Is CDH2 p.Val566Met (c.1696G>A) pathogenic?

CDH2 p.Val566Met (c.1696G>A) is classified Uncertain significance in CDH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-03). AlphaMissense: ambiguous (0.3763); Ultra-rare (popmax 0.099%, mid); Associated with Inborn genetic diseases.

What condition is associated with CDH2 p.Val566Met (c.1696G>A)?

CDH2 p.Val566Met (c.1696G>A) is associated with Inborn genetic diseases, agenesis of corpus callosum, cardiac, ocular, and genital syndrome (ClinVar).

How common is CDH2 p.Val566Met (c.1696G>A) in the general population?

CDH2 p.Val566Met (c.1696G>A) is ultra-rare (popmax 0.099%, mid) (gnomAD).

What do computational predictors say about CDH2 p.Val566Met (c.1696G>A)?

AlphaMissense predicts ambiguous (score 0.3763) — an in-silico prediction, not a clinical call.

CDH2 p.Val566Met

c.1696G>A · rs752473363 · VCV1959614

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3763	ambiguous
REVEL	0.367	indeterminate
SaProt	LLR -10.61	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 27 kb · p 4e-09 · regional, not allelic
Overall
CADD	27.6	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 0.099% Middle Eastern · 6/6,058 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0295%

Overall 0.00171% 25/1,460,832 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
African / African-American	0.00533%	18,755
Remaining individualsnot grpmax-eligible	0.0032%	31,239
European (non-Finnish)	0.0011%	90,705

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.Val566Met
Coding: c.1696G>A
MANE Select: NM_001792
dbSNP: rs752473363
Type: single nucleotide variant
Location: chr18:27988569 (GRCh38)
Gene constraint: LOEUF 0.336 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68
Residue 566: the cadherin 4 domain

Full CDH2 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

Also linked: agenesis of corpus callosum, cardiac, ocular, and genital syndrome

Similar variants

CDH2 p.Val566Leu Uncertain significance ★ ⚠ same residue
CDH2 c.1344+1G>A Pathogenic/Likely pathogenic ★★ same condition
CDH2 c.702+1G>A Pathogenic/Likely pathogenic ★★ same condition
CDH2 p.Tyr676Cys Pathogenic ★★ same condition
CDH2 c.848-16T>G Uncertain significance ★★ same condition
CDH2 p.Ala21Val Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala294Gly Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala299Thr 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/cdh2-p-val566met (accessed [today's date]).

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