Is CDH1 p.Pro3Ser (c.7C>T) pathogenic?

CDH1 p.Pro3Ser (c.7C>T) is classified Uncertain significance in CDH1 (ClinVar, Expert panel, 5 submitters; last evaluated 2023-08-21). AlphaMissense: likely benign (0.0636); Very rare (popmax 8.72e-05%, nfe); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.Pro3Ser (c.7C>T)?

CDH1 p.Pro3Ser (c.7C>T) 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.Pro3Ser (c.7C>T) in the general population?

CDH1 p.Pro3Ser (c.7C>T) is very rare (popmax 8.72e-05%, nfe) (gnomAD).

What do computational predictors say about CDH1 p.Pro3Ser (c.7C>T)?

AlphaMissense predicts likely benign (score 0.0636) — an in-silico prediction, not a clinical call.

CDH1 p.Pro3Ser

c.7C>T · rs1064793079 · VCV418111

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.72e-05%, nfe)

Missense predictors

0/3 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.7C>T (p.Pro3Ser) is absent from gnomAD (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, the clinical significance of this variant is classified as a variant of uncertain significance based on 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	0.0636	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -6.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP -2.5, phastCons 0.17
Regional constraint	o/e 1.05	unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic
Overall
CADD	10.16	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 8.72e-05% European (non-Finnish) · 1/1,146,718 alleles

Overall 7.24e-05% 1/1,381,752 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.Pro3Ser
Coding: c.7C>T
MANE Select: NM_004360
dbSNP: rs1064793079
Type: single nucleotide variant
Location: chr16:68737422 (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

Similar variants

CDH1 p.Pro3Arg Likely benign ★★★ same residue
CDH1 p.Pro3Thr Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro3= Likely benign ★ same residue
CDH1 p.Pro3fs Pathogenic ★ same residue
CDH1 p.Pro3Phe 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

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-pro3ser (accessed [today's date]).

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