Is CDH1 p.Pro201His (c.602C>A) pathogenic?

CDH1 p.Pro201His (c.602C>A) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-10-21). AlphaMissense: likely pathogenic (0.9609); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Pro201His (c.602C>A)?

CDH1 p.Pro201His (c.602C>A) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Pro201His (c.602C>A) in the general population?

CDH1 p.Pro201His (c.602C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CDH1 p.Pro201His (c.602C>A)?

AlphaMissense predicts likely pathogenic (score 0.9609) — an in-silico prediction, not a clinical call.

CDH1 p.Pro201His

c.602C>A · rs146777134 · VCV479493

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9609	likely pathogenic · top 10% in CDH1
REVEL	0.616	indeterminate
SaProt	LLR -13.95	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	24.9	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,990 alleles

Overall 6.84e-05% 1/1,461,832 alleles · very rare

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: CDH1
Protein: p.Pro201His
Coding: c.602C>A
MANE Select: NM_004360
dbSNP: rs146777134
Type: single nucleotide variant
Location: chr16:68808763 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 201: a β-strand; 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

Also linked: hereditary diffuse gastric adenocarcinoma

Similar variants

CDH1 p.Pro201Ala Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro201Leu Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro201Thr Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro201= Benign/Likely benign ★★ same residue
CDH1 p.Pro201Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Pro201Ser Uncertain significance ★ ⚠ same residue
CDH1 p.Pro201fs Pathogenic ★★ same residue
CDH1 c.1008+2T>C 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/cdh1-p-pro201his (accessed [today's date]).

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