Is CDH1 p.Pro143Ser (c.427C>T) pathogenic?

CDH1 p.Pro143Ser (c.427C>T) is classified Conflicting classifications of pathogenicity in CDH1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-03-27). AlphaMissense: likely benign (0.2097); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Pro143Ser (c.427C>T)?

CDH1 p.Pro143Ser (c.427C>T) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Pro143Ser (c.427C>T) in the general population?

CDH1 p.Pro143Ser (c.427C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CDH1 p.Pro143Ser (c.427C>T)?

AlphaMissense predicts likely benign (score 0.2097) — an in-silico prediction, not a clinical call.

CDH1 p.Pro143Ser

c.427C>T · rs876661226 · VCV234803

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2097 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2097	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -6.21	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 6	GERP 1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic
Overall
CADD	19.39	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 0.00223% East Asian · 1/44,894 alleles

Overall 0.00131% 2/152,148 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,894
European (non-Finnish)	8.47e-05%	1,180,013

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.Pro143Ser
Coding: c.427C>T
MANE Select: NM_004360
dbSNP: rs876661226
Type: single nucleotide variant
Location: chr16:68808463 (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.Pro143Leu Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro143Arg 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
CDH1 c.1565+1G>A Pathogenic ★★★ same condition
CDH1 c.1565+1G>C 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-pro143ser (accessed [today's date]).

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