Is CDH1 p.Leu742Val (c.2224C>G) pathogenic?

CDH1 p.Leu742Val (c.2224C>G) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-19). AlphaMissense: likely benign (0.3176); Absent from gnomAD v4.1; Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

How common is CDH1 p.Leu742Val (c.2224C>G) in the general population?

CDH1 p.Leu742Val (c.2224C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH1 p.Leu742Val (c.2224C>G)?

AlphaMissense predicts likely benign (score 0.3176) — an in-silico prediction, not a clinical call.

CDH1 p.Leu742Val

Q: What condition is associated with CDH1 p.Leu742Val (c.2224C>G)?

CDH1 p.Leu742Val (c.2224C>G) is associated with CDH1-related diffuse gastric and lobular breast cancer syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

c.2224C>G · rs2152141467 · VCV2117447

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3176 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CDH1-related diffuse gastric and lobular breast cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.3176	likely benign
REVEL	0.399	indeterminate
SaProt	LLR -7.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.7, phastCons 0.58
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	23.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDH1
Protein: p.Leu742Val
Coding: c.2224C>G
MANE Select: NM_004360
dbSNP: rs2152141467
Type: single nucleotide variant
Location: chr16:68828233 (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

Similar variants

CDH1 p.Leu742Arg Uncertain significance ★ ⚠ same residue
CDH1 p.Leu742= 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
CDH1 c.1565+1G>C 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-leu742val (accessed [today's date]).

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