Is CDH3 p.Glu645Ala (c.1934A>C) pathogenic?

CDH3 p.Glu645Ala (c.1934A>C) is classified Uncertain significance in CDH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0851); Very rare (popmax 0.000508%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CDH3 p.Glu645Ala (c.1934A>C)?

CDH3 p.Glu645Ala (c.1934A>C) is associated with Inborn genetic diseases (ClinVar).

How common is CDH3 p.Glu645Ala (c.1934A>C) in the general population?

CDH3 p.Glu645Ala (c.1934A>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about CDH3 p.Glu645Ala (c.1934A>C)?

AlphaMissense predicts likely benign (score 0.0851) — an in-silico prediction, not a clinical call.

CDH3 p.Glu645Ala

c.1934A>C · rs780349546 · VCV1025092

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0851	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -6.38	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 -0.38	GERP -2.4
Regional constraint	o/e 0.97	unconstrained · MANE · 53 kb · p 0.35 · regional, not allelic
Overall
CADD	0.062	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 0.000508% European (non-Finnish) · 6/1,180,022 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,614,136 alleles · very rare exomes 6/1,461,868 · genomes 0/152,268 · joint denominator

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: CDH3
Protein: p.Glu645Ala
Coding: c.1934A>C
MANE Select: NM_001793
dbSNP: rs780349546
Type: single nucleotide variant
Location: chr16:68691858 (GRCh38)
Gene constraint: LOEUF 0.823 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.71 · 19 PDB
Residue 645: the cadherin 5 domain

Full CDH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH3 p.Glu645Gly Uncertain significance ★ ⚠ same residue
CDH3 p.Glu645Lys Uncertain significance ★ ⚠ same residue
CDH3 p.Ala150Thr Uncertain significance ★★ same condition
CDH3 p.Ala22Glu Uncertain significance ★★ ⚠ same condition
CDH3 p.Ala356Pro Uncertain significance ★★ ⚠ same condition
CDH3 p.Ala361Ser Uncertain significance ★★ ⚠ same condition
CDH3 p.Ala361Val Uncertain significance ★★ ⚠ same condition
CDH3 p.Ala64Ser Uncertain significance ★★ ⚠ 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/cdh3-p-glu645ala (accessed [today's date]).

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