Is CDH2 p.Val289Ile (c.865G>A) pathogenic?

CDH2 p.Val289Ile (c.865G>A) is classified Likely benign in CDH2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-10). AlphaMissense: likely benign (0.1354); Ultra-rare (popmax 0.0899%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CDH2 p.Val289Ile (c.865G>A)?

CDH2 p.Val289Ile (c.865G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CDH2 p.Val289Ile (c.865G>A) in the general population?

CDH2 p.Val289Ile (c.865G>A) is ultra-rare (popmax 0.0899%, nfe) (gnomAD).

What do computational predictors say about CDH2 p.Val289Ile (c.865G>A)?

AlphaMissense predicts likely benign (score 0.1354) — an in-silico prediction, not a clinical call.

CDH2 p.Val289Ile

c.865G>A · rs142589795 · VCV1642699

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1354 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0899%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1354	likely benign
REVEL	0.202	benign-leaning
SaProt	LLR -9.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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	23.7	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 0.0899% European (non-Finnish) · 1,060/1,179,660 alleles

Filtering AF 0.0853% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0835%

Overall 0.0694% 1,119/1,613,500 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0899%	1,113
Remaining individualsnot grpmax-eligible	0.048%	2,082
African / African-American	0.0187%	5,349
Admixed American	0.0183%	5,453
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
East Asian	0.00223%	44,862
South Asian	0.0022%	45,533

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.Val289Ile
Coding: c.865G>A
MANE Select: NM_001792
dbSNP: rs142589795
Type: single nucleotide variant
Location: chr18:28003152 (GRCh38)
Gene constraint: LOEUF 0.336 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68
Residue 289: the cadherin 2 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

Similar variants

CDH2 p.Val289Leu Uncertain significance ★ ⚠ same residue
CDH2 p.Ala21Val Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala294Gly Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala299Thr Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala415Ser Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala418Ser Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala418Thr Uncertain significance ★★ ⚠ same condition
CDH2 p.Ala610Thr 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-val289ile (accessed [today's date]).

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