Is CDH1 p.Arg43Pro (c.128G>C) pathogenic?

CDH1 p.Arg43Pro (c.128G>C) is classified Uncertain significance in CDH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-05). AlphaMissense: likely benign (0.1942); Absent from gnomAD v4.1; Associated with hereditary diffuse gastric adenocarcinoma.

What condition is associated with CDH1 p.Arg43Pro (c.128G>C)?

CDH1 p.Arg43Pro (c.128G>C) is associated with hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Arg43Pro (c.128G>C) in the general population?

CDH1 p.Arg43Pro (c.128G>C) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary diffuse gastric cancer inherited?

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

What do computational predictors say about CDH1 p.Arg43Pro (c.128G>C)?

AlphaMissense predicts likely benign (score 0.1942) — an in-silico prediction, not a clinical call.

CDH1 p.Arg43Pro

c.128G>C · rs1962461060 · VCV2818835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1942 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary diffuse gastric adenocarcinoma

Computational evidence

Protein change
AlphaMissense	0.1942	likely benign
REVEL	0.344	indeterminate
SaProt	LLR -10.74	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 7.5	GERP 0.73, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic
Overall
CADD	24.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDH1
Protein: p.Arg43Pro
Coding: c.128G>C
MANE Select: NM_004360
dbSNP: rs1962461060
Type: single nucleotide variant
Location: chr16:68738376 (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 diffuse gastric adenocarcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary diffuse gastric cancer (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDH1 p.Arg43Trp Uncertain significance ★★ ⚠ same residue
CDH1 p.Arg43Gln Uncertain significance ★ ⚠ same residue
CDH1 p.Arg43Gly Uncertain significance ★ ⚠ same residue
CDH1 p.Arg43= Likely benign ★ same residue
CDH1 p.Arg43Leu 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-arg43pro (accessed [today's date]).

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