Is CBX6 p.Gly405Ser (c.1213G>A) pathogenic?

CBX6 p.Gly405Ser (c.1213G>A) is classified Uncertain significance in CBX6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely benign (0.0784); Rare (popmax 0.684%, afr).

How common is CBX6 p.Gly405Ser (c.1213G>A) in the general population?

CBX6 p.Gly405Ser (c.1213G>A) is rare (popmax 0.684%, afr) (gnomAD).

What do computational predictors say about CBX6 p.Gly405Ser (c.1213G>A)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

CBX6 p.Gly405Ser

c.1213G>A · VCV4648810

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.684%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.085	GERP -1.8
Regional constraint	o/e 0.94	unconstrained · MANE · 73 bp · p 0.7 · regional, not allelic
Overall
CADD	11.66	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 0.684% African / African-American · 513/75,034 alleles

Filtering AF 0.635% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.615%

Overall 0.0347% 560/1,611,860 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.684%	146
Remaining individualsnot grpmax-eligible	0.0273%	3,667
Admixed American	0.025%	3,994
South Asian	0.0022%	45,414
European (non-Finnish)	0.0011%	90,714

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.Gly405Ser
Coding: c.1213G>A
MANE Select: NM_014292
Type: single nucleotide variant
Location: chr22:38866235 (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.Gly405Cys 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-gly405ser (accessed [today's date]).

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