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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is ubiquitously expressed and is involved in the transcriptional coactivation of many different transcription factors. First isolated as a nuclear protein that binds to cAMP-response element binding protein (CREB), this gene is now known to play critical roles in embryonic development, growth control, and homeostasis by coupling chromatin remodeling to transcription factor recognition. The protein encoded by this gene has intrinsic histone acetyltransferase activity and also acts as a scaffold to stabilize additional protein interactions with the transcription complex. This protein acetylates both histone and non-histone proteins. This protein shares regions of very high sequence similarity with protein p300 in its bromodomain, cysteine-histidine-rich regions, and histone acetyltransferase domain. Mutations in this gene cause Rubinstein-Taybi syndrome (RTS). Chromosomal translocations involving this gene have been associated with acute myeloid leukemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

278 unique Pathogenic / Likely Pathogenic· 223 VUS of 1015 total submissions

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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 →

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GeneReview available — CREBBP

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.03 (0.01–0.07)

0≤0.351.4

Missense OE?0.71 (0.67–0.75)

0≤0.61.4

Synonymous OE?1.26

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 Rubinstein-Taybi syndromeLOFAD

definitiveCREBBP-related intellectual disability without typical RTS features (Menke-Hennekam syndrome)OTHERAD

This gene — mechanism propensity

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 · 74% of P/LP variants are LoF · LOEUF 0.07 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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 f1

LOFThe CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma.2

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

References

ClinVar Variant Classifications

1015 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic196

Likely Pathogenic82

VUS223

Likely Benign323

Benign43

Conflicting76

196

Pathogenic

Likely Pathogenic

223

VUS

323

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	176	16	4	0	196
Likely Pathogenic	31	46	5	0	82
VUS	5	208	8	2	223
Likely Benign	0	61	76	186	323
Benign	0	15	4	24	43
Conflicting	—				76
Total	212	346	97	212	943

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

View in ClinVar →

34 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap CREBBP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →