Is CDH1 p.Arg749Gln (c.2246G>A) pathogenic?

CDH1 p.Arg749Gln (c.2246G>A) is classified Conflicting classifications of pathogenicity in CDH1 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-01-23). AlphaMissense: ambiguous (0.5164); Very rare (popmax 0.0022%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Arg749Gln (c.2246G>A)?

CDH1 p.Arg749Gln (c.2246G>A) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma, ovarian cancer (ClinVar).

How common is CDH1 p.Arg749Gln (c.2246G>A) in the general population?

CDH1 p.Arg749Gln (c.2246G>A) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about CDH1 p.Arg749Gln (c.2246G>A)?

AlphaMissense predicts ambiguous (score 0.5164) — an in-silico prediction, not a clinical call.

CDH1 p.Arg749Gln

c.2246G>A · rs530717933 · VCV133849

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

ambiguous

0.5164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5164	ambiguous
REVEL	0.696	pathogenic-leaning
SaProt	LLR -11.14	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	33.0	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 0.0022% European (non-Finnish) · 26/1,180,018 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00173% 28/1,613,964 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0022%	45,385
Admixed American	0.00167%	59,974
African / African-American	0.00134%	74,894

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.Arg749Gln
Coding: c.2246G>A
MANE Select: NM_004360
dbSNP: rs530717933
Type: single nucleotide variant
Location: chr16:68828255 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 749: the 'disordered' region

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 ovarian cancer hereditary breast carcinoma

Similar variants

CDH1 p.Arg749Trp Uncertain significance ★★★ ⚠ same residue
CDH1 p.Arg749= Benign/Likely benign ★★ same residue
CDH1 p.Arg749Gly 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
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-arg749gln (accessed [today's date]).

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