HDAC2

Chr 6

histone deacetylase 2

Also known as: HD2, KDAC2, RPD3, YAF1

HDAC2 encodes a histone deacetylase that removes acetyl groups from core histones H2A, H2B, H3, and H4, leading to transcriptional repression and regulation of cell cycle progression and developmental events. Heterozygous loss-of-function mutations cause a neurodevelopmental disorder with intellectual disability and developmental delay through an autosomal dominant inheritance pattern. The pathogenic mechanism involves haploinsufficiency, as HDAC2 is highly intolerant to loss-of-function variants.

Summary from RefSeq, UniProt, Mechanism
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1
Active trials
224
Pubs (1 yr)
22
P/LP submissions
0%
P/LP missense
0.10
LOEUF· LoF intol.
LOF
Mechanism· predicted
Clinical SummaryHDAC2
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
22 unique Pathogenic / Likely Pathogenic· 29 VUS of 83 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

ensembl: TimeoutError: The operation was aborted due to timeout

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint
0.10LOEUF
pLI 1.000
Z-score 5.05
OE 0.00 (0.000.10)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
4.05Z-score
OE missense 0.30 (0.250.36)
79 obs / 264.4 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.00 (0.000.10)
00.351.4
Missense OE0.30 (0.250.36)
00.61.4
Synonymous OE0.82
01.21.6
LoF obs/exp: 0 / 29.7Missense obs/exp: 79 / 264.4Syn Z: 1.28
DN
0.3694th %ile
GOF
0.3491th %ile
LOF
0.76top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.10

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

83 submitted variants in ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic3
VUS29
Likely Benign5
Benign3
19
Pathogenic
3
Likely Pathogenic
29
VUS
5
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
19
0
19
Likely Pathogenic
0
0
3
0
3
VUS
1
25
3
0
29
Likely Benign
0
0
3
2
5
Benign
0
0
2
1
3
Total12530359

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

View in ClinVar →

Protein Context — Lollipop Plot

HDAC2 · protein map & ClinVar variants

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

Clinical Literature
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