Is CBX2 p.Asp99Asn (c.295G>A) pathogenic?

CBX2 p.Asp99Asn (c.295G>A) is classified Uncertain significance in CBX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-14). AlphaMissense: likely benign (0.0914); Very rare (popmax 0.00392%, amr).

How common is CBX2 p.Asp99Asn (c.295G>A) in the general population?

CBX2 p.Asp99Asn (c.295G>A) is very rare (popmax 0.00392%, amr) (gnomAD).

What do computational predictors say about CBX2 p.Asp99Asn (c.295G>A)?

AlphaMissense predicts likely benign (score 0.0914) — an in-silico prediction, not a clinical call.

CBX2 p.Asp99Asn

c.295G>A · VCV3712507

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0914 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00392%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0914	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -6.25	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 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 5,618 bp · p 0.049 · regional, not allelic
Overall
CADD	21.2	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 0.00392% Admixed American · 2/51,014 alleles

Filtering AF 0.0023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00204%

Overall 0.00264% 41/1,551,972 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00392%	25,507
European (non-Finnish)	0.00314%	31,865
South Asian	0.00237%	42,109
Remaining individualsnot grpmax-eligible	0.00166%	60,114

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: CBX2
Protein: p.Asp99Asn
Coding: c.295G>A
MANE Select: NM_005189
Type: single nucleotide variant
Location: chr17:79783738 (GRCh38)
Gene constraint: LOEUF 0.946 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.29 · 3 PDB
Residue 99: the 'disordered' region

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

Similar variants

CBX2 c.288+52G>T Uncertain significance ★★ same type
CBX2 p.Arg137His Uncertain significance ★★ ⚠ same type
CBX2 p.Gln349His Uncertain significance ★★ ⚠ same type
CBX2 p.Gly133Ser Uncertain significance ★★ ⚠ same type
CBX2 p.Gly287Arg Uncertain significance ★★ ⚠ same type
CBX2 p.Gly332Asp Uncertain significance ★★ ⚠ same type
CBX2 p.Met260Val Uncertain significance ★★ ⚠ same type
CBX2 p.Met404Leu 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-asp99asn (accessed [today's date]).

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