Is CDH1 p.Pro27Ala (c.79C>G) pathogenic?

CDH1 p.Pro27Ala (c.79C>G) is classified Likely benign in CDH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-05). AlphaMissense: likely benign (0.0704); Very rare (popmax 8.76e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Pro27Ala (c.79C>G)?

CDH1 p.Pro27Ala (c.79C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDH1 p.Pro27Ala (c.79C>G) in the general population?

CDH1 p.Pro27Ala (c.79C>G) is very rare (popmax 8.76e-05%, nfe) (gnomAD).

What do computational predictors say about CDH1 p.Pro27Ala (c.79C>G)?

AlphaMissense predicts likely benign (score 0.0704) — an in-silico prediction, not a clinical call.

CDH1 p.Pro27Ala

c.79C>G · VCV3998774

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0704 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.76e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0704	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -6.64	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 1.1	GERP -2.4, phastCons 0.34
Regional constraint	o/e 1.05	unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic
Overall
CADD	16.75	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 8.76e-05% European (non-Finnish) · 1/1,141,750 alleles

Overall 7.17e-05% 1/1,395,486 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.Pro27Ala
Coding: c.79C>G
MANE Select: NM_004360
Type: single nucleotide variant
Location: chr16:68738327 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH1 p.Pro27Ser Uncertain significance ★★★ ⚠ same residue
CDH1 p.Pro27Leu Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro27Thr Uncertain significance ★ ⚠ same residue
CDH1 p.Pro27= 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
CDH1 c.1565+1G>A 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-pro27ala (accessed [today's date]).

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