Is CDH3 p.Arg221Gln (c.662G>A) pathogenic?

CDH3 p.Arg221Gln (c.662G>A) is classified Uncertain significance in CDH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-08). AlphaMissense: likely benign (0.0832); Ultra-rare (popmax 0.0214%, afr); Associated with Inborn genetic diseases.

What condition is associated with CDH3 p.Arg221Gln (c.662G>A)?

CDH3 p.Arg221Gln (c.662G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CDH3 p.Arg221Gln (c.662G>A) in the general population?

CDH3 p.Arg221Gln (c.662G>A) is ultra-rare (popmax 0.0214%, afr) (gnomAD).

What do computational predictors say about CDH3 p.Arg221Gln (c.662G>A)?

AlphaMissense predicts likely benign (score 0.0832) — an in-silico prediction, not a clinical call.

CDH3 p.Arg221Gln

c.662G>A · rs371682154 · VCV1353691

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0832 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0832	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -9.73	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 0.66	GERP -1, phastCons 0.93
Overall
CADD	17.47	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 0.0214% African / African-American · 16/74,936 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00409% 66/1,613,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0214%	4,683
Admixed American	0.0133%	7,501
Remaining individualsnot grpmax-eligible	0.0048%	20,826
East Asian	0.00445%	22,448
European (non-Finnish)	0.00314%	31,893

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.Arg221Gln
Coding: c.662G>A
MANE Select: NM_004933 · reported on NM_001793
dbSNP: rs371682154
Type: single nucleotide variant
Location: chr16:68678877 (GRCh38)
Structure: AlphaFold pLDDT 78.70
Residue 221: the cadherin 2 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.Arg221Ter Pathogenic ★★ 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
CDH3 p.Ala724Ser 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-arg221gln (accessed [today's date]).

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