Is ZEB2 p.Cys495Trp (c.1485C>G) pathogenic?

ZEB2 p.Cys495Trp (c.1485C>G) is classified Uncertain significance in ZEB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-08). AlphaMissense: likely benign (0.2132); Very rare (popmax 0.00223%, eas); Associated with Mowat-Wilson syndrome.

What condition is associated with ZEB2 p.Cys495Trp (c.1485C>G)?

ZEB2 p.Cys495Trp (c.1485C>G) is associated with Mowat-Wilson syndrome (ClinVar).

How common is ZEB2 p.Cys495Trp (c.1485C>G) in the general population?

ZEB2 p.Cys495Trp (c.1485C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ZEB2 p.Cys495Trp (c.1485C>G)?

AlphaMissense predicts likely benign (score 0.2132) — an in-silico prediction, not a clinical call.

ZEB2 p.Cys495Trp

c.1485C>G · rs1703282674 · VCV2694338

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2132 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Mowat-Wilson syndrome

Computational evidence

Protein change
AlphaMissense	0.2132	likely benign
REVEL	0.486	indeterminate
SaProt	LLR -6.53	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 2.1	GERP -1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 695 bp · p 0.0021 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Overall 6.2e-05% 1/1,614,194 alleles · very rare exomes 1/1,461,850 · genomes 0/152,344 · joint denominator

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.Cys495Trp
Coding: c.1485C>G
MANE Select: NM_014795
dbSNP: rs1703282674
Type: single nucleotide variant
Location: chr2:144399702 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 48.91 · 1 PDB

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.Cys495Arg 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
ZEB2 p.Arg343Ter 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-cys495trp (accessed [today's date]).

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