Is CDH1 p.Met1Val (c.1A>G) pathogenic?

CDH1 p.Met1Val (c.1A>G) is classified Pathogenic in CDH1 (ClinVar, Expert panel, 6 submitters; last evaluated 2023-08-25). Very rare (popmax 0.000174%, nfe); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.Met1Val (c.1A>G)?

CDH1 p.Met1Val (c.1A>G) is associated with CDH1-related diffuse gastric and lobular breast cancer syndrome, hereditary diffuse gastric adenocarcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDH1 p.Met1Val (c.1A>G) in the general population?

CDH1 p.Met1Val (c.1A>G) is very rare (popmax 0.000174%, nfe) (gnomAD).

CDH1 p.Met1Val

c.1A>G · rs1555509622 · VCV532457

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Conditions

CDH1-related diffuse gastric and lobular breast cancer syndrome

ClinGen expert panel — CDH1 VCEP

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

PVS1 PM2_Supporting PS4_Supporting PP1

Curation rationale (ClinGen, verbatim)

The c.1A>G (p.Met1Val) variant alters the start codon of the CDH1 coding sequence and is predicted to lead to an absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one proband meeting HDGC clinical criteria (PS4_supporting; SCV000760810.2). This variant was also found to co-segregate with disease in multiple affected family members (PP1; SCV000760810.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 3.1 as specified by the CDH1 Variant Curation Expert Panel: PVS1, PS4_supporting, PM2_supporting, PP1.

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.301	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000174% European (non-Finnish) · 2/1,146,342 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000145% 2/1,381,104 alleles · very rare

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.Met1Val
Coding: c.1A>G
MANE Select: NM_004360
dbSNP: rs1555509622
Type: single nucleotide variant
Location: chr16:68737416 (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 hereditary neoplastic syndrome

Similar variants

CDH1 p.Met1Arg Pathogenic ★★★ same residue
CDH1 p.Met1Ile Pathogenic ★★★ same residue
CDH1 p.Met1Lys Pathogenic ★★★ same residue
CDH1 p.Met1Thr Pathogenic ★★★ same residue
CDH1 p.Met1Leu Pathogenic/Likely pathogenic ★★ 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-met1val (accessed [today's date]).

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