Is CDH8 p.Arg666Cys (c.1996C>T) pathogenic?

CDH8 p.Arg666Cys (c.1996C>T) is classified Likely benign in CDH8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely pathogenic (0.6815); Rare (popmax 0.403%, nfe).

How common is CDH8 p.Arg666Cys (c.1996C>T) in the general population?

CDH8 p.Arg666Cys (c.1996C>T) is rare (popmax 0.403%, nfe) (gnomAD).

What do computational predictors say about CDH8 p.Arg666Cys (c.1996C>T)?

AlphaMissense predicts likely pathogenic (score 0.6815) — an in-silico prediction, not a clinical call.

CDH8 p.Arg666Cys

c.1996C>T · rs140000814 · VCV710638

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6815 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.403%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6815	likely pathogenic
REVEL	0.56	indeterminate
SaProt	LLR -8.27	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
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 0.91	unconstrained · MANE · 136 kb · p 0.061 · regional, not allelic
Overall
CADD	33.0	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 0.403% European (non-Finnish) · 4,749/1,179,132 alleles

Filtering AF 0.393% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.389%

Overall 0.314% 5,059/1,613,080 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.403%	248
Remaining individualsnot grpmax-eligible	0.178%	563
Ashkenazi Jewishnot grpmax-eligible	0.115%	870
Finnishnot grpmax-eligible	0.111%	901
African / African-American	0.0787%	1,271
Middle Eastern	0.066%	1,514
Admixed American	0.05%	2,000
South Asian	0.0011%	91,056

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.Arg666Cys
Coding: c.1996C>T
MANE Select: NM_001796
dbSNP: rs140000814
Type: single nucleotide variant
Location: chr16:61654012 (GRCh38)
Gene constraint: LOEUF 0.369 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.26

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

Similar variants

CDH8 p.Arg666His Uncertain significance ★ ⚠ same residue
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-arg666cys (accessed [today's date]).

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