Is CDH2 p.Asp451Asn (c.1351G>A) pathogenic?

CDH2 p.Asp451Asn (c.1351G>A) is classified Uncertain significance in CDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: ambiguous (0.3503); Ultra-rare (popmax 0.0168%, amr).

How common is CDH2 p.Asp451Asn (c.1351G>A) in the general population?

CDH2 p.Asp451Asn (c.1351G>A) is ultra-rare (popmax 0.0168%, amr) (gnomAD).

What do computational predictors say about CDH2 p.Asp451Asn (c.1351G>A)?

AlphaMissense predicts ambiguous (score 0.3503) — an in-silico prediction, not a clinical call.

CDH2 p.Asp451Asn

c.1351G>A · rs773021925 · VCV1924994

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3503 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, amr)

Computational evidence

Protein change
AlphaMissense	0.3503	ambiguous
REVEL	0.523	indeterminate
SaProt	LLR -8.14	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 27 kb · p 4e-09 · regional, not allelic
Overall
CADD	30.0	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 0.0168% Admixed American · 10/59,598 alleles

Filtering AF 0.00905% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00685%

Overall 0.00241% 35/1,453,162 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0168%	5,960
East Asian	0.00671%	14,895
South Asian	0.00441%	22,661
Remaining individualsnot grpmax-eligible	0.00322%	31,061
African / African-American	0.00134%	74,688
European (non-Finnish)	0.00128%	78,236

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.Asp451Asn
Coding: c.1351G>A
MANE Select: NM_001792
dbSNP: rs773021925
Type: single nucleotide variant
Location: chr18:27990344 (GRCh38)
Gene constraint: LOEUF 0.336 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68
Residue 451: the cadherin 3 domain

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

Similar variants

CDH2 p.Asp451Tyr Uncertain significance ★ 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
CDH2 p.Ala21Val 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-asp451asn (accessed [today's date]).

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