Is CDH3 p.Ser475Arg (c.1423A>C) pathogenic?

CDH3 p.Ser475Arg (c.1423A>C) is classified Uncertain significance in CDH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-22). AlphaMissense: likely benign (0.2343); Rare (popmax 0.149%, mid).

How common is CDH3 p.Ser475Arg (c.1423A>C) in the general population?

CDH3 p.Ser475Arg (c.1423A>C) is rare (popmax 0.149%, mid) (gnomAD).

What do computational predictors say about CDH3 p.Ser475Arg (c.1423A>C)?

AlphaMissense predicts likely benign (score 0.2343) — an in-silico prediction, not a clinical call.

CDH3 p.Ser475Arg

c.1423A>C · rs868428771 · VCV963242

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2343 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2343	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -7.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.89	donor gain · deltas
Pangolin	Δ0.70	loss · gain 0.68 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Overall
CADD	32.0	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 0.149% Middle Eastern · 9/6,058 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0579%

Overall 0.000616% 9/1,461,802 alleles · rare

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.Ser475Arg
Coding: c.1423A>C
MANE Select: NM_004933 · reported on NM_001793
dbSNP: rs868428771
Type: single nucleotide variant
Location: chr16:68684823 (GRCh38)
Structure: AlphaFold pLDDT 78.70
Residue 475: the cadherin 4 domain

Full CDH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH3 c.1796-2A>G Pathogenic ★★ same type
CDH3 c.691+1G>A Pathogenic/Likely pathogenic ★★ same type
CDH3 p.Arg103Ter Pathogenic ★★ same type
CDH3 p.Arg221Ter Pathogenic ★★ same type
CDH3 p.Arg503His Pathogenic/Likely pathogenic ★★ ⚠ same type
CDH3 p.Gln299Ter Pathogenic ★★ same type
CDH3 p.Glu708Ter Likely pathogenic ★★ same type
CDH3 p.Trp362Ter Pathogenic ★★ 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/cdh3-p-ser475arg (accessed [today's date]).

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