CREBBP

Chr 16AD

CREB binding lysine acetyltransferase

Also known as: CBP, KAT3A, MKHK1, RSTS, RSTS1

NCBI Gene: 1387 ENSG00000005339 UniProt: Q92793 OMIM: 600140

The protein functions as a transcriptional coactivator with histone acetyltransferase activity that couples chromatin remodeling to transcription factor recognition, playing critical roles in embryonic development, growth control, and homeostasis. Mutations cause Rubinstein-Taybi syndrome 1 and Menke-Hennekam syndrome 1, inherited in an autosomal dominant pattern, predominantly through loss-of-function mechanisms leading to haploinsufficiency. The gene shows extreme intolerance to loss-of-function variants (pLI = 1, LOEUF = 0.066), consistent with the pathogenic effects of reduced dosage.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.072 OMIM phenotypes

Clinical Summary— CREBBP

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Gene-Disease Validity (ClinGen)

Rubinstein-Taybi syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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Clinical Trials

5 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.07LOEUF

pLI 1.000

Z-score 9.83

OE 0.03 (0.01–0.07)

Highly constrained

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

Missense Constraint

3.90Z-score

OE missense 0.71 (0.67–0.75)

1005 obs / 1418.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.03 (0.01–0.07)

0≤0.351.4

Missense OE0.71 (0.67–0.75)

0≤0.61.4

Synonymous OE1.26

0≤1.21.6

LoF obs/exp: 3 / 118.3Missense obs/exp: 1005 / 1418.2Syn Z: -4.84

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCREBBP-related intellectual disability without typical RTS featuresOTHERAD

definitiveCREBBP-related Rubinstein-Taybi syndromeLOFAD

0.16100th %ile

GOF

0.2198th %ile

LOF

0.91top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.07

DN1 literature citation

Literature Evidence

DNWhen transcribed in vitro, while Ser-133 phosphorylation of KID was maintained upon forskolin treatment, mutated CREB1 protein failed to associate with the KIX domain of co-activator CREBBP/EP300, and thereby, interrupted cAMP-dependent protein kinase A signal transduction as the dominant-negative fPMID:22267179

LOFThe CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma.PMID:28069569

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