Is CDH1 p.Pro3Arg (c.8C>G) pathogenic?

CDH1 p.Pro3Arg (c.8C>G) is classified Likely benign in CDH1 (ClinVar, Expert panel, 21 submitters; last evaluated 2023-08-17). AlphaMissense: likely benign (0.0583); Ultra-rare (popmax 0.012%, nfe); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

How common is CDH1 p.Pro3Arg (c.8C>G) in the general population?

CDH1 p.Pro3Arg (c.8C>G) is ultra-rare (popmax 0.012%, nfe) (gnomAD).

What do computational predictors say about CDH1 p.Pro3Arg (c.8C>G)?

AlphaMissense predicts likely benign (score 0.0583) — an in-silico prediction, not a clinical call.

CDH1 p.Pro3Arg

Q: What condition is associated with CDH1 p.Pro3Arg (c.8C>G)?

CDH1 p.Pro3Arg (c.8C>G) is associated with CDH1-related diffuse gastric and lobular breast cancer syndrome, endometrial carcinoma, breast cancer (ClinVar).

c.8C>G · rs587782484 · VCV142469

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 21 submitters

AlphaMissense

likely benign

0.0583 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, nfe)

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.8C>G (p.Pro3Arg) variant has an allele frequency of 0.00025 (39/155276) in gnomAD and is observed in multiple subpopulations, with a maximum frequency of 0.00072 (7/9712) in the European (Finnish) subpopulation (http://gnomad.broadinstitute.org). This variant was observed more than 70 probands without a personal history of DGC, SRC tumours or LBC and whose families do not meet HDGC clinical criteria (BS2; SCV000210891.12, SCV000186617.6). The variant has also been identified in at least 5 individuals with LBC but whose families do not meet HDGC clinical criteria (PMID: 20921021, SCV000210891.12). This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. However, localization to the plasma membrane was not affected when the variant was expressed in cells lacking endogenous expression of E-cadherin (PMID: 20921021). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.

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

Computational evidence

Protein change
AlphaMissense	0.0583	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -6.58	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 2.4	GERP -0.92, phastCons 0.18
Regional constraint	o/e 1.05	unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic
Overall
CADD	19.71	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 0.012% European (non-Finnish) · 138/1,146,758 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00975%

Overall 0.0122% 187/1,534,038 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0932%	1,073
European (non-Finnish)grpmax	0.012%	8,310
Remaining individualsnot grpmax-eligible	0.01%	9,965
Ashkenazi Jewishnot grpmax-eligible	0.0035%	28,574

Finnish 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.Pro3Arg
Coding: c.8C>G
MANE Select: NM_004360
dbSNP: rs587782484
Type: single nucleotide variant
Location: chr16:68737423 (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: endometrial carcinoma breast cancer hereditary diffuse gastric adenocarcinoma ovarian cancer hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

CDH1 p.Pro3Ser Uncertain significance ★★★ ⚠ 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-pro3arg (accessed [today's date]).

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