Is CBX4 p.Phe537Leu (c.1609T>C) pathogenic?

CBX4 p.Phe537Leu (c.1609T>C) is classified Uncertain significance in CBX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely pathogenic (0.8952); Absent from gnomAD v4.1.

How common is CBX4 p.Phe537Leu (c.1609T>C) in the general population?

CBX4 p.Phe537Leu (c.1609T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBX4 p.Phe537Leu (c.1609T>C)?

AlphaMissense predicts likely pathogenic (score 0.8952) — an in-silico prediction, not a clinical call.

CBX4 p.Phe537Leu

c.1609T>C · rs2509770501 · VCV2287315

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8952 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8952	likely pathogenic
REVEL	0.09	moderately benign-leaning
SaProt	LLR -5.41	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP -3.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,409 bp · p 0.52 · regional, not allelic
Overall
CADD	24.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CBX4
Protein: p.Phe537Leu
Coding: c.1609T>C
MANE Select: NM_003655
dbSNP: rs2509770501
Type: single nucleotide variant
Location: chr17:79834033 (GRCh38)
Gene constraint: LOEUF 0.48 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 55.01 · 3 PDB
Residue 537: the 'interaction with bmi1' region; the 'involved in interaction with h3c15 and rnf2' 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-phe537leu (accessed [today's date]).

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