Is CDH1 p.Pro799Ser (c.2395C>T) pathogenic?

CDH1 p.Pro799Ser (c.2395C>T) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-14). AlphaMissense: likely benign (0.2041); Very rare (popmax 6.2e-05%); Associated with hereditary diffuse gastric adenocarcinoma.

What condition is associated with CDH1 p.Pro799Ser (c.2395C>T)?

CDH1 p.Pro799Ser (c.2395C>T) is associated with hereditary diffuse gastric adenocarcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDH1 p.Pro799Ser (c.2395C>T) in the general population?

CDH1 p.Pro799Ser (c.2395C>T) is very rare (popmax 6.2e-05%) (gnomAD).

How is Hereditary diffuse gastric cancer inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDH1 p.Pro799Ser (c.2395C>T)?

AlphaMissense predicts likely benign (score 0.2041) — an in-silico prediction, not a clinical call.

CDH1 p.Pro799Ser

c.2395C>T · rs1596972749 · VCV640264

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2041 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary diffuse gastric adenocarcinoma

Computational evidence

Protein change
AlphaMissense	0.2041	likely benign
REVEL	0.427	indeterminate
SaProt	LLR -9.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, 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 tolerated — 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 6.2e-05%

Overall 6.2e-05% 1/1,613,954 alleles · very rare exomes 1/1,461,850 · genomes 0/152,104 · joint denominator

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.Pro799Ser
Coding: c.2395C>T
MANE Select: NM_004360
dbSNP: rs1596972749
Type: single nucleotide variant
Location: chr16:68829753 (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

hereditary diffuse gastric adenocarcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Hereditary diffuse gastric cancer (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDH1 p.Pro799Arg 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-pro799ser (accessed [today's date]).

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