Is CDH1 p.Asn751Lys (c.2253C>G) pathogenic?

CDH1 p.Asn751Lys (c.2253C>G) is classified Conflicting classifications of pathogenicity in CDH1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-12). AlphaMissense: likely pathogenic (0.9634); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Asn751Lys (c.2253C>G)?

CDH1 p.Asn751Lys (c.2253C>G) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Asn751Lys (c.2253C>G) in the general population?

CDH1 p.Asn751Lys (c.2253C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH1 p.Asn751Lys (c.2253C>G)?

AlphaMissense predicts likely pathogenic (score 0.9634) — an in-silico prediction, not a clinical call.

CDH1 p.Asn751Lys

c.2253C>G · rs33964119 · VCV925394

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9634 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9634	likely pathogenic · top 9% in CDH1
REVEL	0.478	indeterminate
SaProt	LLR -8.85	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -16	GERP -3.8
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	5.434	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.Asn751Lys
Coding: c.2253C>G
MANE Select: NM_004360
dbSNP: rs33964119
Type: single nucleotide variant
Location: chr16:68828262 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 751: the 'disordered' region; a functional site (cleavage; by caspase-3)

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.Asn751= Benign ★★★ same residue
CDH1 p.Asn751Ser Uncertain significance ★★ ⚠ same residue
CDH1 p.Asn751Tyr Uncertain significance ★ ⚠ same residue
CDH1 p.Asn751del Uncertain significance ★★ same residue
CDH1 p.Asn751fs 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

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-asn751lys (accessed [today's date]).

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