Is CDH1 p.Pro740Ser (c.2218C>T) pathogenic?

CDH1 p.Pro740Ser (c.2218C>T) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-06-09). AlphaMissense: ambiguous (0.3434); Very rare (popmax 0.00669%, eas); Associated with hereditary breast carcinoma.

What condition is associated with CDH1 p.Pro740Ser (c.2218C>T)?

CDH1 p.Pro740Ser (c.2218C>T) is associated with hereditary breast carcinoma, hereditary breast ovarian cancer syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Pro740Ser (c.2218C>T) in the general population?

CDH1 p.Pro740Ser (c.2218C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

How is Hereditary breast cancer inherited?

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

What do computational predictors say about CDH1 p.Pro740Ser (c.2218C>T)?

AlphaMissense predicts ambiguous (score 0.3434) — an in-silico prediction, not a clinical call.

CDH1 p.Pro740Ser

c.2218C>T · rs773795943 · VCV463748

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

ambiguous

0.3434 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.3434	ambiguous
REVEL	0.517	indeterminate
SaProt	LLR -10.13	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	26.1	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 0.00669% East Asian · 3/44,866 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000205% 3/1,461,752 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.Pro740Ser
Coding: c.2218C>T
MANE Select: NM_004360
dbSNP: rs773795943
Type: single nucleotide variant
Location: chr16:68828227 (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 breast carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome hereditary diffuse gastric adenocarcinoma ovarian cancer hereditary neoplastic syndrome

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

CDH1 p.Pro740Ala Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro740= Benign/Likely benign ★★ same residue
CDH1 p.Pro740His Conflicting classifications of pathogenicity ★ same residue
CDH1 p.Pro740Thr 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
CDH1 c.1320+1G>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-pro740ser (accessed [today's date]).

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