Is CBX2 p.Leu4Val (c.10C>G) pathogenic?

CBX2 p.Leu4Val (c.10C>G) is classified Uncertain significance in CBX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely pathogenic (0.8602); Very rare (popmax 8.88e-05%, nfe).

How common is CBX2 p.Leu4Val (c.10C>G) in the general population?

CBX2 p.Leu4Val (c.10C>G) is very rare (popmax 8.88e-05%, nfe) (gnomAD).

What do computational predictors say about CBX2 p.Leu4Val (c.10C>G)?

AlphaMissense predicts likely pathogenic (score 0.8602) — an in-silico prediction, not a clinical call.

CBX2 p.Leu4Val

c.10C>G · rs2145819164 · VCV1413266

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8602 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.88e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8602	likely pathogenic
REVEL	0.16	moderately benign-leaning
SaProt	LLR -11.44	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.46	donor gain · deltas
Constraint at this position
Conservation	phyloP 1	GERP -0.62, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 1,184 bp · p 0.00085 · regional, not allelic
Overall
CADD	25.9	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 8.88e-05% European (non-Finnish) · 1/1,126,500 alleles

Overall 7.44e-05% 1/1,344,680 alleles · very rare

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.Leu4Val
Coding: c.10C>G
MANE Select: NM_005189
dbSNP: rs2145819164
Type: single nucleotide variant
Location: chr17:79778245 (GRCh38)
Gene constraint: LOEUF 0.946 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.29 · 3 PDB
Residue 4: the 'involved in the interaction with h3c15 and h3c1' 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-leu4val (accessed [today's date]).

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