Is CDH1 p.Ala691= (c.2073C>T) pathogenic?

CDH1 p.Ala691= (c.2073C>T) is classified Benign/Likely benign in CDH1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-19). Very rare (popmax 0.00668%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Ala691= (c.2073C>T)?

CDH1 p.Ala691= (c.2073C>T) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Ala691= (c.2073C>T) in the general population?

CDH1 p.Ala691= (c.2073C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

CDH1 p.Ala691=

c.2073C>T · rs536104508 · VCV183737

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Conditions

hereditary neoplastic syndrome

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 -13	GERP -3.8
Overall
CADD	0.377	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% East Asian · 3/44,882 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000867% 14/1,613,916 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,961
Admixed American	0.00333%	29,995
African / African-American	0.00133%	74,970
European (non-Finnish)	0.000678%	147,496

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.Ala691=
Coding: c.2073C>T
MANE Select: NM_004360
dbSNP: rs536104508
Type: single nucleotide variant
Location: chr16:68823535 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 691: the cadherin 5 domain; a β-strand

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.Ala691Asp Uncertain significance ★★ ⚠ same residue
CDH1 p.Ala691Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Ala691Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Ala691fs Pathogenic ★ same residue
CDH1 p.Ala691_Ala692= Benign ★ 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-ala691 (accessed [today's date]).

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