Is CDH8 p.Pro220Ala (c.658C>G) pathogenic?

CDH8 p.Pro220Ala (c.658C>G) is classified Uncertain significance in CDH8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1026); Rare (popmax 0.116%, eas).

How common is CDH8 p.Pro220Ala (c.658C>G) in the general population?

CDH8 p.Pro220Ala (c.658C>G) is rare (popmax 0.116%, eas) (gnomAD).

What do computational predictors say about CDH8 p.Pro220Ala (c.658C>G)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

CDH8 p.Pro220Ala

c.658C>G · rs190954180 · VCV2517407

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -8.81	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 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 232 kb · p 1e-16 · regional, not allelic
Overall
CADD	24.6	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 0.116% East Asian · 52/44,830 alleles

Filtering AF 0.0908% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0818%

Overall 0.00322% 52/1,613,470 alleles · 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: CDH8
Protein: p.Pro220Ala
Coding: c.658C>G
MANE Select: NM_001796
dbSNP: rs190954180
Type: single nucleotide variant
Location: chr16:61857128 (GRCh38)
Gene constraint: LOEUF 0.369 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.26
Residue 220: the cadherin 2 domain

Full CDH8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH8 p.Pro220Thr Uncertain significance ★ ⚠ same residue
CDH8 p.Arg666Cys Likely benign ★★ same type
CDH8 p.Ile429= Benign ★★ same type
CDH8 p.Tyr667= Benign/Likely benign ★★ same type
CDH8 p.Ala30Thr Uncertain significance ★ ⚠ same type
CDH8 p.Ala332Thr Uncertain significance ★ ⚠ same type
CDH8 p.Ala443Thr Uncertain significance ★ ⚠ same type
CDH8 p.Ala502Gly 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/cdh8-p-pro220ala (accessed [today's date]).

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