Is CDH3 p.Arg221Ter (c.661C>T) pathogenic?

CDH3 p.Arg221Ter (c.661C>T) is classified Pathogenic in CDH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-01). Very rare (popmax 0.00167%, amr); Associated with congenital hypotrichosis with juvenile macular dystrophy.

What condition is associated with CDH3 p.Arg221Ter (c.661C>T)?

CDH3 p.Arg221Ter (c.661C>T) is associated with congenital hypotrichosis with juvenile macular dystrophy (ClinVar).

How common is CDH3 p.Arg221Ter (c.661C>T) in the general population?

CDH3 p.Arg221Ter (c.661C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

CDH3 p.Arg221Ter

c.661C>T · rs761941770 · VCV1454138

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

congenital hypotrichosis with juvenile macular dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -2.7, phastCons 0.98
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,008 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000274% 4/1,461,704 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,008
South Asian	0.0011%	91,084
European (non-Finnish)	0.000169%	590,009

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.Arg221Ter
Coding: c.661C>T
MANE Select: NM_004933 · reported on NM_001793
dbSNP: rs761941770
Type: single nucleotide variant
Location: chr16:68678876 (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

congenital hypotrichosis with juvenile macular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH3 p.Arg221Gln Uncertain significance ★★ ⚠ same residue
CDH3 p.Arg103Ter Pathogenic ★★ same condition
CDH3 p.Arg503His Pathogenic/Likely pathogenic ★★ ⚠ same condition
CDH3 p.Glu708Ter Likely pathogenic ★★ same condition
CDH3 p.Trp362Ter Pathogenic ★★ same condition
CDH3 p.Ala159Thr Uncertain significance ★★ ⚠ same condition
CDH3 p.Ala400Gly Uncertain significance ★★ ⚠ same condition
CDH3 p.Asp320Asn 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-arg221ter (accessed [today's date]).

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