Is CDH22 p.Arg146Cys (c.436C>T) pathogenic?

CDH22 p.Arg146Cys (c.436C>T) is classified Uncertain significance in CDH22 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-06). AlphaMissense: likely benign (0.19); Ultra-rare (popmax 0.0133%, afr).

How common is CDH22 p.Arg146Cys (c.436C>T) in the general population?

CDH22 p.Arg146Cys (c.436C>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about CDH22 p.Arg146Cys (c.436C>T)?

AlphaMissense predicts likely benign (score 0.19) — an in-silico prediction, not a clinical call.

CDH22 p.Arg146Cys

c.436C>T · rs368116505 · VCV2333764

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.19 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.19	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -12.97	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.54, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 76 kb · p 5.2e-13 · regional, not allelic
Overall
CADD	34.0	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 0.0133% African / African-American · 10/74,938 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00118% 19/1,614,064 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,494
East Asian	0.00223%	44,888
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000593%	168,577

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.Arg146Cys
Coding: c.436C>T
MANE Select: NM_021248
dbSNP: rs368116505
Type: single nucleotide variant
Location: chr20:46241077 (GRCh38)
Gene constraint: LOEUF 0.782 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.19
Residue 146: the cadherin 1 domain

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-arg146cys (accessed [today's date]).

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