs/exp: 6 / 28.7Missense obs/exp: 92 / 260.9Syn Z: 0.02

ClinVar Variant Classifications

48 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic2
VUS28
Likely Benign5
Benign2
11
Pathogenic
2
Likely Pathogenic
28
VUS
5
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
11
0
11
Likely Pathogenic
0
2
0
0
2
VUS
1
24
3
0
28
Likely Benign
1
0
3
1
5
Benign
0
1
0
1
2
Total22717248

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HDAC3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

HDAC3-related neurodevelopmental disorder

moderate
ADLoss Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation.
Li X et al.·Eur Heart J
2024
Recent histone deacetylase inhibitors in cancer therapy.
Parveen R et al.·Cancer
2023Review
Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3.
Fu B et al.·Bone Res
2024
TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-tumorigenic Memory Fate.
Venturutti L et al.·Cell
2020
The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression.
Mi X et al.·Pharmacol Res
2024
KDELR2 promotes breast cancer proliferation via HDAC3-mediated cell cycle progression.
Wei H et al.·Cancer Commun (Lond)
2021
The LncRNA STEAP3-AS1 promotes liver metastasis in colorectal cancer by regulating histone lactylation through chromatin remodelling.
Lv J et al.·J Exp Clin Cancer Res
2025Functional
Causal Role for Neutrophil Elastase in Thoracic Aortic Dissection in Mice.
Yang M et al.·Arterioscler Thromb Vasc Biol
2023
Entinostat as a combinatorial therapeutic for rhabdomyosarcoma.
Chauhan S et al.·Sci Rep
2024
Nuclear DEK preserves hematopoietic stem cells potential via NCoR1/HDAC3-Akt1/2-mTOR axis.
Chen Z et al.·J Exp Med
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools