Is CDH4 p.Arg659Pro (c.1976G>C) pathogenic?

CDH4 p.Arg659Pro (c.1976G>C) is classified Likely pathogenic in CDH4 (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.4931); Very rare (popmax 8.47e-05%, nfe); Associated with Abnormal brain morphology.

What condition is associated with CDH4 p.Arg659Pro (c.1976G>C)?

CDH4 p.Arg659Pro (c.1976G>C) is associated with Abnormal brain morphology (ClinVar).

How common is CDH4 p.Arg659Pro (c.1976G>C) in the general population?

CDH4 p.Arg659Pro (c.1976G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CDH4 p.Arg659Pro (c.1976G>C)?

AlphaMissense predicts ambiguous (score 0.4931) — an in-silico prediction, not a clinical call.

CDH4 p.Arg659Pro

c.1976G>C · rs765815715 · VCV402151

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Abnormal brain morphology

Computational evidence

Protein change
AlphaMissense	0.4931	ambiguous
REVEL	0.403	indeterminate
SaProt	LLR -10.60	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -2.4, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 160 kb · p 4.6e-12 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,996 alleles

Overall 6.85e-05% 1/1,459,568 alleles · very 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: CDH4
Protein: p.Arg659Pro
Coding: c.1976G>C
MANE Select: NM_001794
dbSNP: rs765815715
Type: single nucleotide variant
Location: chr20:61928394 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.54 (gnomAD)
Structure: AlphaFold pLDDT 79.02
Residue 659: the cadherin 5 domain

Full CDH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Abnormal brain morphology — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH4 p.Arg659Trp Uncertain significance ★ ⚠ same residue
CDH4 p.Thr396Met Uncertain significance ★★ ⚠ same type
CDH4 p.Val580Ile Uncertain significance ★★ ⚠ same type
CDH4 c.1629-8C>T Benign ★★ same type
CDH4 c.2240-4A>G Benign ★★ same type
CDH4 p.Ala33Thr Benign ★★ same type
CDH4 p.Ala344= Benign/Likely benign ★★ same type
CDH4 p.Asn283= Benign/Likely 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/cdh4-p-arg659pro (accessed [today's date]).

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