Is CDH1 p.Thr217Arg (c.650C>G) pathogenic?

CDH1 p.Thr217Arg (c.650C>G) is classified Uncertain significance in CDH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-30). AlphaMissense: ambiguous (0.5253); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Thr217Arg (c.650C>G)?

CDH1 p.Thr217Arg (c.650C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDH1 p.Thr217Arg (c.650C>G) in the general population?

CDH1 p.Thr217Arg (c.650C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH1 p.Thr217Arg (c.650C>G)?

AlphaMissense predicts ambiguous (score 0.5253) — an in-silico prediction, not a clinical call.

CDH1 p.Thr217Arg

c.650C>G · rs778382252 · VCV1753954

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5253 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5253	ambiguous
REVEL	0.317	indeterminate
SaProt	LLR -11.76	damaging
Splicing
SpliceAI	Δ0.53	donor gain · deltas
Constraint at this position
Conservation	phyloP 2.7	GERP 1, phastCons 0.99
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	30.0	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

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.Thr217Arg
Coding: c.650C>G
MANE Select: NM_004360
dbSNP: rs778382252
Type: single nucleotide variant
Location: chr16:68808811 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 217: 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.Thr217Ile Uncertain significance ★★ ⚠ same residue
CDH1 p.Thr217Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Thr217= Benign/Likely benign ★★ same residue
CDH1 p.Thr217Ala 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

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-thr217arg (accessed [today's date]).

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