Is CDH1 p.Asp538Val (c.1613A>T) pathogenic?

CDH1 p.Asp538Val (c.1613A>T) is classified Uncertain significance in CDH1 (ClinVar, Expert panel, 4 submitters; last evaluated 2023-08-21). AlphaMissense: likely benign (0.0825); Absent from gnomAD v4.1; Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.Asp538Val (c.1613A>T)?

CDH1 p.Asp538Val (c.1613A>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.Asp538Val (c.1613A>T) in the general population?

CDH1 p.Asp538Val (c.1613A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH1 p.Asp538Val (c.1613A>T)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

CDH1 p.Asp538Val

c.1613A>T · rs863224726 · VCV216589

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 PS4_Moderate

Curation rationale (ClinGen, verbatim)

The c.1613A>T (p.Asp538Val) variant is absent in the gnomAD cohort (PM2_Supporting). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; SCV000254814.3). In summary, this variant meets criteria to be classified as a variant of uncertain significance based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS4_Moderate.

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

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -5.60	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 9.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	23.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDH1
Protein: p.Asp538Val
Coding: c.1613A>T
MANE Select: NM_004360
dbSNP: rs863224726
Type: single nucleotide variant
Location: chr16:68819327 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 538: the cadherin 4 domain; a turn

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.Asp538Tyr Uncertain significance ★★ ⚠ same residue
CDH1 p.Asp538Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Asp538= Likely benign ★ same residue
CDH1 p.Asp538fs Pathogenic ★★★ same residue
CDH1 p.Asp538Gly 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-asp538val (accessed [today's date]).

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