CREB1

Chr 2

cAMP responsive element binding protein 1

Also known as: CREB, CREB-1

NCBI Gene: 1385ENSG00000118260UniProt: P16220

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]

Primary Disease Associations & Inheritance

Histiocytoma, angiomatoid fibrous, somaticMIM #612160
55
ClinVar variants
26
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— CREB1
⚡
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
26 Pathogenic / Likely Pathogenic· 24 VUS of 55 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.22LOEUF
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?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.
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?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.0.05 (0.02–0.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.40 (0.33–0.48)
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.0.86
0≤1.21.6
LoF obs/exp: 1 / 21.3Missense obs/exp: 73 / 183.9Syn Z: 0.90

ClinVar Variant Classifications

55 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26
VUS24
Likely Benign2
Benign3
26
Pathogenic
24
VUS
2
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
26
0
26
Likely Pathogenic
0
0
0
0
0
VUS
0
23
1
0
24
Likely Benign
0
0
0
2
2
Benign
0
0
0
3
3
Total02327555

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

View in ClinVar →

Protein Context — Lollipop Plot

CREB1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Histiocytoma, angiomatoid fibrous, somatic

MIM #612160

Molecular basis of disorder known

📖
GeneReview available — CREB1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
CREB1-driven CXCR4(hi) neutrophils promote skin inflammation in mouse models and human patients.
Chen J et al.·Nat Commun
2023Cohort
Transcutaneous auricular vagus nerve stimulation for post-stroke depression: A double-blind, randomized, placebo-controlled trial.
Liu C et al.·J Affect Disord
2024
Sensory neurons drive immune exclusion by stimulating a dense extracellular matrix in the breast cancer tumor microenvironment.
Zhang SW et al.·Cell
2026
Intracranial mesenchymal tumor with FET-CREB fusion-A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms.
Sloan EA et al.·Brain Pathol
2021
Characterization of dipyridamole as a novel ferroptosis inhibitor and its therapeutic potential in acute respiratory distress syndrome management.
Chen X et al.·Theranostics
2024
MAFF confers vulnerability to cisplatin-based and ionizing radiation treatments by modulating ferroptosis and cell cycle progression in lung adenocarcinoma.
Liang J et al.·Drug Resist Updat
2024
Molecularly Defined Thoracic Neoplasms.
Roden AC·Adv Anat Pathol
2024Review
KDELR2 promotes breast cancer proliferation via HDAC3-mediated cell cycle progression.
Wei H et al.·Cancer Commun (Lond)
2021
Expanding the clinicopathologic spectrum and genomic landscape of tumors with SMARCA2/4::CREM fusions.
Cyrta J et al.·J Pathol
2024
Plasma miRNA Biomarker Signatures in Parkinsonian Syndromes.
Ravanidis S et al.·Mol Neurobiol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Neurofilament light chain protein exposure contributes to protein aggregation, microgliosis, astrogliosis and neuroinflammation via p38/MK2/NF-κB/CREB1/Nrf2/HO-1 signalling leading to Parkinson's disease.
Nanda A et al.·Int J Biol Macromol
2026
Aspartame exacerbates cerebral ischemia-reperfusion injury via mitochondrial dysfunction and ERK/CREB1 pathway suppression.
Bai Y et al.·Ecotoxicol Environ Saf
2026
Regulation of stress tolerance by CREB1 sustains multiple myeloma cell survival.
Kudalkar R et al.·Cell Death Dis
2026🔓 Open Access
OX-LDL causes vascular endothelial injury by interfering with the CREB1-MDH1B-malate axis.
Pu C et al.·Free Radic Biol Med
2026
Circadian disruption increases sperm DNA damage through impaired CREB1-mediated of homologous recombination repair†.
Zhu W et al.·Biol Reprod
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Ischemic Stroke, AcuteAcute Hemiparesis

Effect of Exercise Gene Expression and Histone Modifications in Patients With Hemiplegia

RECRUITING
NCT06726941Phase NAAfyonkarahisar Health Sciences UniversityStarted 2024-12-20
Physiotherapy and Rehabilitation Practices

External Resources

Links to major genomics databases and tools