Is CBX2 p.Arg70Trp (c.208C>T) pathogenic?

CBX2 p.Arg70Trp (c.208C>T) is classified Uncertain significance in CBX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-03). AlphaMissense: ambiguous (0.3419); Ultra-rare (popmax 0.0493%, mid).

How common is CBX2 p.Arg70Trp (c.208C>T) in the general population?

CBX2 p.Arg70Trp (c.208C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about CBX2 p.Arg70Trp (c.208C>T)?

AlphaMissense predicts ambiguous (score 0.3419) — an in-silico prediction, not a clinical call.

CBX2 p.Arg70Trp

c.208C>T · rs782303034 · VCV2557085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3419 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3419	ambiguous
REVEL	0.278	benign-leaning
SaProt	LLR -9.93	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 5,618 bp · p 0.049 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.0493% Middle Eastern · 3/6,082 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.0026% 42/1,613,846 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,027
South Asian	0.00768%	13,013
East Asian	0.00446%	22,438
European (non-Finnish)	0.00237%	42,142
Admixed American	0.00167%	60,000
African / African-American	0.00134%	74,904

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.Arg70Trp
Coding: c.208C>T
MANE Select: NM_005189
dbSNP: rs782303034
Type: single nucleotide variant
Location: chr17:79781721 (GRCh38)
Gene constraint: LOEUF 0.946 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.29 · 3 PDB
Residue 70: the chromo domain; 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-arg70trp (accessed [today's date]).

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