Is CBX6 p.Arg221Pro (c.662G>C) pathogenic?

CBX6 p.Arg221Pro (c.662G>C) is classified Uncertain significance in CBX6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). AlphaMissense: likely pathogenic (0.8991); Very rare (popmax 0.00136%, nfe).

How common is CBX6 p.Arg221Pro (c.662G>C) in the general population?

CBX6 p.Arg221Pro (c.662G>C) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about CBX6 p.Arg221Pro (c.662G>C)?

AlphaMissense predicts likely pathogenic (score 0.8991) — an in-silico prediction, not a clinical call.

CBX6 p.Arg221Pro

c.662G>C · VCV3996190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8991	likely pathogenic
REVEL	0.14	moderately benign-leaning
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 541 bp · p 0.34 · regional, not allelic
Overall
CADD	25.5	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 0.00136% European (non-Finnish) · 16/1,179,408 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000992% 16/1,612,490 alleles · very 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: CBX6
Protein: p.Arg221Pro
Coding: c.662G>C
MANE Select: NM_014292
Type: single nucleotide variant
Location: chr22:38866786 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 62.15 · 2 PDB

Full CBX6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBX6 p.Arg72= Benign/Likely benign ★★ same type
CBX6 p.Ala196Val Uncertain significance ★ ⚠ same type
CBX6 p.Ala240Thr Uncertain significance ★ ⚠ same type
CBX6 p.Ala304Asp Uncertain significance ★ ⚠ same type
CBX6 p.Ala304Val Uncertain significance ★ ⚠ same type
CBX6 p.Ala339Val Uncertain significance ★ ⚠ same type
CBX6 p.Ala343Asp Uncertain significance ★ ⚠ same type
CBX6 p.Ala347Thr 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/cbx6-p-arg221pro (accessed [today's date]).

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