Is CDH1 p.Pro42Leu (c.125C>T) pathogenic?

CDH1 p.Pro42Leu (c.125C>T) is classified Likely benign in CDH1 (ClinVar, Expert panel, 8 submitters; last evaluated 2023-08-02). AlphaMissense: likely benign (0.1407); Very rare (popmax 0.00392%, amr); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.Pro42Leu (c.125C>T)?

CDH1 p.Pro42Leu (c.125C>T) is associated with CDH1-related diffuse gastric and lobular breast cancer syndrome, hereditary diffuse gastric adenocarcinoma, ovarian cancer (ClinVar).

How common is CDH1 p.Pro42Leu (c.125C>T) in the general population?

CDH1 p.Pro42Leu (c.125C>T) is very rare (popmax 0.00392%, amr) (gnomAD).

What do computational predictors say about CDH1 p.Pro42Leu (c.125C>T)?

AlphaMissense predicts likely benign (score 0.1407) — an in-silico prediction, not a clinical call.

CDH1 p.Pro42Leu

c.125C>T · rs876659333 · VCV231745

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1407 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00392%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDH1-related diffuse gastric and lobular breast cancer syndrome

ClinGen expert panel — CDH1 VCEP

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

BS2

Curation rationale (ClinGen, verbatim)

The c.125C>T (NM_004360.5) variant in CDH1 is a missense variant predicted to cause substitution of Pro by Leu at amino acid 42 (p.Pro42Leu). This variant has been observed in more than 10 heterozygous individuals with no DGC, SRC tumours and whose families do not suggest HDGC (BS2; GeneDx, Invitae, Color). In summary, the CDH1 VCEP classified the variant as likely benign for DGLBCS based on BS2 alone based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023)

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

Computational evidence

Protein change
AlphaMissense	0.1407	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -7.64	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 2.6	GERP 0.81, phastCons 0.99
Regional constraint	o/e 1.05	unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic
Overall
CADD	22.3	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

Grpmax group 0.00392% Admixed American · 2/50,958 alleles

Filtering AF 0.000651% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000244%

Overall 0.000322% 5/1,550,900 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00499%	20,023
Admixed Americangrpmax	0.00392%	25,479

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro42Leu
Coding: c.125C>T
MANE Select: NM_004360
dbSNP: rs876659333
Type: single nucleotide variant
Location: chr16:68738373 (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 ovarian cancer hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

CDH1 p.Pro42Ser Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro42Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Pro42= Likely benign ★ same residue
CDH1 p.Pro42His Likely benign ★ same residue
CDH1 p.Pro42fs Pathogenic ★★★ 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-pro42leu (accessed [today's date]).

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