Is CDH2 p.Glu614Lys (c.1840G>A) pathogenic?

CDH2 p.Glu614Lys (c.1840G>A) is classified Uncertain significance in CDH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-01). AlphaMissense: ambiguous (0.4037); Ultra-rare (popmax 0.0329%, mid); Associated with Cardiovascular phenotype.

What condition is associated with CDH2 p.Glu614Lys (c.1840G>A)?

CDH2 p.Glu614Lys (c.1840G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is CDH2 p.Glu614Lys (c.1840G>A) in the general population?

CDH2 p.Glu614Lys (c.1840G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about CDH2 p.Glu614Lys (c.1840G>A)?

AlphaMissense predicts ambiguous (score 0.4037) — an in-silico prediction, not a clinical call.

CDH2 p.Glu614Lys

c.1840G>A · rs750540712 · VCV2177247

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4037 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4037	ambiguous
REVEL	0.589	indeterminate
SaProt	LLR -8.26	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	28.3	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.0013% 21/1,613,632 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
African / African-American	0.00401%	24,956
South Asian	0.00329%	30,359
Admixed American	0.00167%	59,996
European (non-Finnish)	0.00102%	98,310

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.Glu614Lys
Coding: c.1840G>A
MANE Select: NM_001792
dbSNP: rs750540712
Type: single nucleotide variant
Location: chr18:27985663 (GRCh38)
Gene constraint: LOEUF 0.336 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68
Residue 614: the cadherin 5 domain

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH2 p.Arg430Trp Uncertain significance ★★ ⚠ same condition
CDH2 p.Arg561Gln Uncertain significance ★★ ⚠ same condition
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-glu614lys (accessed [today's date]).

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