Is CDH2 p.Val700Phe (c.2098G>T) pathogenic?

CDH2 p.Val700Phe (c.2098G>T) is classified Uncertain significance in CDH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-13). AlphaMissense: likely pathogenic (0.9312); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with CDH2 p.Val700Phe (c.2098G>T)?

CDH2 p.Val700Phe (c.2098G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CDH2 p.Val700Phe (c.2098G>T) in the general population?

CDH2 p.Val700Phe (c.2098G>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CDH2 p.Val700Phe (c.2098G>T)?

AlphaMissense predicts likely pathogenic (score 0.9312) — an in-silico prediction, not a clinical call.

CDH2 p.Val700Phe

c.2098G>T · rs1027567929 · VCV2535322

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9312 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9312	likely pathogenic
REVEL	0.515	indeterminate
SaProt	LLR -14.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 27 kb · p 4e-09 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,012 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000753% 11/1,461,762 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,006
European (non-Finnish)	0.000763%	131,102

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.Val700Phe
Coding: c.2098G>T
MANE Select: NM_001792
dbSNP: rs1027567929
Type: single nucleotide variant
Location: chr18:27985111 (GRCh38)
Gene constraint: LOEUF 0.336 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68
Residue 700: the cadherin 5 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.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
CDH2 p.Ala825Val 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-val700phe (accessed [today's date]).

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