Is ZEB2 p.Pro4Ala (c.10C>G) pathogenic?

ZEB2 p.Pro4Ala (c.10C>G) is classified Benign/Likely benign in ZEB2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0846); Ultra-rare (popmax 0.06%, amr); Associated with Inborn genetic diseases.

What condition is associated with ZEB2 p.Pro4Ala (c.10C>G)?

ZEB2 p.Pro4Ala (c.10C>G) is associated with Inborn genetic diseases, Mowat-Wilson syndrome (ClinVar).

How common is ZEB2 p.Pro4Ala (c.10C>G) in the general population?

ZEB2 p.Pro4Ala (c.10C>G) is ultra-rare (popmax 0.06%, amr) (gnomAD).

What do computational predictors say about ZEB2 p.Pro4Ala (c.10C>G)?

AlphaMissense predicts likely benign (score 0.0846) — an in-silico prediction, not a clinical call.

ZEB2 p.Pro4Ala

c.10C>G · rs146394306 · VCV181761

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0846 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0846	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -5.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 112 kb · p 0.0024 · regional, not allelic
Overall
CADD	24.3	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 0.06% Admixed American · 36/60,020 alleles

Filtering AF 0.0444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0392%

Overall 0.0138% 223/1,613,612 alleles · ultra-rare exomes 200/1,461,382 · genomes 23/152,230 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.06%	1,667
Remaining individualsnot grpmax-eligible	0.0176%	5,680
European (non-Finnish)	0.0143%	6,981
African / African-American	0.00933%	10,715

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.Pro4Ala
Coding: c.10C>G
MANE Select: NM_014795
dbSNP: rs146394306
Type: single nucleotide variant
Location: chr2:144517341 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Mowat-Wilson syndrome

Similar variants

ZEB2 p.Pro4Arg Conflicting classifications of pathogenicity ★ ⚠ 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-pro4ala (accessed [today's date]).

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