Is CDH13 p.Pro417Arg (c.1250C>G) pathogenic?

CDH13 p.Pro417Arg (c.1250C>G) is classified Uncertain significance in CDH13 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely benign (0.1231); Ultra-rare (popmax 0.0174%, afr).

How common is CDH13 p.Pro417Arg (c.1250C>G) in the general population?

CDH13 p.Pro417Arg (c.1250C>G) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about CDH13 p.Pro417Arg (c.1250C>G)?

AlphaMissense predicts likely benign (score 0.1231) — an in-silico prediction, not a clinical call.

CDH13 p.Pro417Arg

c.1250C>G · VCV3488723

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1231 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1231	likely benign
REVEL	0.418	indeterminate
SaProt	LLR -9.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.6, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 1,168 kb · p 1.2e-06 · regional, not allelic
Overall
CADD	23.6	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 0.0174% African / African-American · 13/74,734 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00814%

Overall 0.00112% 18/1,606,678 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,749
Admixed American	0.00336%	29,778
Remaining individualsnot grpmax-eligible	0.00161%	62,134
European (non-Finnish)	0.00017%	587,465

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.Pro417Arg
Coding: c.1250C>G
MANE Select: NM_001257
Type: single nucleotide variant
Location: chr16:83670938 (GRCh38)
Gene constraint: LOEUF 0.456 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.19 · 1 PDB
Residue 417: the cadherin 3 domain

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

Similar variants

CDH13 c.1102-6T>C Benign ★★ same type
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CDH13 c.1539-109T>C Benign ★★ same type
CDH13 c.1681+64T>C Benign ★★ same type
CDH13 c.1682-151C>T Benign ★★ same type
CDH13 c.1682-180G>A Benign ★★ same type
CDH13 c.1682-59A>G Benign ★★ same type
CDH13 c.1682-62G>A Benign ★★ same type

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-pro417arg (accessed [today's date]).

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