ZEB1

Chr 10

zinc finger E-box binding homeobox 1

Also known as: AREB6, BZP, DELTAEF1, FECD6, NIL2A, PPCD3, TCF8, ZFHEP

NCBI Gene: 6935 ENSG00000148516 UniProt: P37275

This zinc finger transcription factor acts as a transcriptional repressor, inhibiting interleukin-2 gene expression and regulating epithelial-mesenchymal transition and neuronal differentiation. Mutations cause autosomal dominant corneal dystrophies including Fuchs endothelial corneal dystrophy and posterior polymorphous corneal dystrophy. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a zinc finger transcription factor. The encoded protein likely plays a role in transcriptional repression of interleukin 2. Mutations in this gene have been associated with posterior polymorphous corneal dystrophy-3 and late-onset Fuchs endothelial corneal dystrophy. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Mar 2010]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.32

Clinical Summary— ZEB1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

34 unique Pathogenic / Likely Pathogenic· 126 VUS of 212 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.967

Z-score 4.96

OE 0.17 (0.10–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.60Z-score

OE missense 0.81 (0.75–0.88)

465 obs / 573.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.10–0.32)

0≤0.351.4

Missense OE?0.81 (0.75–0.88)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 7 / 41.4Missense obs/exp: 465 / 573.1Syn Z: 0.73

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveZEB1-related corneal dystrophy, posterior polymorphousLOFAD

limitedZEB1-related corneal dystrophy Fuchs endothelialLOFAD

This gene — mechanism propensity

0.2599th %ile

GOF

0.1999th %ile

LOF

0.80top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 88% of P/LP variants are LoF · LOEUF 0.32

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

212 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23

Likely Pathogenic11

VUS126

Likely Benign25

Benign17

Conflicting5

Pathogenic

Likely Pathogenic

126

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	21	2	0	0	23
Likely Pathogenic	9	2	0	0	11
VUS	2	123	1	0	126
Likely Benign	0	8	3	14	25
Benign	0	7	2	8	17
Conflicting	—				5
Total	32	142	6	22	207

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap ZEB1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →