Is CDH1 p.Arg779Trp (c.2335C>T) pathogenic?

CDH1 p.Arg779Trp (c.2335C>T) is classified Conflicting classifications of pathogenicity in CDH1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-29). AlphaMissense: likely pathogenic (0.5827); Very rare (popmax 0.0022%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Arg779Trp (c.2335C>T)?

CDH1 p.Arg779Trp (c.2335C>T) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma, hereditary breast carcinoma (ClinVar).

How common is CDH1 p.Arg779Trp (c.2335C>T) in the general population?

CDH1 p.Arg779Trp (c.2335C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CDH1 p.Arg779Trp (c.2335C>T)?

AlphaMissense predicts likely pathogenic (score 0.5827) — an in-silico prediction, not a clinical call.

CDH1 p.Arg779Trp

c.2335C>T · rs876660183 · VCV233087

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.5827 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5827	likely pathogenic
REVEL	0.5	indeterminate
SaProt	LLR -12.29	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.88, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	27.6	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% South Asian · 2/91,076 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000991% 16/1,613,988 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,538
Admixed American	0.00167%	59,992
European (non-Finnish)	0.0011%	90,770

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.Arg779Trp
Coding: c.2335C>T
MANE Select: NM_004360
dbSNP: rs876660183
Type: single nucleotide variant
Location: chr16:68829693 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary diffuse gastric adenocarcinoma hereditary breast carcinoma

Similar variants

CDH1 p.Arg779Gln Benign ★★★ same residue
CDH1 p.Arg779Gly Uncertain significance ★★ ⚠ same residue
CDH1 p.Arg779Leu Uncertain significance ★ ⚠ same residue
CDH1 p.Arg779Pro Uncertain significance ★ ⚠ same residue
CDH1 p.Arg779= Likely 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-arg779trp (accessed [today's date]).

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