CREB1

Chr 2

cAMP responsive element binding protein 1

Also known as: CREB, CREB-1

NCBI Gene: 1385 ENSG00000118260 UniProt: P16220 OMIM: 123810

CREB1 encodes a phosphorylation-dependent transcription factor that binds to cAMP response elements to regulate gene expression in response to hormonal stimulation and is involved in circadian rhythms and cellular differentiation. Mutations cause autosomal dominant developmental delay, intellectual disability, and seizures, often with additional features including autism spectrum disorder and behavioral abnormalities. This gene is highly constrained against loss-of-function variants (pLI 0.997), indicating that heterozygous mutations are likely pathogenic.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a transcription factor that is a member of the leucine zipper family of DNA binding proteins. This protein binds as a homodimer to the cAMP-responsive element, an octameric palindrome. The protein is phosphorylated by several protein kinases, and induces transcription of genes in response to hormonal stimulation of the cAMP pathway. Alternate splicing of this gene results in several transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.221 OMIM phenotype

Clinical Summary— CREB1

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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

23 VUS of 37 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CREB1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.22LOEUF

pLI 0.997

Z-score 4.07

OE 0.05 (0.02–0.22)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.91Z-score

OE missense 0.40 (0.33–0.48)

73 obs / 183.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.22)

0≤0.351.4

Missense OE?0.40 (0.33–0.48)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 1 / 21.3Missense obs/exp: 73 / 183.9Syn Z: 0.90

This gene — mechanism propensity

0.3892th %ile

GOF

0.15100th %ile

LOF

0.80top 5%

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

LOFprediction above median · LOEUF 0.22

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

37 submitted variants in ClinVar

ClinVar

Classification Summary

VUS23

Likely Benign2

Benign3

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	23	0	23
Likely Benign	0	2	2
Benign	0	3	3
Total	23	5	28

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap CREB1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →