Is CDH22 p.Glu696Asp (c.2088G>C) pathogenic?

CDH22 p.Glu696Asp (c.2088G>C) is classified Uncertain significance in CDH22 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely benign (0.1147); Ultra-rare (popmax 0.0164%, afr).

How common is CDH22 p.Glu696Asp (c.2088G>C) in the general population?

CDH22 p.Glu696Asp (c.2088G>C) is ultra-rare (popmax 0.0164%, afr) (gnomAD).

What do computational predictors say about CDH22 p.Glu696Asp (c.2088G>C)?

AlphaMissense predicts likely benign (score 0.1147) — an in-silico prediction, not a clinical call.

CDH22 p.Glu696Asp

c.2088G>C · VCV3265246

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1147 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1147	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -6.06	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 0.94	GERP -1.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 396 bp · p 0.36 · regional, not allelic
Overall
CADD	19.25	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0164% African / African-American · 11/66,914 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00712%

Overall 0.000921% 13/1,411,556 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0164%	6,083
Admixed American	0.00211%	47,490
Remaining individualsnot grpmax-eligible	0.00194%	51,550

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: CDH22
Protein: p.Glu696Asp
Coding: c.2088G>C
MANE Select: NM_021248
Type: single nucleotide variant
Location: chr20:46174905 (GRCh38)
Gene constraint: LOEUF 0.782 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.19

Full CDH22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH22 p.Ala782Val Benign ★★ ⚠ same type
CDH22 p.Pro624= Benign ★★ same type
CDH22 p.Ala121Val Uncertain significance ★ ⚠ same type
CDH22 p.Ala15Pro Uncertain significance ★ ⚠ same type
CDH22 p.Ala19Thr Uncertain significance ★ ⚠ same type
CDH22 p.Ala384Thr Uncertain significance ★ ⚠ same type
CDH22 p.Ala39Val Uncertain significance ★ ⚠ same type
CDH22 p.Ala450Thr 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/cdh22-p-glu696asp (accessed [today's date]).

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