Is CDH22 p.Ala718Pro (c.2152G>C) pathogenic?

CDH22 p.Ala718Pro (c.2152G>C) is classified Uncertain significance in CDH22 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely benign (0.0649); Ultra-rare (popmax 0.0191%, amr).

How common is CDH22 p.Ala718Pro (c.2152G>C) in the general population?

CDH22 p.Ala718Pro (c.2152G>C) is ultra-rare (popmax 0.0191%, amr) (gnomAD).

What do computational predictors say about CDH22 p.Ala718Pro (c.2152G>C)?

AlphaMissense predicts likely benign (score 0.0649) — an in-silico prediction, not a clinical call.

CDH22 p.Ala718Pro

c.2152G>C · rs1201138723 · VCV3141198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0649 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0191%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0649	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -6.55	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 -1.4	GERP -4.2
Regional constraint	o/e 1.07	unconstrained · MANE · 396 bp · p 0.36 · regional, not allelic
Overall
CADD	7.358	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 0.0191% Admixed American · 5/26,180 alleles

Filtering AF 0.00747% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000755% 10/1,324,402 alleles · ultra-rare exomes 4/1,173,592 · genomes 6/150,810 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0191%	5,236
Remaining individualsnot grpmax-eligible	0.00201%	49,826
European (non-Finnish)	0.000383%	260,788

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.Ala718Pro
Coding: c.2152G>C
MANE Select: NM_021248
dbSNP: rs1201138723
Type: single nucleotide variant
Location: chr20:46174841 (GRCh38)
Gene constraint: LOEUF 0.782 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.19
Residue 718: the 'disordered' region

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

Similar variants

CDH22 p.Ala718Gly 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-ala718pro (accessed [today's date]).

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