Is CBX2 p.Arg91Trp (c.271C>T) pathogenic?

CBX2 p.Arg91Trp (c.271C>T) is classified Uncertain significance in CBX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely benign (0.1405); Ultra-rare (popmax 0.035%, amr).

How common is CBX2 p.Arg91Trp (c.271C>T) in the general population?

CBX2 p.Arg91Trp (c.271C>T) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about CBX2 p.Arg91Trp (c.271C>T)?

AlphaMissense predicts likely benign (score 0.1405) — an in-silico prediction, not a clinical call.

CBX2 p.Arg91Trp

c.271C>T · rs375170872 · VCV2378704

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1405 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1405	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -8.62	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 1.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 5,618 bp · p 0.049 · regional, not allelic
Overall
CADD	25.8	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 0.035% Admixed American · 21/60,012 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00774% 125/1,613,996 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,858
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)	0.00754%	13,259
Finnishnot grpmax-eligible	0.00469%	21,335
East Asian	0.00446%	22,443
African / African-American	0.004%	24,972
South Asian	0.0022%	45,545

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.Arg91Trp
Coding: c.271C>T
MANE Select: NM_005189
dbSNP: rs375170872
Type: single nucleotide variant
Location: chr17:79781784 (GRCh38)
Gene constraint: LOEUF 0.946 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.29 · 3 PDB
Residue 91: the 'disordered' region

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

Similar variants

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CBX2 p.Arg137His Uncertain significance ★★ ⚠ same type
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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-arg91trp (accessed [today's date]).

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