Is CDH1 p.Lys440Arg (c.1319A>G) pathogenic?

CDH1 p.Lys440Arg (c.1319A>G) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-08-17). AlphaMissense: likely benign (0.0951); Ultra-rare (popmax 0.033%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Lys440Arg (c.1319A>G)?

CDH1 p.Lys440Arg (c.1319A>G) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma, hereditary breast carcinoma (ClinVar).

How common is CDH1 p.Lys440Arg (c.1319A>G) in the general population?

CDH1 p.Lys440Arg (c.1319A>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about CDH1 p.Lys440Arg (c.1319A>G)?

AlphaMissense predicts likely benign (score 0.0951) — an in-silico prediction, not a clinical call.

CDH1 p.Lys440Arg

c.1319A>G · rs864622165 · VCV219581

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0951 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0951	likely benign
REVEL	0.413	indeterminate
SaProt	LLR -7.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.22 · evaluated, not missing
Pangolin	Δ0.23	loss · gain 0.04 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000558% 9/1,614,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
European (non-Finnish)	0.000593%	168,566

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.Lys440Arg
Coding: c.1319A>G
MANE Select: NM_004360
dbSNP: rs864622165
Type: single nucleotide variant
Location: chr16:68813494 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 440: the cadherin 3 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 hereditary breast carcinoma

Similar variants

CDH1 p.Lys440Glu Uncertain significance ★★ ⚠ same residue
CDH1 p.Lys440Asn Likely pathogenic ★ ⚠ same residue
CDH1 p.Lys440fs Likely pathogenic ★ same residue
CDH1 p.Lys440= 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

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-lys440arg (accessed [today's date]).

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