Is CDH1 p.Pro126Gln (c.377C>A) pathogenic?

CDH1 p.Pro126Gln (c.377C>A) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0607); Very rare (popmax 0.00668%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Pro126Gln (c.377C>A)?

CDH1 p.Pro126Gln (c.377C>A) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Pro126Gln (c.377C>A) in the general population?

CDH1 p.Pro126Gln (c.377C>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about CDH1 p.Pro126Gln (c.377C>A)?

AlphaMissense predicts likely benign (score 0.0607) — an in-silico prediction, not a clinical call.

CDH1 p.Pro126Gln

c.377C>A · rs746703615 · VCV463778

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0607	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.33	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	0.054	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 0.00668% East Asian · 3/44,878 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000411% 6/1,461,282 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,959
African / African-American	0.00133%	75,040
European (non-Finnish)	0.00017%	589,762

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.Pro126Gln
Coding: c.377C>A
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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary diffuse gastric adenocarcinoma

Similar variants

CDH1 p.Pro126= Benign/Likely benign ★★ same residue
CDH1 p.Pro126Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Pro126Leu 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-pro126gln (accessed [today's date]).

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