Is CBX4 p.Val402Ile (c.1204G>A) pathogenic?

CBX4 p.Val402Ile (c.1204G>A) is classified Uncertain significance in CBX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-30). AlphaMissense: likely benign (0.0838); Very rare (popmax 0.00169%, nfe).

How common is CBX4 p.Val402Ile (c.1204G>A) in the general population?

CBX4 p.Val402Ile (c.1204G>A) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about CBX4 p.Val402Ile (c.1204G>A)?

AlphaMissense predicts likely benign (score 0.0838) — an in-silico prediction, not a clinical call.

CBX4 p.Val402Ile

c.1204G>A · VCV4648805

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0838 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0838	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -7.39	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 0.92	GERP 0.18, phastCons 0.01
Regional constraint	o/e 0.98	unconstrained · MANE · 1,409 bp · p 0.52 · regional, not allelic
Overall
CADD	10.21	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 0.00169% European (non-Finnish) · 18/1,065,174 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000871%

Overall 0.00139% 18/1,290,714 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: CBX4
Protein: p.Val402Ile
Coding: c.1204G>A
MANE Select: NM_003655
Type: single nucleotide variant
Location: chr17:79834438 (GRCh38)
Gene constraint: LOEUF 0.48 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 55.01 · 3 PDB
Residue 402: the 'interaction with bmi1' region; the 'disordered' region

Full CBX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBX4 p.Arg70= Benign ★★ same type
CBX4 p.Ala138Val Uncertain significance ★ ⚠ same type
CBX4 p.Ala236Val Uncertain significance ★ ⚠ same type
CBX4 p.Ala298Val Uncertain significance ★ ⚠ same type
CBX4 p.Ala314Pro Uncertain significance ★ ⚠ same type
CBX4 p.Ala316Ser Uncertain significance ★ ⚠ same type
CBX4 p.Ala316Thr Uncertain significance ★ ⚠ same type
CBX4 p.Ala323Glu 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/cbx4-p-val402ile (accessed [today's date]).

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