ZEB1

Chr 10AD

zinc finger E-box binding homeobox 1

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

NCBI Gene: 6935 ENSG00000148516 UniProt: P37275 OMIM: 189909

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Corneal dystrophy, Fuchs endothelial, 6MIM #613270

Corneal dystrophy, posterior polymorphous, 3MIM #609141

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Corneal dystrophy, Fuchs endothelial; Corneal dystrophy, posterior polymorphous; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

481

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.32

LOEUF· LoF intol.

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in ZEB1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 65

1,185 rare PASS variants

Rare truncating (LoF)

1 in 2,800

81 rare PASS variants

Rare synonymous (reference)

1 in 89

450 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ZEB1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 2,600
South Asian	~43k	1 in 45	1 in 2,700
Remaining (unassigned)	~30k	1 in 50	1 in 4,300
European (Finnish)	~27k	1 in 180	1 in 2,700
Admixed American	~22k	1 in 60	1 in 3,200
African / African American	~21k	1 in 40	≈ 1 in 4,400
East Asian	~20k	1 in 50	≈ 1 in 6,500
Ashkenazi Jewish	~13k	1 in 210	1 in 2,200
Middle Eastern	~2,884	1 in 78	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 9 of 9 coding exons well covered in gnomAD exomes. Genomes: 8 of 9 (exon 1 below).? see exons ↓