Is CDH1 p.Asn751= (c.2253C>T) pathogenic?

CDH1 p.Asn751= (c.2253C>T) is classified Benign in CDH1 (ClinVar, Expert panel, 18 submitters; last evaluated 2023-08-10). Common (popmax 8.84%, amr) — too common for a highly-penetrant pathogenic allele; Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.Asn751= (c.2253C>T)?

CDH1 p.Asn751= (c.2253C>T) is associated with CDH1-related diffuse gastric and lobular breast cancer syndrome, breast cancer, hereditary diffuse gastric adenocarcinoma (ClinVar).

CDH1 p.Asn751=

Q: How common is CDH1 p.Asn751= (c.2253C>T) in the general population?

CDH1 p.Asn751= (c.2253C>T) is common (popmax 8.84%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2253C>T · rs33964119 · VCV142145

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 18 submitters

gnomAD v4.1

Common

common (popmax 8.84%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

CDH1-related diffuse gastric and lobular breast cancer syndrome

ClinGen expert panel — CDH1 VCEP

Benign for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):

BP2 BA1

Curation rationale (ClinGen, verbatim)

The NM_004360.5(CDH1):c.2253C>T (p.Asn751=) variant has an allele frequency of 0.10006 (10%, 3546/35438 alleles, 185 homozygotes) in the Latino subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -16	GERP -3.8
Overall
CADD	0.556	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.84% Admixed American · 5,305/59,988 alleles

Filtering AF 8.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.56%

Overall 3.36% 54,268/1,613,832 alleles · common exomes 48,303/1,461,686 · genomes 5,965/152,146 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	8.84%	11
East Asian	7.42%	13
African / African-American	5.28%	19
South Asian	3.97%	25
Remaining individualsnot grpmax-eligible	3.32%	30
European (non-Finnish)	2.91%	34
Middle Eastern	2.11%	47
Finnishnot grpmax-eligible	1.71%	59
Ashkenazi Jewishnot grpmax-eligible	1.35%	74
Amishnot grpmax-eligible	0.33%	303

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.Asn751=
Coding: c.2253C>T
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

Also linked: breast cancer hereditary diffuse gastric adenocarcinoma prostate cancer hereditary neoplastic syndrome

Similar variants

CDH1 p.Asn751Ser Uncertain significance ★★ ⚠ same residue
CDH1 p.Asn751Lys Conflicting classifications of pathogenicity ★ ⚠ 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-asn751 (accessed [today's date]).

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