Is ZEB2 p.Ser1069Leu (c.3206C>T) pathogenic?

ZEB2 p.Ser1069Leu (c.3206C>T) is classified Uncertain significance in ZEB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-08). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1.

How common is ZEB2 p.Ser1069Leu (c.3206C>T) in the general population?

ZEB2 p.Ser1069Leu (c.3206C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ZEB2 p.Ser1069Leu (c.3206C>T)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

ZEB2 p.Ser1069Leu

c.3206C>T · rs1553960778 · VCV2497906

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9975	likely pathogenic · top 6% in ZEB2
REVEL	0.463	indeterminate
SaProt	LLR -15.72	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
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 0.15	constrained · MANE · 6,659 bp · p 2.5e-20 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ZEB2
Protein: p.Ser1069Leu
Coding: c.3206C>T
MANE Select: NM_014795
dbSNP: rs1553960778
Type: single nucleotide variant
Location: chr2:144389890 (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

Similar variants

ZEB2 p.Ser1069Ter Pathogenic ★★ same residue
ZEB2 p.Ser1069Trp Uncertain significance ★ ⚠ same residue
ZEB2 p.Ser1069= Likely benign ★ same residue
ZEB2 c.2886+1G>A Pathogenic ★★ same type
ZEB2 c.73+1G>A Pathogenic ★★ same type
ZEB2 c.73+2T>C Pathogenic/Likely pathogenic ★★ same type
ZEB2 c.808-2A>G Pathogenic ★★ same type
ZEB2 p.Arg1016Ter Pathogenic/Likely pathogenic ★★ same type

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-ser1069leu (accessed [today's date]).

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