Is CDH3 p.Arg681Gln (c.2042G>A) pathogenic?

CDH3 p.Arg681Gln (c.2042G>A) is classified Conflicting classifications of pathogenicity in CDH3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-23). AlphaMissense: likely benign (0.075); Rare (popmax 0.346%, mid); Associated with EEM syndrome.

What condition is associated with CDH3 p.Arg681Gln (c.2042G>A)?

CDH3 p.Arg681Gln (c.2042G>A) is associated with EEM syndrome (ClinVar).

How common is CDH3 p.Arg681Gln (c.2042G>A) in the general population?

CDH3 p.Arg681Gln (c.2042G>A) is rare (popmax 0.346%, mid) (gnomAD).

What do computational predictors say about CDH3 p.Arg681Gln (c.2042G>A)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

CDH3 p.Arg681Gln

c.2042G>A · rs758614807 · VCV281442

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.346%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EEM syndrome

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -7.87	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 2.9	GERP 1.2, phastCons 1
Overall
CADD	21.2	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 0.346% Middle Eastern · 21/6,062 alleles

Filtering AF 0.232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.195%

Overall 0.00966% 156/1,614,076 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.346%	289
Admixed American	0.103%	968
Remaining individualsnot grpmax-eligible	0.0096%	10,418
European (non-Finnish)	0.00525%	19,032
Finnishnot grpmax-eligible	0.00312%	32,014
South Asian	0.0022%	45,532
African / African-American	0.00133%	75,006

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.Arg681Gln
Coding: c.2042G>A
MANE Select: NM_001793
dbSNP: rs758614807
Type: single nucleotide variant
Location: chr16:68695294 (GRCh38)
Gene constraint: LOEUF 0.823 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.71 · 19 PDB

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

Similar variants

CDH3 p.Arg681Trp Uncertain significance ★★ ⚠ same residue
CDH3 p.Glu708Ter Likely 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.Ala159Thr Uncertain significance ★★ ⚠ same condition
CDH3 p.Ala34Thr Uncertain significance ★★ ⚠ same condition
CDH3 p.Ala400Gly 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-arg681gln (accessed [today's date]).

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