CREB3

Chr 9

cAMP responsive element binding protein 3

Also known as: LUMAN, LZIP, sLZIP

NCBI Gene: 10488ENSG00000107175UniProt: O43889

This gene encodes a transcription factor that is a member of the leucine zipper family of DNA binding proteins. This protein binds to the cAMP-response element and regulates cell proliferation. The protein interacts with host cell factor C1, which also associates with the herpes simplex virus (HSV) protein VP16 that induces transcription of HSV immediate-early genes. This protein and VP16 both bind to the same site on host cell factor C1. It is thought that the interaction between this protein and host cell factor C1 plays a role in the establishment of latency during HSV infection. This protein also plays a role in leukocyte migration, tumor suppression, and endoplasmic reticulum stress-associated protein degradation. Additional transcript variants have been identified, but their biological validity has not been determined.[provided by RefSeq, Nov 2009]

141
ClinVar variants
74
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— CREB3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
74 Pathogenic / Likely Pathogenic· 53 VUS of 141 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
1.01LOEUF
pLI 0.000
Z-score 1.54
OE 0.60 (0.37–1.01)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.04Z-score
OE missense 0.99 (0.88–1.12)
194 obs / 195.5 exp
Tolerant

Mild missense constraint

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.0.60 (0.37–1.01)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.88–1.12)
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.1.04
0≤1.21.6
LoF obs/exp: 10 / 16.8Missense obs/exp: 194 / 195.5Syn Z: -0.27

ClinVar Variant Classifications

141 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic65
Likely Pathogenic9
VUS53
Likely Benign3
Benign2
65
Pathogenic
9
Likely Pathogenic
53
VUS
3
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
64
0
65
Likely Pathogenic
0
0
9
0
9
VUS
0
45
8
0
53
Likely Benign
0
2
0
1
3
Benign
0
0
1
1
2
Total147822132

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

View in ClinVar →

Protein Context — Lollipop Plot

CREB3 · 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
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Intrinsic heterogeneity of primary cilia revealed through spatial proteomics.
Hansen JN et al.·Cell
2025
CREB3 gain of function variants protect against ALS.
Megat S et al.·Nat Commun
2025
Founder Homozygous Nonsense CREB3 Variant and Variable-Onset Retinal Degeneration.
Salameh M et al.·JAMA Ophthalmol
2025
Genetics of ALS - genes and modifier.
Menge S et al.·Curr Opin Neurol
2025Review
Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation.
Torres-Odio S et al.·J Neuroinflammation
2017Functional
Endothelial NMMHC IIA dissociation from PAR1 activates the CREB3/ARF4 signaling in thrombin-mediated intracerebral hemorrhage.
Dai Y et al.·J Adv Res
2025
Single-cell analysis uncovers high-proliferative tumour cell subtypes and their interactions in the microenvironment of gastric cancer.
Zhang W et al.·J Cell Mol Med
2024
A CREB3-regulated ER-Golgi trafficking signature promotes metastatic progression in breast cancer.
Howley BV et al.·Oncogene
2018
Multivariate analysis of a missense variant in CREBRF reveals associations with measures of adiposity in people of Polynesian ancestries.
Zhang JZ et al.·Genet Epidemiol
2023
The protective effect of rs373863828 on type 2 diabetes does not operate through a body composition pathway in adult Samoans.
Hawley NL et al.·Obesity (Silver Spring)
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools