CREB3

Chr 9

cAMP responsive element binding protein 3

Also known as: LUMAN, LZIP, sLZIP

NCBI Gene: 10488 ENSG00000107175 UniProt: O43889 OMIM: 606443

CREB3 encodes an endoplasmic reticulum-bound transcription factor that regulates the unfolded protein response, cell proliferation, and leukocyte migration by directly binding DNA and activating target gene transcription. Mutations cause autosomal recessive osteogenesis imperfecta with bone fragility and skeletal deformities. The gene shows minimal constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

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 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]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.01

Clinical Summary— CREB3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 46 VUS of 61 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.04Z-score

OE missense 0.99 (0.88–1.12)

194 obs / 195.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.37–1.01)

0≤0.351.4

Missense OE?0.99 (0.88–1.12)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 10 / 16.8Missense obs/exp: 194 / 195.5Syn Z: -0.27

This gene — mechanism propensity

0.6840th %ile

GOF

0.4480th %ile

LOF

0.3843th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

61 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS46

Likely Benign3

Benign2

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	0	0	0	1
VUS	0	46	0	0	46
Likely Benign	0	2	0	1	3
Benign	0	0	1	1	2
Total	1	48	1	2	52

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

View in ClinVar →

74 pathogenic / likely-pathogenic (of 82) ClinVar copy-number / structural variants overlap CREB3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →