Is CBX2 p.Pro98Leu (c.293C>T) pathogenic?

CBX2 p.Pro98Leu (c.293C>T) is classified Pathogenic in CBX2 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2009-05-01). AlphaMissense: likely benign (0.0873); Absent from gnomAD v4.1; Associated with 46,XY sex reversal 5.

What condition is associated with CBX2 p.Pro98Leu (c.293C>T)?

CBX2 p.Pro98Leu (c.293C>T) is associated with 46,XY sex reversal 5 (ClinVar).

How common is CBX2 p.Pro98Leu (c.293C>T) in the general population?

CBX2 p.Pro98Leu (c.293C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBX2 p.Pro98Leu (c.293C>T)?

AlphaMissense predicts likely benign (score 0.0873) — an in-silico prediction, not a clinical call.

CBX2 p.Pro98Leu

c.293C>T · rs121908255 · VCV6826

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0873 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

46,XY sex reversal 5

Computational evidence

Protein change
AlphaMissense	0.0873	likely benign ⚠ discordant with ClinVar
REVEL	0.165	moderately benign-leaning
SaProt	LLR -6.56	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 3.8	GERP 1.5, phastCons 0.19
Regional constraint	o/e 1.08	unconstrained · MANE · 5,618 bp · p 0.049 · regional, not allelic
Overall
CADD	16.34	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CBX2
Protein: p.Pro98Leu
Coding: c.293C>T
MANE Select: NM_005189
dbSNP: rs121908255
Type: single nucleotide variant
Location: chr17:79783736 (GRCh38)
Gene constraint: LOEUF 0.946 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.29 · 3 PDB
Residue 98: a UniProt-annotated variant site (in srxy5); the 'disordered' region

Full CBX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

46,XY sex reversal 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CBX2 p.Pro98Ala Uncertain significance ★ ⚠ same residue
CBX2 p.Leu56= Uncertain significance ★ same condition
CBX2 p.Ser111Phe Likely benign ★ ⚠ same condition
CBX2 p.Arg443Pro Pathogenic ⚠ same condition
CBX2 c.117-18del Uncertain significance ★★ same condition
CBX2 p.Cys89fs Uncertain significance ★ same condition
CBX2 c.288+52G>T Uncertain significance ★★ same type
CBX2 p.Arg137His 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/cbx2-p-pro98leu (accessed [today's date]).

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