Is CDH8 p.Ile224Val (c.670A>G) pathogenic?

CDH8 p.Ile224Val (c.670A>G) is classified Uncertain significance in CDH8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-09). AlphaMissense: likely benign (0.0578); Ultra-rare (popmax 0.0555%, nfe).

How common is CDH8 p.Ile224Val (c.670A>G) in the general population?

CDH8 p.Ile224Val (c.670A>G) is ultra-rare (popmax 0.0555%, nfe) (gnomAD).

What do computational predictors say about CDH8 p.Ile224Val (c.670A>G)?

AlphaMissense predicts likely benign (score 0.0578) — an in-silico prediction, not a clinical call.

CDH8 p.Ile224Val

c.670A>G · rs199624386 · VCV2238783

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0578 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0555%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0578	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -5.60	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 1.2	GERP -1.6, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 232 kb · p 1e-16 · regional, not allelic
Overall
CADD	16.49	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 0.0555% European (non-Finnish) · 651/1,173,812 alleles

Filtering AF 0.0519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0505%

Overall 0.0423% 675/1,595,786 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0555%	1,803
Middle Eastern	0.0168%	5,966
Remaining individualsnot grpmax-eligible	0.0162%	6,174
African / African-American	0.00811%	12,323
South Asian	0.00686%	14,570
Ashkenazi Jewishnot grpmax-eligible	0.0035%	28,586

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.Ile224Val
Coding: c.670A>G
MANE Select: NM_001796
dbSNP: rs199624386
Type: single nucleotide variant
Location: chr16:61825177 (GRCh38)
Gene constraint: LOEUF 0.369 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.26
Residue 224: the cadherin 2 domain

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

Similar variants

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
CDH8 p.Ala629Val 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-ile224val (accessed [today's date]).

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