Is CBX4 p.Ala314Pro (c.940G>C) pathogenic?

CBX4 p.Ala314Pro (c.940G>C) is classified Uncertain significance in CBX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-25). AlphaMissense: likely benign (0.0806); Ultra-rare (popmax 0.0777%, afr).

How common is CBX4 p.Ala314Pro (c.940G>C) in the general population?

CBX4 p.Ala314Pro (c.940G>C) is ultra-rare (popmax 0.0777%, afr) (gnomAD).

What do computational predictors say about CBX4 p.Ala314Pro (c.940G>C)?

AlphaMissense predicts likely benign (score 0.0806) — an in-silico prediction, not a clinical call.

CBX4 p.Ala314Pro

c.940G>C · rs150230495 · VCV2221398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0806 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0777%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0806	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -6.38	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 -2.2	GERP -3.3
Regional constraint	o/e 0.98	unconstrained · MANE · 1,409 bp · p 0.52 · regional, not allelic
Overall
CADD	7.445	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 0.0777% African / African-American · 58/74,666 alleles

Filtering AF 0.0616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0559%

Overall 0.00419% 67/1,600,084 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0777%	1,287
Remaining individualsnot grpmax-eligible	0.0097%	10,304
Admixed American	0.00337%	29,653
South Asian	0.00111%	90,352

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.Ala314Pro
Coding: c.940G>C
MANE Select: NM_003655
dbSNP: rs150230495
Type: single nucleotide variant
Location: chr17:79834702 (GRCh38)
Gene constraint: LOEUF 0.48 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 55.01 · 3 PDB
Residue 314: 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.Ala316Ser Uncertain significance ★ ⚠ same type
CBX4 p.Ala316Thr Uncertain significance ★ ⚠ same type
CBX4 p.Ala323Glu Uncertain significance ★ ⚠ same type
CBX4 p.Ala354Ser 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-ala314pro (accessed [today's date]).

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