Is CDH1 p.Pro126Leu (c.377C>T) pathogenic?

CDH1 p.Pro126Leu (c.377C>T) is classified Conflicting classifications of pathogenicity in CDH1 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0642); Ultra-rare (popmax 0.0132%, sas); Associated with hereditary diffuse gastric adenocarcinoma.

What condition is associated with CDH1 p.Pro126Leu (c.377C>T)?

CDH1 p.Pro126Leu (c.377C>T) is associated with hereditary diffuse gastric adenocarcinoma, endometrial carcinoma, hereditary breast ovarian cancer syndrome (ClinVar).

How common is CDH1 p.Pro126Leu (c.377C>T) in the general population?

CDH1 p.Pro126Leu (c.377C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

How is Hereditary diffuse gastric cancer inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDH1 p.Pro126Leu (c.377C>T)?

AlphaMissense predicts likely benign (score 0.0642) — an in-silico prediction, not a clinical call.

CDH1 p.Pro126Leu

c.377C>T · rs746703615 · VCV184629

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.0642 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary diffuse gastric adenocarcinoma

Computational evidence

Protein change
AlphaMissense	0.0642	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.52	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 -1.1	GERP -3.1
Regional constraint	o/e 1.05	unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic
Overall
CADD	1.017	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 0.0132% South Asian · 12/91,074 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00186% 30/1,613,478 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,589
East Asian	0.00446%	22,445
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,470
African / African-American	0.00133%	74,918
European (non-Finnish)	0.0011%	90,733

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.Pro126Leu
Coding: c.377C>T
MANE Select: NM_004360
dbSNP: rs746703615
Type: single nucleotide variant
Location: chr16:68801883 (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

hereditary diffuse gastric adenocarcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: endometrial carcinoma hereditary breast ovarian cancer syndrome ovarian cancer prostate cancer hereditary neoplastic syndrome hereditary breast carcinoma ovarian neoplasm blepharocheilodontic syndrome 1

For Hereditary diffuse gastric cancer (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDH1 p.Pro126Gln Uncertain significance ★★ ⚠ same residue
CDH1 p.Pro126= Benign/Likely benign ★★ same residue
CDH1 p.Pro126Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Pro126Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Pro126fs 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-pro126leu (accessed [today's date]).

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