Is CBX6 p.Pro283Ser (c.847C>T) pathogenic?

CBX6 p.Pro283Ser (c.847C>T) is classified Uncertain significance in CBX6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-30). AlphaMissense: likely benign (0.0684); Ultra-rare (popmax 0.0998%, sas).

How common is CBX6 p.Pro283Ser (c.847C>T) in the general population?

CBX6 p.Pro283Ser (c.847C>T) is ultra-rare (popmax 0.0998%, sas) (gnomAD).

What do computational predictors say about CBX6 p.Pro283Ser (c.847C>T)?

AlphaMissense predicts likely benign (score 0.0684) — an in-silico prediction, not a clinical call.

CBX6 p.Pro283Ser

c.847C>T · rs758158657 · VCV3138076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0684 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0998%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0684	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -5.24	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 8.3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 541 bp · p 0.34 · regional, not allelic
Overall
CADD	15.43	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 0.0998% South Asian · 86/86,184 alleles

Filtering AF 0.0828% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0764%

Overall 0.0059% 92/1,560,192 alleles · ultra-rare exomes 91/1,408,182 · genomes 1/152,010 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0998%	1,002
Middle Eastern	0.0178%	5,604
Remaining individualsnot grpmax-eligible	0.00495%	20,197
Ashkenazi Jewishnot grpmax-eligible	0.00358%	27,938
European (non-Finnish)	8.62e-05%	1,159,734

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.Pro283Ser
Coding: c.847C>T
MANE Select: NM_014292
dbSNP: rs758158657
Type: single nucleotide variant
Location: chr22:38866601 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 62.15 · 2 PDB
Residue 283: the 'disordered' region

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

Similar variants

CBX6 p.Pro283Arg Uncertain significance ★ ⚠ same residue
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

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-pro283ser (accessed [today's date]).

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