Is CDH13 p.Pro228= (c.684G>A) pathogenic?

CDH13 p.Pro228= (c.684G>A) is classified Likely benign in CDH13 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-12-09). Ultra-rare (popmax 0.0329%, mid); Associated with CDH13-related disorder.

What condition is associated with CDH13 p.Pro228= (c.684G>A)?

CDH13 p.Pro228= (c.684G>A) is associated with CDH13-related disorder (ClinVar).

How common is CDH13 p.Pro228= (c.684G>A) in the general population?

CDH13 p.Pro228= (c.684G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

CDH13 p.Pro228=

c.684G>A · rs201452763 · VCV3048992

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

CDH13-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -13	GERP -3.7
Overall
CADD	0.755	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0155%

Overall 0.0146% 236/1,613,780 alleles · ultra-rare exomes 224/1,461,584 · genomes 12/152,196 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
European (non-Finnish)	0.0183%	5,462
Remaining individualsnot grpmax-eligible	0.016%	6,246
African / African-American	0.00667%	14,986
South Asian	0.00329%	30,359

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: CDH13
Protein: p.Pro228=
Coding: c.684G>A
MANE Select: NM_001257
dbSNP: rs201452763
Type: single nucleotide variant
Location: chr16:83344909 (GRCh38)
Gene constraint: LOEUF 0.456 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.19 · 1 PDB
Residue 228: the cadherin 1 domain; a β-strand

Full CDH13 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CDH13-related disorder

Similar variants

CDH13 p.Ile585Val Uncertain significance ★ ⚠ same condition
CDH13 p.Lys293Gln Uncertain significance ⚠ same condition
CDH13 c.45+12327A>G Benign same condition
CDH13 c.45+8A>G Likely benign same condition
CDH13 c.781+4T>A Likely benign same condition
CDH13 p.Asn420= Likely benign same condition
CDH13 p.Asp577= Likely benign same condition
CDH13 p.Gly261= Likely benign 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/cdh13-p-pro228 (accessed [today's date]).

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