Is CDH1 p.Val425Leu (c.1273G>C) pathogenic?

CDH1 p.Val425Leu (c.1273G>C) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-06-17). AlphaMissense: ambiguous (0.343); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Val425Leu (c.1273G>C)?

CDH1 p.Val425Leu (c.1273G>C) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma, hereditary breast carcinoma (ClinVar).

How common is CDH1 p.Val425Leu (c.1273G>C) in the general population?

CDH1 p.Val425Leu (c.1273G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CDH1 p.Val425Leu (c.1273G>C)?

AlphaMissense predicts ambiguous (score 0.343) — an in-silico prediction, not a clinical call.

CDH1 p.Val425Leu

c.1273G>C · rs570930882 · VCV463706

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.343 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.343	ambiguous
REVEL	0.201	benign-leaning
SaProt	LLR -10.31	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.007, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	16.63	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 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 6.2e-05% 1/1,614,142 alleles · very rare exomes 1/1,461,884 · genomes 0/152,258 · joint denominator

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.Val425Leu
Coding: c.1273G>C
MANE Select: NM_004360
dbSNP: rs570930882
Type: single nucleotide variant
Location: chr16:68813448 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 425: 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.Val425Ile Likely benign ★★★ same residue
CDH1 p.Val425= Benign/Likely benign ★★ same residue
CDH1 p.Val425Ala Uncertain significance ★ same residue
CDH1 p.Val425fs 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
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-val425leu (accessed [today's date]).

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