Is CDH22 p.His354Pro (c.1061A>C) pathogenic?

CDH22 p.His354Pro (c.1061A>C) is classified Uncertain significance in CDH22 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.9555); Ultra-rare (popmax 0.0189%, mid).

How common is CDH22 p.His354Pro (c.1061A>C) in the general population?

CDH22 p.His354Pro (c.1061A>C) is ultra-rare (popmax 0.0189%, mid) (gnomAD).

What do computational predictors say about CDH22 p.His354Pro (c.1061A>C)?

AlphaMissense predicts likely pathogenic (score 0.9555) — an in-silico prediction, not a clinical call.

CDH22 p.His354Pro

c.1061A>C · VCV4223820

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9555 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0189%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9555	likely pathogenic
REVEL	0.392	indeterminate
SaProt	LLR -14.86	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 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 76 kb · p 5.2e-13 · regional, not allelic
Overall
CADD	31.0	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 0.0189% Middle Eastern · 1/5,302 alleles

Filtering AF 0.00848% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00789%

Overall 0.00932% 119/1,276,916 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0189%	5,302
European (non-Finnish)	0.01%	9,982
Remaining individualsnot grpmax-eligible	0.00741%	13,503
South Asian	0.00474%	21,100
African / African-American	0.00298%	33,547

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.His354Pro
Coding: c.1061A>C
MANE Select: NM_021248
Type: single nucleotide variant
Location: chr20:46210532 (GRCh38)
Gene constraint: LOEUF 0.782 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.19
Residue 354: the cadherin 3 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-his354pro (accessed [today's date]).

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