Is CDH26 p.Ala189Gly (c.566C>G) pathogenic?

CDH26 p.Ala189Gly (c.566C>G) is classified Uncertain significance in CDH26 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: ambiguous (0.3703); Ultra-rare (popmax 0.0152%, amr).

How common is CDH26 p.Ala189Gly (c.566C>G) in the general population?

CDH26 p.Ala189Gly (c.566C>G) is ultra-rare (popmax 0.0152%, amr) (gnomAD).

What do computational predictors say about CDH26 p.Ala189Gly (c.566C>G)?

AlphaMissense predicts ambiguous (score 0.3703) — an in-silico prediction, not a clinical call.

CDH26 p.Ala189Gly

c.566C>G · VCV3999009

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3703 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0152%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3703	ambiguous
REVEL	0.23	benign-leaning
SaProt	LLR -10.89	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.13, phastCons 0.53
Regional constraint	o/e 0.98	unconstrained · MANE · 54 kb · p 0.44 · regional, not allelic
Overall
CADD	22.0	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 0.0152% Admixed American · 9/59,394 alleles

Filtering AF 0.0079% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00584%

Overall 0.000682% 11/1,612,188 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0152%	6,599
Remaining individualsnot grpmax-eligible	0.0032%	31,227

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: CDH26
Protein: p.Ala189Gly
Coding: c.566C>G
MANE Select: NM_177980
Type: single nucleotide variant
Location: chr20:59984663 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.84
Residue 189: the cadherin 2 domain

Full CDH26 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH26 p.Ala238Thr Uncertain significance ★ ⚠ same type
CDH26 p.Ala274Glu Uncertain significance ★ ⚠ same type
CDH26 p.Ala308Ser Uncertain significance ★ ⚠ same type
CDH26 p.Ala390Thr Uncertain significance ★ ⚠ same type
CDH26 p.Ala598Gly Uncertain significance ★ ⚠ same type
CDH26 p.Ala617Asp Uncertain significance ★ ⚠ same type
CDH26 p.Ala617Pro Uncertain significance ★ ⚠ same type
CDH26 p.Ala623Ser 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/cdh26-p-ala189gly (accessed [today's date]).

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