Is CDH2 p.Arg656Leu (c.1967G>T) pathogenic?

CDH2 p.Arg656Leu (c.1967G>T) is classified Uncertain significance in CDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-02). AlphaMissense: likely pathogenic (0.6051); Very rare (popmax 8.55e-05%, nfe).

How common is CDH2 p.Arg656Leu (c.1967G>T) in the general population?

CDH2 p.Arg656Leu (c.1967G>T) is very rare (popmax 8.55e-05%, nfe) (gnomAD).

What do computational predictors say about CDH2 p.Arg656Leu (c.1967G>T)?

AlphaMissense predicts likely pathogenic (score 0.6051) — an in-silico prediction, not a clinical call.

CDH2 p.Arg656Leu

c.1967G>T · rs1374084310 · VCV2904428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6051 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.55e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6051	likely pathogenic
REVEL	0.519	indeterminate
SaProt	LLR -8.92	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 27 kb · p 4e-09 · regional, not allelic
Overall
CADD	29.0	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 8.55e-05% European (non-Finnish) · 1/1,169,302 alleles

Overall 6.9e-05% 1/1,449,996 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: CDH2
Protein: p.Arg656Leu
Coding: c.1967G>T
MANE Select: NM_001792
dbSNP: rs1374084310
Type: single nucleotide variant
Location: chr18:27985536 (GRCh38)
Gene constraint: LOEUF 0.336 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68
Residue 656: the cadherin 5 domain

Full CDH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH2 p.Arg656Trp Uncertain significance ★ ⚠ same residue
CDH2 p.Arg656= Likely benign ★ same residue
CDH2 c.1344+1G>A Pathogenic/Likely pathogenic ★★ same type
CDH2 c.702+1G>A Pathogenic/Likely pathogenic ★★ same type
CDH2 p.Tyr676Cys Pathogenic ★★ same type
CDH2 c.61-1G>A Uncertain significance ★★ same type
CDH2 c.848-16T>G Uncertain significance ★★ same type
CDH2 p.Ala106Val Uncertain significance ★★ ⚠ 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/cdh2-p-arg656leu (accessed [today's date]).

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