ZEB2

Chr 2AD

zinc finger E-box binding homeobox 2

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

NCBI Gene: 9839 ENSG00000169554 UniProt: O60315 OMIM: 605802

The encoded protein is a DNA-binding transcriptional repressor that interacts with activated SMADs and localizes to the nucleus. Loss-of-function mutations cause Mowat-Wilson syndrome through an autosomal dominant inheritance pattern. The gene is highly intolerant to loss-of-function variation, consistent with haploinsufficiency as the disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Mowat-Wilson syndromeMIM #235730

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Mowat-Wilson syndrome · AD · ClinGen 2026

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

199

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.11

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — ZEB2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.02 (0.01–0.11)

0≤0.351.4

Missense OE?0.57 (0.52–0.62)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 1 / 44.3Missense obs/exp: 378 / 663.9Syn Z: -0.23

Background carrier burden — how many people carry a rare variant somewhere in ZEB2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 73

1,275 rare PASS variants

Rare truncating (LoF)

1 in 670

59 rare PASS variants

Rare synonymous (reference)

1 in 84

559 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ZEB2. 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 87	1 in 810
South Asian	~43k	1 in 56	1 in 420
Remaining (unassigned)	~30k	1 in 66	1 in 510
European (Finnish)	~27k	1 in 270	1 in 1,200
Admixed American	~22k	1 in 53	1 in 310
African / African American	~21k	1 in 57	1 in 560
East Asian	~20k	1 in 78	1 in 2,300
Ashkenazi Jewish	~13k	1 in 230	≈ 1 in 4,200
Middle Eastern	~2,884	1 in 59	≈ 1 in 950

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.