Is CDH1 p.Val41Leu (c.121G>T) pathogenic?

CDH1 p.Val41Leu (c.121G>T) is classified Uncertain significance in CDH1 (ClinVar, Expert panel, 3 submitters; last evaluated 2023-08-02). AlphaMissense: likely benign (0.2876); Very rare (popmax 8.72e-05%, nfe); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.Val41Leu (c.121G>T)?

CDH1 p.Val41Leu (c.121G>T) 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.Val41Leu (c.121G>T) in the general population?

CDH1 p.Val41Leu (c.121G>T) is very rare (popmax 8.72e-05%, nfe) (gnomAD).

What do computational predictors say about CDH1 p.Val41Leu (c.121G>T)?

AlphaMissense predicts likely benign (score 0.2876) — an in-silico prediction, not a clinical call.

CDH1 p.Val41Leu

c.121G>T · rs786202465 · VCV481692

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.72e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDH1-related diffuse gastric and lobular breast cancer syndrome

ClinGen expert panel — CDH1 VCEP

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

PM2_Supporting BS2_Supporting

Curation rationale (ClinGen, verbatim)

The c.121G>T (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Val by Leu at amino acid 41 (p.Val41Leu). This variant has been observed in Variant seen in >3 heterozygous individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; Ambry, GeneDx, Invitae). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023)

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

Computational evidence

Protein change
AlphaMissense	0.2876	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic
Overall
CADD	24.4	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 8.72e-05% European (non-Finnish) · 1/1,146,716 alleles

Overall 7.15e-05% 1/1,398,738 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.Val41Leu
Coding: c.121G>T
MANE Select: NM_004360
dbSNP: rs786202465
Type: single nucleotide variant
Location: chr16:68738369 (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.Val41Gly Uncertain significance ★ ⚠ same residue
CDH1 p.Val41Met 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
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-val41leu (accessed [today's date]).

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