Is CDH1 p.Arg90Gln (c.269G>A) pathogenic?

CDH1 p.Arg90Gln (c.269G>A) is classified Likely benign in CDH1 (ClinVar, Expert panel, 11 submitters; last evaluated 2023-08-10). AlphaMissense: likely benign (0.064); Very rare (popmax 0.005%, amr); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.Arg90Gln (c.269G>A)?

CDH1 p.Arg90Gln (c.269G>A) is associated with CDH1-related diffuse gastric and lobular breast cancer syndrome, hereditary diffuse gastric adenocarcinoma, ovarian cancer (ClinVar).

How common is CDH1 p.Arg90Gln (c.269G>A) in the general population?

CDH1 p.Arg90Gln (c.269G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CDH1 p.Arg90Gln (c.269G>A)?

AlphaMissense predicts likely benign (score 0.064) — an in-silico prediction, not a clinical call.

CDH1 p.Arg90Gln

c.269G>A · rs587782647 · VCV142692

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.064 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDH1-related diffuse gastric and lobular breast cancer syndrome

ClinGen expert panel — CDH1 VCEP

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

BS2

Curation rationale (ClinGen, verbatim)

The c.269G>A (p.Arg90Gln) missense variant has a frequency of 0.00001989 (5 of 251,334) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.00004401 (5 of 113,622) in the European non-Finnish subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in ≥10 (55) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000567761.3, SCV000254829.7). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.

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

Computational evidence

Protein change
AlphaMissense	0.064	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -7.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.5	GERP 0.33, phastCons 0.009
Regional constraint	o/e 1.05	unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic
Overall
CADD	3.821	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

Grpmax group 0.005% Admixed American · 3/59,992 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00143% 23/1,614,008 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,997
European (non-Finnish)	0.00161%	62,105
South Asian	0.0011%	91,082

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.Arg90Gln
Coding: c.269G>A
MANE Select: NM_004360
dbSNP: rs587782647
Type: single nucleotide variant
Location: chr16:68801775 (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

Also linked: hereditary diffuse gastric adenocarcinoma ovarian cancer hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

CDH1 p.Arg90= Likely benign ★★ same residue
CDH1 p.Arg90Leu Uncertain significance ★ ⚠ same residue
CDH1 p.Arg90Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Arg90fs Pathogenic ★ same residue
CDH1 p.Arg90Pro 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-arg90gln (accessed [today's date]).

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