Is CDH3 p.Ile204= (c.612C>A) pathogenic?

CDH3 p.Ile204= (c.612C>A) is classified Benign in CDH3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 29.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with EEM syndrome.

What condition is associated with CDH3 p.Ile204= (c.612C>A)?

CDH3 p.Ile204= (c.612C>A) is associated with EEM syndrome (ClinVar).

CDH3 p.Ile204=

Q: How common is CDH3 p.Ile204= (c.612C>A) in the general population?

CDH3 p.Ile204= (c.612C>A) is common (popmax 29.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.612C>A · rs8049247 · VCV320227

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 29.1%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

EEM syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -4.4
Overall
CADD	2.562	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 29.1% African / African-American · 21,824/74,942 alleles

Filtering AF 28.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 28.7%

Overall 13.9% 223,856/1,613,738 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	29.1%	3
Finnishnot grpmax-eligible	17.2%	6
Amishnot grpmax-eligible	16.4%	6
European (non-Finnish)	14.1%	7
Remaining individualsnot grpmax-eligible	13.5%	7
Middle Eastern	12.7%	8
Ashkenazi Jewishnot grpmax-eligible	11.4%	9
Admixed American	8.46%	12
South Asian	7.58%	13
East Asian	0.0624%	1,602

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.Ile204=
Coding: c.612C>A
MANE Select: NM_004933 · reported on NM_001793
dbSNP: rs8049247
Type: single nucleotide variant
Location: chr16:68678827 (GRCh38)
Structure: AlphaFold pLDDT 78.70
Residue 204: the cadherin 2 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

Similar variants

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
CDH3 p.Ala414Thr 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-ile204 (accessed [today's date]).

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