Is CBX8 p.Pro147Leu (c.440C>T) pathogenic?

CBX8 p.Pro147Leu (c.440C>T) is classified Uncertain significance in CBX8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-26). AlphaMissense: likely benign (0.1056); Very rare (popmax 0.00177%, amr).

How common is CBX8 p.Pro147Leu (c.440C>T) in the general population?

CBX8 p.Pro147Leu (c.440C>T) is very rare (popmax 0.00177%, amr) (gnomAD).

What do computational predictors say about CBX8 p.Pro147Leu (c.440C>T)?

AlphaMissense predicts likely benign (score 0.1056) — an in-silico prediction, not a clinical call.

CBX8 p.Pro147Leu

c.440C>T · VCV4220093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1056 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00177%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1056	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Regional constraint	o/e 1.17	unconstrained · MANE · 1,341 bp · p 0.00071 · regional, not allelic
Overall
CADD	22.2	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 0.00177% Admixed American · 1/56,500 alleles

Filtering AF 0.00104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000836%

Overall 0.00125% 20/1,595,902 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00177%	56,500
European (non-Finnish)	0.00162%	61,680

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: CBX8
Protein: p.Pro147Leu
Coding: c.440C>T
MANE Select: NM_020649
Type: single nucleotide variant
Location: chr17:79795365 (GRCh38)
Gene constraint: LOEUF 0.428 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.27 · 3 PDB
Residue 147: the 'disordered' region

Full CBX8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBX8 p.Ala133Val Uncertain significance ★ ⚠ same type
CBX8 p.Ala251Thr Uncertain significance ★ ⚠ same type
CBX8 p.Ala276Thr Uncertain significance ★ ⚠ same type
CBX8 p.Ala51Thr Uncertain significance ★ ⚠ same type
CBX8 p.Ala55Glu Uncertain significance ★ ⚠ same type
CBX8 p.Ala55Val Uncertain significance ★ ⚠ same type
CBX8 p.Ala83Val Uncertain significance ★ ⚠ same type
CBX8 p.Arg109Pro 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/cbx8-p-pro147leu (accessed [today's date]).

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