Is CDH1 p.Leu220Pro (c.659T>C) pathogenic?

CDH1 p.Leu220Pro (c.659T>C) is classified Uncertain significance in CDH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-27). AlphaMissense: likely pathogenic (0.9879); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Leu220Pro (c.659T>C)?

CDH1 p.Leu220Pro (c.659T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDH1 p.Leu220Pro (c.659T>C) in the general population?

CDH1 p.Leu220Pro (c.659T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH1 p.Leu220Pro (c.659T>C)?

AlphaMissense predicts likely pathogenic (score 0.9879) — an in-silico prediction, not a clinical call.

CDH1 p.Leu220Pro

c.659T>C · VCV3998751

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9879 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9879	likely pathogenic · top 4% in CDH1
REVEL	0.88	moderately pathogenic-leaning
SaProt	LLR -13.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	27.2	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: CDH1
Protein: p.Leu220Pro
Coding: c.659T>C
MANE Select: NM_004360
Type: single nucleotide variant
Location: chr16:68808820 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 220: the cadherin 1 domain

Full CDH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH1 p.Leu220Met Uncertain significance ★★ ⚠ same residue
CDH1 p.Leu220= Benign/Likely benign ★★ same residue
CDH1 p.Leu220Arg Uncertain significance ★ ⚠ same residue
CDH1 c.1008+2T>C Likely pathogenic ★★★ same condition
CDH1 c.1137+1G>A Pathogenic ★★★ same condition
CDH1 c.1137+2T>C Likely pathogenic ★★★ same condition
CDH1 c.1565+1G>A Pathogenic ★★★ same condition
CDH1 c.1565+1G>C 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/cdh1-p-leu220pro (accessed [today's date]).

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