Is ZEB2 p.Pro4Arg (c.11C>G) pathogenic?

ZEB2 p.Pro4Arg (c.11C>G) is classified Conflicting classifications of pathogenicity in ZEB2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-08). AlphaMissense: likely benign (0.2218); Very rare (popmax 0.00167%, amr); Associated with Mowat-Wilson syndrome.

What condition is associated with ZEB2 p.Pro4Arg (c.11C>G)?

ZEB2 p.Pro4Arg (c.11C>G) is associated with Mowat-Wilson syndrome (ClinVar).

How common is ZEB2 p.Pro4Arg (c.11C>G) in the general population?

ZEB2 p.Pro4Arg (c.11C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ZEB2 p.Pro4Arg (c.11C>G)?

AlphaMissense predicts likely benign (score 0.2218) — an in-silico prediction, not a clinical call.

ZEB2 p.Pro4Arg

c.11C>G · rs577362409 · VCV2839019

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2218 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Mowat-Wilson syndrome

Computational evidence

Protein change
AlphaMissense	0.2218	likely benign
REVEL	0.368	indeterminate
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 112 kb · p 0.0024 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,016 alleles

Overall 0.000137% 2/1,461,390 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,016
South Asian	0.0011%	91,082

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ZEB2
Protein: p.Pro4Arg
Coding: c.11C>G
MANE Select: NM_014795
dbSNP: rs577362409
Type: single nucleotide variant
Location: chr2:144517340 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 48.91 · 1 PDB
Residue 4: the 'disordered' region

Full ZEB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Mowat-Wilson syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ZEB2 p.Pro4Ala Benign/Likely benign ★★ same residue
ZEB2 p.Pro4Leu Uncertain significance ★ ⚠ same residue
ZEB2 c.2886+1G>A Pathogenic ★★ same condition
ZEB2 c.73+1G>A Pathogenic ★★ same condition
ZEB2 c.73+2T>C Pathogenic/Likely pathogenic ★★ same condition
ZEB2 c.808-2A>G Pathogenic ★★ same condition
ZEB2 p.Arg1016Ter Pathogenic/Likely pathogenic ★★ same condition
ZEB2 p.Arg302Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/zeb2-p-pro4arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown