Is CDH1 p.Ala692= (c.2076T>C) pathogenic?

CDH1 p.Ala692= (c.2076T>C) is classified Benign in CDH1 (ClinVar, Expert panel, 21 submitters; last evaluated 2023-08-09). Common (popmax 88.9%, afr) — 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.Ala692= (c.2076T>C)?

CDH1 p.Ala692= (c.2076T>C) is associated with CDH1-related diffuse gastric and lobular breast cancer syndrome, hereditary diffuse gastric adenocarcinoma, prostate cancer (ClinVar).

CDH1 p.Ala692=

Q: How common is CDH1 p.Ala692= (c.2076T>C) in the general population?

CDH1 p.Ala692= (c.2076T>C) is common (popmax 88.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2076T>C · rs1801552 · VCV142770

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 21 submitters

gnomAD v4.1

Common

common (popmax 88.9%, afr) — 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_Supporting BA1

Curation rationale (ClinGen, verbatim)

The NM_004360.5(CDH1):c.2076T>C (p.Ala692=) variant has an allele frequency of 0.88894 (88.89%, 22156/24924 alleles, 9856 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2_Supporting). 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_Supporting.

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 0.021	GERP -1.7
Overall
CADD	6.258	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 88.9% African / African-American · 66,635/74,940 alleles

Filtering AF 88.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 88.1%

Overall 64.1% 1,034,771/1,613,322 alleles · common exomes 928,592/1,461,334 · genomes 106,179/151,988 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	88.9%	1
Admixed American	65.9%	2
Remaining individualsnot grpmax-eligible	65.3%	2
South Asian	64.9%	2
Middle Eastern	63.7%	2
European (non-Finnish)	62.8%	2
Ashkenazi Jewishnot grpmax-eligible	62.3%	2
East Asian	61%	2
Amishnot grpmax-eligible	59.5%	2
Finnishnot grpmax-eligible	59.2%	2

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.Ala692=
Coding: c.2076T>C
MANE Select: NM_004360
dbSNP: rs1801552
Type: single nucleotide variant
Location: chr16:68823538 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 692: the cadherin 5 domain

Full CDH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary diffuse gastric adenocarcinoma prostate cancer hereditary neoplastic syndrome hereditary breast carcinoma blepharocheilodontic syndrome 1

Similar variants

CDH1 p.Ala692Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Ala692Val Uncertain significance ★ ⚠ same residue
CDH1 p.Ala692_Gly693= 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
CDH1 c.1320+1G>C Likely pathogenic ★★★ same condition
CDH1 c.1565+1G>A 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-ala692 (accessed [today's date]).

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