Is CDH3 p.Arg393Lys (c.1178G>A) pathogenic?

CDH3 p.Arg393Lys (c.1178G>A) is classified Conflicting classifications of pathogenicity in CDH3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.0596); Rare (popmax 0.479%, mid); Associated with EEM syndrome.

What condition is associated with CDH3 p.Arg393Lys (c.1178G>A)?

CDH3 p.Arg393Lys (c.1178G>A) is associated with EEM syndrome, inherited retinal dystrophy (ClinVar).

How common is CDH3 p.Arg393Lys (c.1178G>A) in the general population?

CDH3 p.Arg393Lys (c.1178G>A) is rare (popmax 0.479%, mid) (gnomAD).

What do computational predictors say about CDH3 p.Arg393Lys (c.1178G>A)?

AlphaMissense predicts likely benign (score 0.0596) — an in-silico prediction, not a clinical call.

CDH3 p.Arg393Lys

c.1178G>A · rs766325919 · VCV320235

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0596 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.479%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EEM syndrome

Computational evidence

Protein change
AlphaMissense	0.0596	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -5.06	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 -2.1	GERP -4.4
Overall
CADD	2.453	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 0.479% Middle Eastern · 29/6,058 alleles

Filtering AF 0.342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.296%

Overall 0.00223% 36/1,614,092 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.479%	209
Remaining individualsnot grpmax-eligible	0.008%	12,502
European (non-Finnish)	0.000169%	590,012

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.Arg393Lys
Coding: c.1178G>A
MANE Select: NM_004933 · reported on NM_001793
dbSNP: rs766325919
Type: single nucleotide variant
Location: chr16:68682483 (GRCh38)
Structure: AlphaFold pLDDT 78.70
Residue 393: the cadherin 4 domain

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

Disease context

EEM syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inherited retinal dystrophy

Similar variants

CDH15 p.Leu393Pro Likely benign ★ same residue
CDH3 p.Arg503His Pathogenic/Likely pathogenic ★★ ⚠ same condition
CDH3 p.Glu708Ter Likely pathogenic ★★ same condition
CDH3 p.Trp362Ter Pathogenic ★★ same condition
CDH3 c.1571-7C>G Uncertain significance ★★ same condition
CDH3 c.45+6C>T Uncertain significance ★★ same condition
CDH3 c.867+6T>C Uncertain significance ★★ same condition
CDH3 p.Ala150Thr 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-arg393lys (accessed [today's date]).

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