Is CDH8 p.Arg645Gln (c.1934G>A) pathogenic?

CDH8 p.Arg645Gln (c.1934G>A) is classified Uncertain significance in CDH8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). AlphaMissense: ambiguous (0.5552); Very rare (popmax 0.00401%, afr).

How common is CDH8 p.Arg645Gln (c.1934G>A) in the general population?

CDH8 p.Arg645Gln (c.1934G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CDH8 p.Arg645Gln (c.1934G>A)?

AlphaMissense predicts ambiguous (score 0.5552) — an in-silico prediction, not a clinical call.

CDH8 p.Arg645Gln

c.1934G>A · VCV3265336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5552 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Computational evidence

Protein change
AlphaMissense	0.5552	ambiguous
REVEL	0.375	indeterminate
SaProt	LLR -6.12	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 136 kb · p 0.061 · regional, not allelic
Overall
CADD	31.0	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 0.00401% African / African-American · 3/74,846 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00205% 33/1,613,672 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,949
European (non-Finnish)	0.00246%	40,687
East Asian	0.00223%	44,880

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.Arg645Gln
Coding: c.1934G>A
MANE Select: NM_001796
Type: single nucleotide variant
Location: chr16:61654074 (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.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-arg645gln (accessed [today's date]).

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