Is CDH6 p.Arg83Lys (c.248G>A) pathogenic?

CDH6 p.Arg83Lys (c.248G>A) is classified Uncertain significance in CDH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-09). AlphaMissense: likely benign (0.0608); Very rare (popmax 0.00223%, eas).

How common is CDH6 p.Arg83Lys (c.248G>A) in the general population?

CDH6 p.Arg83Lys (c.248G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CDH6 p.Arg83Lys (c.248G>A)?

AlphaMissense predicts likely benign (score 0.0608) — an in-silico prediction, not a clinical call.

CDH6 p.Arg83Lys

c.248G>A · rs777479833 · VCV2248875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0608 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0608	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -3.86	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 8.6	GERP 2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 50 kb · p 7.7e-20 · regional, not allelic
Overall
CADD	18.83	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 0.00223% East Asian · 1/44,854 alleles

Filtering AF 0.000765% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000607%

Overall 0.00112% 18/1,608,264 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,854
Remaining individualsnot grpmax-eligible	0.00161%	62,182
European (non-Finnish)	0.00127%	78,441
South Asian	0.0011%	90,920

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: CDH6
Protein: p.Arg83Lys
Coding: c.248G>A
MANE Select: NM_004932
dbSNP: rs777479833
Type: single nucleotide variant
Location: chr5:31293981 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 78.67 · 1 PDB
Residue 83: the cadherin 1 domain

Full CDH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH6 p.Ala130Val Uncertain significance ★ ⚠ same type
CDH6 p.Ala489Ser Uncertain significance ★ ⚠ same type
CDH6 p.Ala634Gly Uncertain significance ★ ⚠ same type
CDH6 p.Ala671Ser Uncertain significance ★ ⚠ same type
CDH6 p.Ala706Val Uncertain significance ★ ⚠ same type
CDH6 p.Ala729Val Uncertain significance ★ ⚠ same type
CDH6 p.Ala739Val Uncertain significance ★ ⚠ same type
CDH6 p.Arg115Lys 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/cdh6-p-arg83lys (accessed [today's date]).

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