Is CBX2 p.Ala452Val (c.1355C>T) pathogenic?

CBX2 p.Ala452Val (c.1355C>T) is classified Benign in CBX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.076); Common (popmax 14.7%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CBX2 p.Ala452Val (c.1355C>T)?

AlphaMissense predicts likely benign (score 0.076) — an in-silico prediction, not a clinical call.

CBX2 p.Ala452Val

Q: How common is CBX2 p.Ala452Val (c.1355C>T) in the general population?

CBX2 p.Ala452Val (c.1355C>T) is common (popmax 14.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1355C>T · rs76915888 · VCV1630038

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.076 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 14.7%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.076	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -7.29	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 0.74	GERP 1.4, phastCons 0.001
Regional constraint	o/e 1.08	unconstrained · MANE · 5,618 bp · p 0.049 · regional, not allelic
Overall
CADD	10.13	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 14.7% African / African-American · 11,048/74,946 alleles

Filtering AF 14.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.4%

Overall 0.964% 15,530/1,610,558 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	14.7%	7
Admixed American	1.99%	50
Middle Eastern	1.65%	61
Remaining individualsnot grpmax-eligible	1.41%	71
European (non-Finnish)	0.181%	551
South Asian	0.138%	726
Ashkenazi Jewishnot grpmax-eligible	0.0982%	1,019
Finnishnot grpmax-eligible	0.0303%	3,305
East Asian	0.00447%	22,370

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.Ala452Val
Coding: c.1355C>T
MANE Select: NM_005189
dbSNP: rs76915888
Type: single nucleotide variant
Location: chr17:79784798 (GRCh38)
Gene constraint: LOEUF 0.946 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.29 · 3 PDB
Residue 452: the 'disordered' region

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

Similar variants

CBX2 p.Ala452= Benign/Likely benign ★★ same residue
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

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-ala452val (accessed [today's date]).

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