# NM_014795.4(ZEB2):c.216A>C (p.Pro72=)

https://sugi.bio/variant/zeb2-p-pro72

## Summary

**ZEB2 p.Pro72= (c.216A>C)** is classified **Likely benign** in ZEB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-01). Ultra-rare (popmax 0.01%, amr); Associated with Mowat-Wilson syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs764560219 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.01%, amr)

## For patients & families {#patients}

This is a change in the ZEB2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Mowat-Wilson syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009673/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ZEB2](https://sugi.bio/atlas/gene/ZEB2/) |
| Protein change (HGVS p.) | p.Pro72= |
| Coding change (HGVS c.) | c.216A>C |
| MANE Select transcript | [NM_014795](https://www.ncbi.nlm.nih.gov/nuccore/NM_014795) |
| dbSNP | [rs764560219](https://www.ncbi.nlm.nih.gov/snp/rs764560219/) |
| Variant type | single nucleotide variant |
| Location | chr2:144429884-144429884 (GRCh38) |
| ClinVar | [VCV534646](https://www.ncbi.nlm.nih.gov/clinvar/variation/534646/) |

**All HGVS expressions:** `NC_000002.11:g.145187451T>G`, `NC_000002.12:g.144429884T>G`, `NG_016431.1:g.95508A>C`, `NM_001171653.2:c.216A>C`, `NM_014795.4:c.216A>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.504, GERP -1.95, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 7.586**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for ZEB2 (818 scored positions, the nearest 3 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.01%** (amr) · FAF95 0.00429% · FAF99 0.00295% · 6/59,932 in the highest group · 6/1,613,734 alleles overall — ultra-rare (popmax 0.01%, amr).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ZEB2** population constraint: LOEUF 0.114, pLI 1, missense-Z 5.6355; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Mowat-Wilson syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **72** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 48.91, 5% of residues very-high.

**1 experimental structure(s)** (PDB): [2DA7](https://www.rcsb.org/structure/2DA7).

## What this gene does {#gene-function}

*Describes the biological roles of ZEB2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ZEB2's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. p.Pro72= falls in the disordered region.


### Pathways affected {#pathways}

ZEB2 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Negative Regulation of CDH1 Gene Transcription](https://reactome.org/content/detail/R-HSA-9764725) | curated |
| [Positive Regulation of CDH1 Gene Transcription](https://reactome.org/content/detail/R-HSA-9764790) | curated |
| [Formation of the anterior neural plate](https://reactome.org/content/detail/R-HSA-9823739) | electronic |
| [Formation of the posterior neural plate](https://reactome.org/content/detail/R-HSA-9832991) | electronic |
| [Regulation of CDH11 gene transcription](https://reactome.org/content/detail/R-HSA-9762293) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription repressor activity, RNA polymerase II-specific.

**Biological process:** negative regulation of transcription by RNA polymerase II, positive regulation of transforming growth factor beta receptor signaling pathway, positive regulation of transcription by RNA polymerase II, positive regulation of canonical Wnt signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-01.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2021–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-06-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-01 |

## Associated conditions {#conditions}

[Mowat-Wilson syndrome](https://sugi.bio/atlas/disease/mowat-wilson-syndrome/).

**Reported phenotype names (ClinVar):** Mowat-Wilson syndrome, not provided, none provided, Classic Mowat-Wilson Syndrome.

## Similar variants {#similar}

Related ZEB2 variant pages (same residue, condition, or type): [ZEB2 p.Pro72Arg](/variant/zeb2-p-pro72arg), [ZEB2 p.Pro72Leu](/variant/zeb2-p-pro72leu), [ZEB2 c.2886+1G>A](/variant/zeb2-c-2886-plus-1g-a), [ZEB2 c.73+1G>A](/variant/zeb2-c-73-plus-1g-a), [ZEB2 c.73+2T>C](/variant/zeb2-c-73-plus-2t-c), [ZEB2 c.808-2A>G](/variant/zeb2-c-808-minus-2a-g), [ZEB2 p.Arg1016Ter](/variant/zeb2-p-arg1016ter), [ZEB2 p.Arg302Ter](/variant/zeb2-p-arg302ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 534646). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*