ZEB2

Chr 2AD

zinc finger E-box binding homeobox 2

Also known as: HSPC082, SIP-1, SIP1, SMADIP1, ZFHX1B

NCBI Gene: 9839ENSG00000169554UniProt: O60315

The protein encoded by this gene is a member of the Zfh1 family of 2-handed zinc finger/homeodomain proteins. It is located in the nucleus and functions as a DNA-binding transcriptional repressor that interacts with activated SMADs. Mutations in this gene are associated with Hirschsprung disease/Mowat-Wilson syndrome. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jan 2010]

Primary Disease Associations & Inheritance

Mowat-Wilson syndromeMIM #235730
AD
1663
ClinVar variants
66
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— ZEB2
⚡
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
66 Pathogenic / Likely Pathogenic· 191 VUS of 1663 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.11LOEUF
pLI 1.000
Z-score 6.03
OE 0.02 (0.01–0.11)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
3.94Z-score
OE missense 0.57 (0.52–0.62)
378 obs / 663.9 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.02 (0.01–0.11)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.57 (0.52–0.62)
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.1.02
0≤1.21.6
LoF obs/exp: 1 / 44.3Missense obs/exp: 378 / 663.9Syn Z: -0.23

ClinVar Variant Classifications

1663 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44
Likely Pathogenic22
VUS191
Likely Benign102
Benign21
Conflicting4
44
Pathogenic
22
Likely Pathogenic
191
VUS
102
Likely Benign
21
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
24
6
14
0
44
Likely Pathogenic
12
4
6
0
22
VUS
3
175
12
1
191
Likely Benign
0
6
21
75
102
Benign
0
16
5
0
21
Conflicting
—4
Total392075876384

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

View in ClinVar →

Protein Context — Lollipop Plot

ZEB2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ZEB2-related Mowat-Wilson syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mowat-Wilson syndrome

MIM #235730

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Human dendritic cell subsets: an update.
Collin M et al.·Immunology
2018Review
Age-associated CD4(+) T cells with B cell-promoting functions are regulated by ZEB2 in autoimmunity.
Goto M et al.·Sci Immunol
2024
Mechanism of epithelial-mesenchymal transition in cancer and its regulation by natural compounds.
Ang HL et al.·Med Res Rev
2023Review
Expanding the genotypes and phenotypes for 19 rare diseases by exome sequencing performed in pediatric intensive care unit.
Liu J et al.·Hum Mutat
2021
14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia.
Di Giacomo D et al.·Blood
2021Clinical trial
Mowat-Wilson syndrome.
Garavelli L et al.·Orphanet J Rare Dis
2007Review
Cathepsin L upregulation-induced EMT phenotype is associated with the acquisition of cisplatin or paclitaxel resistance in A549 cells.
Han ML et al.·Acta Pharmacol Sin
2016
Long non-coding RNA AFAP1-AS1 accelerates lung cancer cells migration and invasion by interacting with SNIP1 to upregulate c-Myc.
Zhong Y et al.·Signal Transduct Target Ther
2021
Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery.
Di Franco S et al.·Nat Commun
2021
ZEB2 Shapes the Epigenetic Landscape of Atherosclerosis.
Cheng P et al.·Circulation
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
KDM6B/Pdk1 glycolytic pathway-driven ZEB2 lactylation promotes cellular cementum formation.
Yang Z et al.·Int J Oral Sci
2026🔓 Open Access
Case Report: Identification of a de novo missense variant in the N-terminal zinc-finger domain of ZEB2 in a patient presenting with neurodevelopmental delay and recurrent pulmonary infections.
Chen J et al.·Front Genet
2026🔓 Open AccessCase report
LncRNA ZEB2-AS1 Modulates ox-LDL-Induced Vascular Endothelial Cell Dysfunction in Atherosclerosis by Sponging miR-149-5p.
Zhang K et al.·J Biochem Mol Toxicol
2026
Zeb2os Hinders Cardiac Healing by Suppressing ZEB2 Reactivation and Cardiomyocyte Dedifferentiation.
Caliandro R et al.·Circ Res
2026
Hyperglycemia-induced P300/CBP acetyltransferase drives ZEB2-mediated pro-inflammatory macrophages and delays wound healing.
Roy S et al.·JCI Insight
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Peri-implantitis

Expression of Epithelial-Mesenchymal Transition Associated Markers in Peri-implant Tissues

RECRUITING
NCT05832541University of BaghdadStarted 2022-08-18

External Resources

Links to major genomics databases and tools