Is CDH1 p.Pro799Arg (c.2396C>G) pathogenic?

CDH1 p.Pro799Arg (c.2396C>G) is classified Uncertain significance in CDH1 (ClinVar, Expert panel, 4 submitters; last evaluated 2023-08-21). AlphaMissense: likely benign (0.2798); Absent from gnomAD v4.1; Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.Pro799Arg (c.2396C>G)?

CDH1 p.Pro799Arg (c.2396C>G) is associated with CDH1-related diffuse gastric and lobular breast cancer syndrome, hereditary diffuse gastric adenocarcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDH1 p.Pro799Arg (c.2396C>G) in the general population?

CDH1 p.Pro799Arg (c.2396C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH1 p.Pro799Arg (c.2396C>G)?

AlphaMissense predicts likely benign (score 0.2798) — an in-silico prediction, not a clinical call.

CDH1 p.Pro799Arg

c.2396C>G · rs587781335 · VCV140871

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2798 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDH1-related diffuse gastric and lobular breast cancer syndrome

ClinGen expert panel — CDH1 VCEP

Uncertain Significance for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):

PM2_Supporting

Curation rationale (ClinGen, verbatim)

The c.2396C>G (p.Pro799Arg) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is no other supporting data that meet criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.2798	likely benign
REVEL	0.722	pathogenic-leaning
SaProt	LLR -10.66	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	26.3	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.Pro799Arg
Coding: c.2396C>G
MANE Select: NM_004360
dbSNP: rs587781335
Type: single nucleotide variant
Location: chr16:68829754 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB

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

Disease context

Also linked: hereditary diffuse gastric adenocarcinoma hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

CDH1 p.Pro799Ser Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro799Thr Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro799Ala Uncertain significance ★ ⚠ same residue
CDH1 p.Pro799Leu Uncertain significance ★ ⚠ same residue
CDH1 p.Pro799= Likely benign ★ 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

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-pro799arg (accessed [today's date]).

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