Is CDH1 p.Ala130Val (c.389C>T) pathogenic?

CDH1 p.Ala130Val (c.389C>T) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-07). AlphaMissense: likely benign (0.0774); Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Ala130Val (c.389C>T)?

CDH1 p.Ala130Val (c.389C>T) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Ala130Val (c.389C>T) in the general population?

CDH1 p.Ala130Val (c.389C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CDH1 p.Ala130Val (c.389C>T)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

CDH1 p.Ala130Val

c.389C>T · rs1960723934 · VCV921657

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -6.35	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 6.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic
Overall
CADD	13.16	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 0.0011% South Asian · 1/91,088 alleles

Overall 6.84e-05% 1/1,461,860 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.Ala130Val
Coding: c.389C>T
MANE Select: NM_004360
dbSNP: rs1960723934
Type: single nucleotide variant
Location: chr16:68808425 (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.Ala130Gly Uncertain significance ★★ ⚠ same residue
CDH1 p.Ala130= Benign/Likely benign ★★ same residue
CDH1 p.Ala130Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Ala130Pro Uncertain significance ★ ⚠ same residue
CDH1 p.Ala130Thr 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

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-ala130val (accessed [today's date]).

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