Is ZEB2 p.Pro918Ser (c.2752C>T) pathogenic?

ZEB2 p.Pro918Ser (c.2752C>T) is classified Conflicting classifications of pathogenicity in ZEB2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-01-04). AlphaMissense: ambiguous (0.3689); Ultra-rare (popmax 0.0166%, mid); Associated with ZEB2-related disorder.

What condition is associated with ZEB2 p.Pro918Ser (c.2752C>T)?

ZEB2 p.Pro918Ser (c.2752C>T) is associated with ZEB2-related disorder (ClinVar).

How common is ZEB2 p.Pro918Ser (c.2752C>T) in the general population?

ZEB2 p.Pro918Ser (c.2752C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about ZEB2 p.Pro918Ser (c.2752C>T)?

AlphaMissense predicts ambiguous (score 0.3689) — an in-silico prediction, not a clinical call.

ZEB2 p.Pro918Ser

c.2752C>T · rs1560605894 · VCV808806

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3689 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ZEB2-related disorder

Computational evidence

Protein change
AlphaMissense	0.3689	ambiguous
REVEL	0.187	benign-leaning
SaProt	LLR -7.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 2,879 bp · p 1.1e-07 · regional, not allelic
Overall
CADD	28.6	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 0.0166% Middle Eastern · 1/6,034 alleles

Overall 0.000274% 4/1,461,796 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,034
Remaining individualsnot grpmax-eligible	0.0048%	20,835

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.Pro918Ser
Coding: c.2752C>T
MANE Select: NM_014795
dbSNP: rs1560605894
Type: single nucleotide variant
Location: chr2:144398435 (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

ZEB2-related disorder

Similar variants

ZEB2 p.Arg1016Ter Pathogenic/Likely pathogenic ★★ same condition
ZEB2 p.Arg302Ter Pathogenic/Likely pathogenic ★★ same condition
ZEB2 p.Arg695Ter Pathogenic ★★ same condition
ZEB2 p.His1049Pro Pathogenic/Likely pathogenic ★★ same condition
ZEB2 p.His300Tyr Pathogenic/Likely pathogenic ★★ same condition
ZEB2 p.Tyr489Ter Pathogenic ★★ same condition
ZEB2 p.Gln550Ter Likely pathogenic ★ same condition
ZEB2 p.Glu146Ter 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-pro918ser (accessed [today's date]).

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