CREBBP

Chr 16AD

CREB binding protein

NCBI Gene: 1387ENSG00000005339UniProt: Q92793

Acetylates histones, giving a specific tag for transcriptional activation (PubMed:21131905, PubMed:24616510). Mediates acetylation of histone H3 at 'Lys-18' and 'Lys-27' (H3K18ac and H3K27ac, respectively) (PubMed:21131905). Also acetylates non-histone proteins, like DDX21, FBL, IRF2, MAFG, NCOA3, POLR1E/PAF53 and FOXO1 (PubMed:10490106, PubMed:11154691, PubMed:12738767, PubMed:12929931, PubMed:24207024, PubMed:28790157, PubMed:30540930, PubMed:35675826, PubMed:9707565). Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-BMAL1 and CLOCK-BMAL1 heterodimers (PubMed:14645221). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates POLR1E/PAF53, leading to decreased association of RNA polymerase I with the rDNA promoter region and coding region (PubMed:24207024). Acetylates DDX21, thereby inhibiting DDX21 helicase activity (PubMed:28790157). Acetylates FBL, preventing methylation of 'Gln-105' of histone H2A (H2AQ104me) (PubMed:30540930). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as lactoyl-CoA, and is able to mediate protein lactylation (PubMed:38128537). Catalyzes lactylation of MRE11 in response to DNA damage, thereby promoting DNA double-strand breaks (DSBs) via homologous recombination (HR) (PubMed:38128537). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493)

Primary Disease Associations & Inheritance

Menke-Hennekam syndrome 1MIM #618332
AD
Rubinstein-Taybi syndrome 1MIM #180849
AD
525
ClinVar variants
65
Pathogenic / LP
1.00
pLI score· haploinsufficient
4
Active trials
Clinical Summary— CREBBP
🧬
Gene-Disease Validity (ClinGen)
Rubinstein-Taybi syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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.
📋
ClinVar Variants
65 Pathogenic / Likely Pathogenic· 342 VUS of 525 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.07LOEUF
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?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.
3.90Z-score
OE missense 0.71 (0.67–0.75)
1005 obs / 1418.2 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?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.0.03 (0.01–0.07)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.71 (0.67–0.75)
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.1.26
0≤1.21.6
LoF obs/exp: 3 / 118.3Missense obs/exp: 1005 / 1418.2Syn Z: -4.84

ClinVar Variant Classifications

525 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic32
VUS342
Likely Benign103
Benign10
Conflicting5
33
Pathogenic
32
Likely Pathogenic
342
VUS
103
Likely Benign
10
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
19
2
12
0
33
Likely Pathogenic
15
13
4
0
32
VUS
1
303
29
9
342
Likely Benign
0
15
32
56
103
Benign
0
5
0
5
10
Conflicting
—5
Total353387770525

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

View in ClinVar →

Protein Context — Lollipop Plot

CREBBP · protein map & ClinVar variants

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

Gene2Phenotype Curations

CREBBP-related intellectual disability without typical RTS features

definitive
ADUndeterminedUncertain
Skin
G2P ↗

CREBBP-related Rubinstein-Taybi syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersEyeSkinSkeletal
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Menke-Hennekam syndrome 1

MIM #618332

Molecular basis of disorder known

Autosomal dominant

Rubinstein-Taybi syndrome 1

MIM #180849

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — CREBBP
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Neonatal leukaemia.
Roberts I et al.·Br J Haematol
2018Review
Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement.
Lacombe D et al.·J Med Genet
2024Review
Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder.
Van Gils J et al.·Genes (Basel)
2021Review
Simplified algorithm for genetic subtyping in diffuse large B-cell lymphoma.
Shen R et al.·Signal Transduct Target Ther
2023
Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease.
Nann D et al.·Blood Adv
2020
Identification of genomic alterations in oesophageal squamous cell cancer.
Song Y et al.·Nature
2014
Histone lysine acetyltransferase inhibitors: an emerging class of drugs for cancer therapy.
White J et al.·Trends Pharmacol Sci
2024Review
CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis.
Huang YH et al.·Signal Transduct Target Ther
2021
De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.
Pande S et al.·Eur J Hum Genet
2024Cohort
Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature.
Rots D et al.·Am J Hum Genet
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Differential role of CREBBP missense and truncating mutations in germinal center development and lymphomagenesis.
Yu C et al.·Blood
2026
Daidzein reprograms EP300/CREBBP-deficient immune evasion via targeting the PPARγ-ANGPT4/Tie2 axis in hypopharyngeal squamous cell carcinoma.
Mao W et al.·Phytomedicine
2025
Mutations in CREBBP and EP300 HAT and Bromo Domains Drive Hypermutation and Predict Survival in GI Cancers Treated with Immunotherapy.
Gusakova M et al.·Biomedicines
2025🔓 Open Access
miR-31a-5p targeting Crebbp suppresses Wnt/β-catenin and TGF-β pathways to alleviate oil mist particulate matter-induced pulmonary fibrosis.
Nie H et al.·Ecotoxicol Environ Saf
2025
Rubinstein-Taybi Syndrome: A Comprehensive Analysis of a Polish Cohort with Most Cases Due to Novel CREBBP and EP300 Variants.
Cieślikowska A et al.·Genes (Basel)
2025🔓 Open AccessCohort
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10
Uroepithelial Carcinoma

Current Status of Diagnosis and Treatment of Uroepithelial Carcinoma

NOT YET RECRUITING
NCT06663735The First Affiliated Hospital of Xinxiang Medical CollegeStarted 2024-10-30
Rare DiseasesAlbinismIntellectual Disability

Implementation of Long-read Sequencing for the Diagnosis of Rare Diseases.

NOT YET RECRUITING
NCT07400913University Hospital, BordeauxStarted 2026-02
Long-read sequencing
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation

External Resources

Links to major genomics databases and tools