CREBZF

Summary

CREBZF (CREB/ATF bZIP transcription factor, HGNC:24905) is a protein-coding gene on chromosome 11q14.1, encoding CREB/ATF bZIP transcription factor (Q9NS37). Strongly activates transcription when bound to HCFC1.

Enables identical protein binding activity. Involved in regulation of gene expression and response to virus. Located in nucleus.

Source: NCBI Gene 58487 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 53 total
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈5% of expected missense variation)
• GTEx eGene: eQTL in 7 tissues, sQTL in 2 (q < 0.05)
• Constraint (gnomAD): pLI 0.32 (intermediate), LOEUF 0.74 (unconstrained)
• Transcription factor: yes — 22 downstream targets (CollecTRI)
• MANE Select transcript: NM_001039618
• Notable: 53 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24905
Approved symbol	CREBZF
Name	CREB/ATF bZIP transcription factor
Location	11q14.1
Locus type	gene with protein product
Status	Approved
Aliases	ZF, SMILE
Ensembl gene	ENSG00000137504
Ensembl biotype	protein_coding
OMIM	606444
Entrez	58487

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 nonsense_mediated_decay, 2 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000527447

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 3: 2, TSL 4: 1, TSL 5: 3

ENST00000527447, ENST00000260058, ENST00000490820, ENST00000525639, ENST00000527529, ENST00000528561, ENST00000528889, ENST00000531515, ENST00000534224, ENST00000682836, ENST00000850607

RefSeq mRNA: 1 — MANE Select: NM_001039618 NM_001039618

CCDS: CCDS41697

Canonical transcript exons

ENST00000527447 — 1 exons

Exon	Start	End
ENSE00004282314	85657990	85665129

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 95.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.1545 / max 407.9332, expressed in 1813 samples.

Highest expression (Bgee): sural nerve, adrenal tissue, ovary, body of uterus, hemisphere of cerebellum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CREBZF is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 7 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

9 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Gastroesophageal Junction	eqtl	1.9e-03	+0.18	11:86480110:C:T
Brain Cerebellar Hemisphere	eqtl	7.9e-03	+0.44	11:85876455:G:GTGAA
Vagina	eqtl	1.3e-02	-0.84	11:85218760:G:A
Esophagus Mucosa	sqtl	2.8e-02	+0.30	11:86115121:A:G
Esophagus Mucosa	eqtl	2.9e-02	-0.13	11:85689204:C:G
Lung	sqtl	3.2e-02	+0.36	11:85078820:A:G
Brain Cerebellum	eqtl	3.4e-02	-0.40	11:85730157:C:T
Cells EBV-transformed lymphocytes	eqtl	4.1e-02	-0.11	11:86249162:A:G
Muscle Skeletal	eqtl	4.8e-02	+0.43	11:86004201:G:A

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
121685	33.6174	1812
121684	0.9690	654
121686	0.6626	265
121682	0.5571	218
121683	0.3485	189

Top tissues by expression

showing 100 of 298 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	95.80	gold quality
adrenal tissue	UBERON:0018303	95.72	gold quality
left ovary	UBERON:0002119	95.71	gold quality
right ovary	UBERON:0002118	95.41	gold quality
body of uterus	UBERON:0009853	95.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.87	gold quality
cardia of stomach	UBERON:0001162	94.78	gold quality
cerebellar hemisphere	UBERON:0002245	94.72	gold quality
cerebellar cortex	UBERON:0002129	94.58	gold quality
ventricular zone	UBERON:0003053	94.53	gold quality
right lung	UBERON:0002167	94.47	gold quality
endocervix	UBERON:0000458	94.44	gold quality
left lobe of thyroid gland	UBERON:0001120	94.30	gold quality
fundus of stomach	UBERON:0001160	94.29	gold quality
left uterine tube	UBERON:0001303	94.29	gold quality
pylorus	UBERON:0001166	94.27	gold quality
ganglionic eminence	UBERON:0004023	94.19	gold quality
nerve	UBERON:0001021	94.13	gold quality
tibial nerve	UBERON:0001323	94.13	gold quality
ovary	UBERON:0000992	94.11	gold quality
body of pancreas	UBERON:0001150	94.11	gold quality
tibial artery	UBERON:0007610	93.91	gold quality
popliteal artery	UBERON:0002250	93.90	gold quality
right lobe of thyroid gland	UBERON:0001119	93.88	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.80	gold quality
thyroid gland	UBERON:0002046	93.79	gold quality
artery	UBERON:0001637	93.72	gold quality
right coronary artery	UBERON:0001625	93.61	gold quality
right uterine tube	UBERON:0001302	93.54	gold quality
mucosa of stomach	UBERON:0001199	93.53	gold quality
cerebellum	UBERON:0002037	93.48	gold quality
ectocervix	UBERON:0012249	93.47	gold quality
lymph node	UBERON:0000029	93.39	gold quality
aorta	UBERON:0000947	93.39	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.37	gold quality
descending thoracic aorta	UBERON:0002345	93.36	gold quality
minor salivary gland	UBERON:0001830	93.33	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.32	gold quality
renal medulla	UBERON:0000362	93.27	gold quality
left coronary artery	UBERON:0001626	93.24	gold quality
pons	UBERON:0000988	93.22	gold quality
tendon of biceps brachii	UBERON:0008188	93.17	gold quality
body of stomach	UBERON:0001161	93.14	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.11	gold quality
lower esophagus	UBERON:0013473	93.09	gold quality
coronary artery	UBERON:0001621	93.04	gold quality
vagina	UBERON:0000996	92.97	gold quality
small intestine	UBERON:0002108	92.95	gold quality
inferior vagus X ganglion	UBERON:0005363	92.90	gold quality
rectum	UBERON:0001052	92.82	gold quality
thoracic aorta	UBERON:0001515	92.74	gold quality
medial globus pallidus	UBERON:0002477	92.72	gold quality
ascending aorta	UBERON:0001496	92.71	gold quality
cortical plate	UBERON:0005343	92.71	gold quality
metanephros cortex	UBERON:0010533	92.66	gold quality
urethra	UBERON:0000057	92.62	gold quality
pituitary gland	UBERON:0000007	92.57	gold quality
right adrenal gland cortex	UBERON:0035827	92.56	gold quality
stomach	UBERON:0000945	92.55	gold quality
endometrium	UBERON:0001295	92.54	gold quality
subthalamic nucleus	UBERON:0001906	92.52	gold quality
adenohypophysis	UBERON:0002196	92.46	gold quality
adrenal cortex	UBERON:0001235	92.43	gold quality
superior vestibular nucleus	UBERON:0007227	92.42	gold quality
skin of abdomen	UBERON:0001416	92.34	gold quality
left adrenal gland cortex	UBERON:0035825	92.30	gold quality
spleen	UBERON:0002106	92.20	gold quality
transverse colon	UBERON:0001157	92.18	gold quality
globus pallidus	UBERON:0001875	92.13	gold quality
gall bladder	UBERON:0002110	92.05	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.96	gold quality
left adrenal gland	UBERON:0001234	91.95	gold quality
endothelial cell	CL:0000115	91.87	gold quality
mouth mucosa	UBERON:0003729	91.87	gold quality
right adrenal gland	UBERON:0001233	91.84	gold quality
sigmoid colon	UBERON:0001159	91.71	gold quality
upper lobe of left lung	UBERON:0008952	91.71	gold quality
uterus	UBERON:0000995	91.67	gold quality
adrenal gland	UBERON:0002369	91.57	gold quality
female reproductive system	UBERON:0000474	91.56	gold quality
skin of leg	UBERON:0001511	91.48	gold quality
peritoneum	UBERON:0002358	91.44	gold quality
omental fat pad	UBERON:0010414	91.44	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.41	gold quality
spinal cord	UBERON:0002240	91.35	gold quality
tonsil	UBERON:0002372	91.35	gold quality
superior surface of tongue	UBERON:0007371	91.32	gold quality
upper lobe of lung	UBERON:0008948	91.24	gold quality
intestine	UBERON:0000160	91.23	gold quality
pericardium	UBERON:0002407	91.20	gold quality
saliva-secreting gland	UBERON:0001044	91.19	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.19	gold quality
esophagus	UBERON:0001043	91.10	gold quality
colon	UBERON:0001155	90.80	gold quality
vermiform appendix	UBERON:0001154	90.76	gold quality
large intestine	UBERON:0000059	90.65	gold quality
right atrium auricular region	UBERON:0006631	90.59	gold quality
prostate gland	UBERON:0002367	90.57	gold quality
primary visual cortex	UBERON:0002436	90.51	gold quality
stromal cell of endometrium	CL:0002255	90.44	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.33

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebellum	tissue	39.7	medium
Cerebral cortex	tissue	29.3	medium
Somatosensory cortex	tissue	29.3
Occipital cortex	tissue	27.9
Olfactory bulb	tissue	27.5
Corpus callosum	tissue	26.3
Superior colliculi	tissue	25.6
Motor cortex	tissue	25.1
Temporal cortex	tissue	24.8
Insular cortex	tissue	24.7
Retrosplenial and cingulate cortex	tissue	24.6
Hippocampal formation	tissue	24.1
Entorhinal cortex	tissue	24.1
Retrosplenial cortex	tissue	24.1
Prefrontal cortex	tissue	23.9
Midbrain	tissue	22.8
Retina	tissue	22.6
Thalamus	tissue	22.2
Periaqueductal gray	tissue	22.0
Putamen	tissue	21.9
Ventral forebrain	tissue	21.9
Hypothalamus	tissue	21.8
Spinal cord	tissue	21.7
Basal ganglia	tissue	21.6	medium
Amygdala	tissue	21.6
Medulla oblongata	tissue	21.6
Septum	tissue	21.4
Pons	tissue	20.3
Endometrium 1	tissue	19.1	low
Substantia nigra	tissue	18.8
Lymph node	tissue	16.7	not detected
Vagina	tissue	16.2	low
Spleen	tissue	15.5	not detected
Choroid plexus	tissue	15.0
Pancreas	tissue	13.8	not detected
Tonsil	tissue	13.6	low
Ovary	tissue	13.5	not detected
Duodenum	tissue	12.9	not detected
Pituitary gland	tissue	12.3
Breast	tissue	12.3	not detected
Small intestine	tissue	12.3	low
Thymus	tissue	12.3
Skin 1	tissue	12.2	not detected
Postcentral gyrus	tissue	12.2
Rectum	tissue	12.1
Nucleus accumbens	tissue	11.9
Prostate	tissue	11.8	not detected
Placenta	tissue	11.6	medium
Appendix	tissue	11.6	low
Adrenal gland	tissue	11.4	not detected
Stomach 1	tissue	11.3	low
Epididymis	tissue	11.3	not detected
Thyroid gland	tissue	10.6	medium
Parathyroid gland	tissue	10.5	medium
Hippocampus	tissue	10.1	low
Salivary gland	tissue	9.6	medium
Locus coeruleus	tissue	9.6
Liver	tissue	9.5	not detected
Gallbladder	tissue	9.2	medium
Cervix	tissue	9.1	not detected

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — White matter (26.3), Cerebellar cortex (26.2), Flocculonodular lobe (25.4), Vermis (24.3), Dorsal hippocampus (23.8).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

22 targets:

Target	Regulation
ACACA
AP3B1
BGLAP
CD86
CREBZF
ESRRG
FASN
FPR2
GAST
HCFC1
INS
NR1H3
NTRK1	Activation
PDK4	Repression
PPARGC1B
PRKAA1
SERPINB5
SREBF1	Repression
STK11
TERT
TSHB
WT1

Upstream regulators (CollecTRI, top): CREBZF, ESR1, ESRRG, SSRP1

miRNA regulators (miRDB)

Targeting CREBZF by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 360 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-511-3P	99.99	68.85	1467

Functional genomics

gnomAD constraint: pLI 0.319, LOEUF 0.738, missense Z -0.273 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000527447 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈5% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
11:85,663,814–85,664,117	114 / 134.1	0.85	no
11:85,664,118–85,664,173	8 / 25.8	0.31	yes (p 4.5e-04)
11:85,664,174–85,664,875	396 / 324.4	1.22	no

Literature-anchored findings (GeneRIF, showing 23)

• ZF suppresses the ability of Luman/CREB3 to activate gene expression (PMID:15705566)
• ZF suppresses the ability of VP16 to activate herpes simplex virus IE gene expression (PMID:16282471)
• ZF binds ATF4/CREB2 and enhances its response to MEK1 activation. (PMID:16343488)
• These results indicate that SMILE isoforms regulate the inhibition of estrogen receptor transactivation by SHP in a cell-type-specific manner and act as a novel transcriptional co-regulator in ER signalling. (PMID:18657049)
• Zhangfei causes medulloblastoma cells to undergo apoptosis (PMID:18719857)
• findings showed Zhangfei activated the expression of trkA and Egr1 in medulloblastoma cells and caused these cells to display markers of apoptosis (PMID:18719857)
• In differentiated PC12 cells, Zhangfei activated the trkA promoter and induced the expression of endogenous trkA. (PMID:19016376)
• SMILE is a novel corepressor of ERRgamma, and SIRT1 has a role as a novel repressive mechanism for SMILE and ERRgamma inverse agonist (PMID:19690166)
• SMILE is involved in the endoplasmic reticulum stress response, by modulating proteasome activity and XBP-1 transcript expression. This function of SMILE may influence immune cell behavior in the context of transplantation. (PMID:21603654)
• the curcumin/LKB1/AMPK/SMILE/PGC1alpha pathway differentially regulates ER stress-mediated gene transcription (PMID:21994947)
• a microarray study of SMILE knock-down and PMA activation in HeLa cells was compared to earlier analysis based on microarray data of kidney allograft tolerance and rejection to determine possible new genes and gene networks involved in kidney transplantation (PMID:22134986)
• CREBZF, a novel Smad8-binding protein. (PMID:22707059)
• Our objective was to determine the molecular mechanisms by which Zhangfei influences medulloblastoma cell lines (PMID:22798206)
• The transcription factor CREBZF is a novel positive regulator of p53. (PMID:22983008)
• Zhangfei had a suppressive effect on most unfolded protein response genes. (PMID:24155933)
• Zhangfei/CREBZF stabilizes p53 and co-localizes with it in cellular nuclei; the bLZip domain of Zhangfei is required for its profound effects on cell growth and interaction with p53. (PMID:24200963)
• Results indicate that Ursodeoxycholic acid (UDCA) activates SMILE gene expression, which leads to repression of liver X receptor alpha (LXRalpha)-mediated hepatic lipogenic enzyme gene expression. (PMID:24265317)
• miRNAs as potential biomarkers for the progression of gastric cancer inhibit CREBZF and regulate migration of gastric adenocarcinoma cells. (PMID:32218690)
• Up-regulation of long noncoding RNA MBNL1-AS1 suppresses breast cancer progression by modulating miR-423-5p/CREBZF axis. (PMID:35094653)
• SMILE Downregulation during Melanogenesis Induces MITF Transcription in B16F10 Cells. (PMID:36499416)
• Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression. (PMID:36680394)
• When molecular outsmarts morphology: Malignant ossifying fibromyxoid tumors masquerading as osteosarcomas, including a novel CREBZF::PHF1 fusion. (PMID:37819540)
• Macrophage CREBZF Orchestrates Inflammatory Response to Potentiate Insulin Resistance and Type 2 Diabetes. (PMID:38286660)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	crebzf	ENSDARG00000089787
mus_musculus	Crebzf	ENSMUSG00000051451
rattus_norvegicus	Crebzf	ENSRNOG00000018987

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2675296) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased grip strength	1

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CCDC83	protein-coding	220047
CCDC89	protein-coding	220388
SYTL2	protein-coding	54843
TMEM126B	protein-coding	55863
TMEM126A	protein-coding	84233
DLG2	protein-coding	1740

Protein

Protein identifiers

CREB/ATF bZIP transcription factor — Q9NS37 (reviewed: Q9NS37)

Alternative names: Host cell factor-binding transcription factor Zhangfei

All UniProt accessions (4): Q9NS37, E9PIM0, H0YDC7, J3KN20

UniProt curated annotations — full annotation on UniProt →

Function. Strongly activates transcription when bound to HCFC1. Suppresses the expression of HSV proteins in cells infected with the virus in a HCFC1-dependent manner. Also suppresses the HCFC1-dependent transcriptional activation by CREB3 and reduces the amount of CREB3 in the cell. Able to down-regulate expression of some cellular genes in CREBZF-expressing cells.

Subunit / interactions. Interacts with HCFC1; the interaction inhibits CREB3 transcriptional activity. Interacts with CREB3; the interaction occurs only in combination with HCFC1.

Subcellular location. Nucleus.

Tissue specificity. In adults, expressed most abundantly in heart, liver and skeletal muscle, moderately abundant in kidney and pancreas, and barely detectable in lung. In fetal tissues, expressed most abundantly in kidney and very low amounts in heart, lung and liver.

Miscellaneous. Named ‘Zhangfei’ after a legendary Chinese warrior who was contemporary with Luman in around 220 AD.

Similarity. Belongs to the bZIP family. ATF subfamily.

RefSeq proteins (1): NP_001034707* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004827	bZIP	Domain
IPR046347	bZIP_sf	Homologous_superfamily

Pfam: PF00170

UniProt features (17 total): region of interest 5, compositionally biased region 4, mutagenesis site 3, chain 1, domain 1, modified residue 1, sequence conflict 1, short sequence motif 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NS37-F1	62.65	0.18

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Basic domains

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria; nucleoplasm

Antibody reliability (HPA): IH uncertain · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1)

Type	Positions
Phosphoserine	50

Mutagenesis-validated functional residues (3)

Position	Phenotype
303	significantly reduced binding to hcfc1.
304	significantly reduced binding to hcfc1.
306	does not interact with hcfc1 and is inefficient at inhibiting creb3 transcriptional activity. does not colocalize with creb3 in …

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 308 (showing top): AHRARNT_01, GGGACCA_MIR133A_MIR133B, MODULE_97, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, PAX4_01, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, MODULE_182, GGAMTNNNNNTCCY_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, ATGTTAA_MIR302C, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, NFKB_Q6, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, CATTTCA_MIR203

GO Biological Process (9): DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), response to virus (GO:0009615), ATF6-mediated unfolded protein response (GO:0036500), negative regulation of gene expression, epigenetic (GO:0045814), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), integrated stress response signaling (GO:0140467), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (5): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), identical protein binding (GO:0042802), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

28 GO namespaces:

Category	Terms
regulation of DNA-templated transcription	3
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
gene expression	1
RNA biosynthetic process	1
response to other organism	1
ER-nucleus signaling pathway	1
endoplasmic reticulum unfolded protein response	1
negative regulation of gene expression	1
epigenetic regulation of gene expression	1
negative regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cellular response to stress	1
intracellular signaling cassette	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
nucleic acid binding	1
protein binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 16 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of DNA-templated transcription	BP	mutant phenotype
negative regulation of gene expression, epigenetic	BP	expression pattern
positive regulation of transcription by RNA polymerase II	BP	direct assay
regulation of transcription by RNA polymerase II	BP	direct assay
response to virus	BP	direct assay
nucleus	CC	direct assay
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 758 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CREBZF	HCFC2	Q9Y5Z7	891
CREBZF	CREB3	O43889	873
CREBZF	HCFC1	P51610	840
CREBZF	CREB3L4	Q8TEY5	759
CREBZF	POU2F1	P14859	603
CREBZF	CANX	P27824	490
CREBZF	KAT7	O95251	370
CREBZF	FNBP1L	Q5T0N5	370
CREBZF	TLK1	Q9UKI8	370
CREBZF	SLC35F4	A4IF30	365
CREBZF	EDF1	O60869	362
CREBZF	NR0B2	Q15466	337
CREBZF	EVA1B	Q9NVM1	321
CREBZF	CREB1	P16220	307
CREBZF	RBM18	Q96H35	304

IntAct

Human interaction partners of CREBZF in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

25 partners by confidence:

Partner	Interaction type	MIscore	Records
ATF4	direct interaction	0.780	7
HCFC1	physical association	0.770	11
RALBP1	physical association	0.740	3
NFE2L2	physical association	0.630	5
XBP1	direct interaction	0.620	4
NFE2L1	direct interaction	0.620	3
CREB3	direct interaction	0.620	2
TTC23	physical association	0.560	6
ACYP2	physical association	0.560	3
CTNNBL1	physical association	0.560	3
HBZ	direct interaction	0.560	3
TAF4	direct interaction	0.560	2
SIRT1	physical association	0.520	3
ATF6B	direct interaction	0.440	1
NFE2	direct interaction	0.440	1
ESRRG	physical association	0.400	1
SPG11	physical association	0.370	1
ZNF512B	physical association	0.370	1
BTG3	physical association	0.000	1
DSCR9	physical association	0.000	1
FMR1	physical association	0.000	1
LCOR	physical association	0.000	1
NRIP1	physical association	0.000	1
RSPH1	physical association	0.000	1
TIAM1	physical association	0.000	1

BioGRID (44 interactions; top human partners by supporting records): HCFC1 (Two-hybrid; 4 records), NFE2L2 (Two-hybrid; 3 records), RALBP1 (Affinity Capture-MS; 3 records), BACH1 (Affinity Capture-MS; 2 records), TP53 (Reconstituted Complex; 2 records), TTC23 (Two-hybrid; 2 records), VWA5A (Affinity Capture-MS; 2 records), XBP1 (FRET; 2 records), ACYP2 (Two-hybrid), APEX1 (Affinity Capture-RNA), ATF4 (FRET), ATF6B (FRET), BTG3 (Two-hybrid), CREB3L3 (Affinity Capture-Western), CTNNBL1 (Two-hybrid)

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
endoplasmic reticulum unfolded protein response	6	73.9×	6e-08

Disease & clinical

Genetic variants

Variant evidence for CREBZF: 53 ClinVar records (0 pathogenic / likely pathogenic); 1 GWAS association.

ClinVar

53 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	48
Likely benign	0
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 20 predictions of 498):

Position(s)	Effect	Δscore	Sites
11:85662460	acceptor_gain	0.9900
11:85663875	donor_gain	0.9900
11:85660598–85660599	acceptor_loss	0.9800	6
11:85662459	acceptor_gain	0.9800
11:85663097	donor_gain	0.9800
11:85663837	donor_gain	0.9800
11:85660600	acceptor_loss	0.9700
11:85663708	donor_gain	0.9700
11:85663522–85663523	donor_loss	0.9500	6
11:85663805	donor_gain	0.9300

AlphaMissense

869 missense substitutions predicted likely pathogenic (of 2,263 scored), across 188 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H330	8	0.998	1.000
N221	8	0.994	0.999
N243	8	0.993	0.999
F340	8	0.986	1.000
H304	8	0.979	0.991
N250	8	0.973	0.995
N273	8	0.972	0.999
F296	8	0.949	0.993
D332	8	0.948	0.989
F159	8	0.947	0.996
D305	8	0.944	0.986
D303	8	0.905	0.974
D100	8	0.902	0.971
D109	8	0.880	0.964
D112	8	0.786	0.888
C328	7	1.000	1.000
C341	7	0.999	1.000
C344	7	0.999	1.000
E233	7	0.995	0.999
K225	7	0.991	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000135
Rectum Adenocarcinoma (TCGA)	favorable	0.000156

Disease associations

OMIM: gene MIM:606444 | disease phenotypes:

GWAS associations

1 associations:

Study	Trait	p-value
GCST010002_196	Refractive error	2e-53

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
trichostatin A	affects cotreatment, decreases expression	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
tetrathiomolybdate	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	increases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
dorsomorphin	affects cotreatment, decreases expression	1
Vehicle Emissions	decreases expression, decreases reaction	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	decreases expression	1
Demecolcine	decreases expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	increases expression	1
Methyl Methanesulfonate	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.