Is CDH3 p.Pro458Arg (c.1373C>G) pathogenic?

CDH3 p.Pro458Arg (c.1373C>G) is classified Uncertain significance in CDH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-25). AlphaMissense: likely benign (0.0845); Ultra-rare (popmax 0.0187%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CDH3 p.Pro458Arg (c.1373C>G)?

CDH3 p.Pro458Arg (c.1373C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CDH3 p.Pro458Arg (c.1373C>G) in the general population?

CDH3 p.Pro458Arg (c.1373C>G) is ultra-rare (popmax 0.0187%, nfe) (gnomAD).

What do computational predictors say about CDH3 p.Pro458Arg (c.1373C>G)?

AlphaMissense predicts likely benign (score 0.0845) — an in-silico prediction, not a clinical call.

CDH3 p.Pro458Arg

c.1373C>G · rs200493479 · VCV858599

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0845 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0845	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -5.28	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 -0.24	GERP -1.3
Overall
CADD	4.549	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 0.0187% European (non-Finnish) · 221/1,180,038 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0159%

Overall 0.0147% 237/1,614,070 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0187%	5,340
Finnishnot grpmax-eligible	0.0125%	8,004
Remaining individualsnot grpmax-eligible	0.008%	12,498
African / African-American	0.00267%	37,467
Admixed American	0.00167%	60,000

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.Pro458Arg
Coding: c.1373C>G
MANE Select: NM_004933 · reported on NM_001793
dbSNP: rs200493479
Type: single nucleotide variant
Location: chr16:68684773 (GRCh38)
Structure: AlphaFold pLDDT 78.70
Residue 458: the cadherin 4 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.Pro458Ala Uncertain significance ★ ⚠ same residue
CDH3 p.Pro458Ser Uncertain significance ★ ⚠ 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

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-pro458arg (accessed [today's date]).

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