EP300

Chr 22AD

EP300 lysine acetyltransferase

Also known as: KAT3B, MKHK2, RSTS2, p300

NCBI Gene: 2033 ENSG00000100393 UniProt: Q09472 OMIM: 602700

The protein functions as a histone acetyltransferase that regulates transcription via chromatin remodeling and is essential for cell proliferation and differentiation. Heterozygous loss-of-function mutations cause Rubinstein-Taybi syndrome 2 and Menke-Hennekam syndrome 2 through autosomal dominant inheritance. The gene is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the underlying pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein. It functions as histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and thus plays a role in the stimulation of hypoxia-induced genes such as VEGF. Defects in this gene are a cause of Rubinstein-Taybi syndrome and may also play a role in epithelial cancer. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Colorectal cancer, somaticMIM #114500

Menke-Hennekam syndrome 2MIM #618333

Rubinstein-Taybi syndrome 2MIM #613684

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · Rubinstein-Taybi syndrome due to EP300 haploinsufficiency · AD · ClinGen 2022
Definitive · Rubinstein-Taybi syndrome · AD · Illumina
Limited · retinitis pigmentosa · AD · G2P — not for standalone diagnostic reporting

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.10

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — EP300

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.10LOEUF

pLI 1.000

Z-score 9.65

OE 0.05 (0.03–0.10)

Highly constrained

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

Missense Constraint?

2.03Z-score

OE missense 0.84 (0.80–0.89)

1119 obs / 1327.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.03–0.10)

0≤0.351.4

Missense OE?0.84 (0.80–0.89)

0≤0.61.4

Synonymous OE?1.42

0≤1.21.6

LoF obs/exp: 6 / 120.1Missense obs/exp: 1119 / 1327.6Syn Z: -7.05

Background carrier burden — how many people carry a rare variant somewhere in EP300?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 27

2,956 rare PASS variants

Rare truncating (LoF)

1 in 9,200

55 rare PASS variants

Rare synonymous (reference)

1 in 31

1,435 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for EP300. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 35	1 in 12,000
South Asian	~43k	1 in 25	1 in 2,000
Remaining (unassigned)	~30k	1 in 29	≈ 1 in 15,000
European (Finnish)	~27k	1 in 98	≈ 1 in 13,000
Admixed American	~22k	1 in 30	≈ 1 in 7,400
African / African American	~21k	1 in 28	≈ 1 in 4,200
East Asian	~20k	1 in 33	1 in 3,300
Ashkenazi Jewish	~13k	1 in 80	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 28	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 30 of 31 coding exons well covered in gnomAD exomes; exon 26 marginal. Genomes: all 31.? see exons ↓