Is CBX4 p.Asn91Ser (c.272A>G) pathogenic?

CBX4 p.Asn91Ser (c.272A>G) is classified Uncertain significance in CBX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.0784); Ultra-rare (popmax 0.0133%, amr).

How common is CBX4 p.Asn91Ser (c.272A>G) in the general population?

CBX4 p.Asn91Ser (c.272A>G) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about CBX4 p.Asn91Ser (c.272A>G)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

CBX4 p.Asn91Ser

c.272A>G · VCV4220060

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -4.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.48	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,409 bp · p 0.52 · regional, not allelic
Overall
CADD	26.7	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 0.0133% Admixed American · 8/60,000 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00242% 39/1,613,796 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,500
European (non-Finnish)	0.00254%	39,332
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Asn91Ser
Coding: c.272A>G
MANE Select: NM_003655
Type: single nucleotide variant
Location: chr17:79835370 (GRCh38)
Gene constraint: LOEUF 0.48 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 55.01 · 3 PDB
Residue 91: the 'interaction with bmi1' 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-asn91ser (accessed [today's date]).

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