Is CDH22 p.Arg820Cys (c.2458C>T) pathogenic?

CDH22 p.Arg820Cys (c.2458C>T) is classified Uncertain significance in CDH22 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-09). AlphaMissense: likely benign (0.1734); Very rare (popmax 0.000439%, nfe).

How common is CDH22 p.Arg820Cys (c.2458C>T) in the general population?

CDH22 p.Arg820Cys (c.2458C>T) is very rare (popmax 0.000439%, nfe) (gnomAD).

What do computational predictors say about CDH22 p.Arg820Cys (c.2458C>T)?

AlphaMissense predicts likely benign (score 0.1734) — an in-silico prediction, not a clinical call.

CDH22 p.Arg820Cys

c.2458C>T · rs766967938 · VCV2259866

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1734 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000439%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1734	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -7.79	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 8.1	GERP 1.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 396 bp · p 0.36 · regional, not allelic
Overall
CADD	31.0	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 0.000439% European (non-Finnish) · 5/1,139,806 alleles

Filtering AF 0.000129% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.3e-05%

Overall 0.000329% 5/1,519,140 alleles · very rare

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.Arg820Cys
Coding: c.2458C>T
MANE Select: NM_021248
dbSNP: rs766967938
Type: single nucleotide variant
Location: chr20:46174535 (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.Arg820Gly Uncertain significance ★ ⚠ same residue
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

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-arg820cys (accessed [today's date]).

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