Is CDH1 p.Pro30Ser (c.88C>T) pathogenic?

CDH1 p.Pro30Ser (c.88C>T) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-22). AlphaMissense: likely benign (0.1537); Very rare (popmax 8.79e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Pro30Ser (c.88C>T)?

CDH1 p.Pro30Ser (c.88C>T) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Pro30Ser (c.88C>T) in the general population?

CDH1 p.Pro30Ser (c.88C>T) is very rare (popmax 8.79e-05%, nfe) (gnomAD).

What do computational predictors say about CDH1 p.Pro30Ser (c.88C>T)?

AlphaMissense predicts likely benign (score 0.1537) — an in-silico prediction, not a clinical call.

CDH1 p.Pro30Ser

c.88C>T · rs139866691 · VCV1390649

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1537 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.79e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1537	likely benign
REVEL	0.458	indeterminate
SaProt	LLR -11.06	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.039, phastCons 0.63
Regional constraint	o/e 1.05	unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic
Overall
CADD	18.33	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 8.79e-05% European (non-Finnish) · 1/1,137,742 alleles

Overall 7.19e-05% 1/1,391,190 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.Pro30Ser
Coding: c.88C>T
MANE Select: NM_004360
dbSNP: rs139866691
Type: single nucleotide variant
Location: chr16:68738336 (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

Also linked: hereditary diffuse gastric adenocarcinoma

Similar variants

CDH1 p.Pro30Thr Benign ★★★ ⚠ same residue
CDH1 p.Pro30Arg Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro30= Likely benign ★ same residue
CDH1 p.Pro30fs 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
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-pro30ser (accessed [today's date]).

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