Is CBX2 p.Thr348Ser (c.1043C>G) pathogenic?

CBX2 p.Thr348Ser (c.1043C>G) is classified Uncertain significance in CBX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-27). AlphaMissense: likely benign (0.0664); Very rare (popmax 0.000593%, nfe).

How common is CBX2 p.Thr348Ser (c.1043C>G) in the general population?

CBX2 p.Thr348Ser (c.1043C>G) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about CBX2 p.Thr348Ser (c.1043C>G)?

AlphaMissense predicts likely benign (score 0.0664) — an in-silico prediction, not a clinical call.

CBX2 p.Thr348Ser

c.1043C>G · rs782047271 · VCV2054066

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0664 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0664	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -5.28	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 2.5	GERP 0.2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 5,618 bp · p 0.049 · regional, not allelic
Overall
CADD	11.3	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 0.000593% European (non-Finnish) · 7/1,179,906 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,612,588 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: CBX2
Protein: p.Thr348Ser
Coding: c.1043C>G
MANE Select: NM_005189
dbSNP: rs782047271
Type: single nucleotide variant
Location: chr17:79784486 (GRCh38)
Gene constraint: LOEUF 0.946 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.29 · 3 PDB
Residue 348: the 'disordered' region

Full CBX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBX2 p.Thr348Asn Uncertain significance ★ ⚠ same residue
CBX2 c.288+52G>T Uncertain significance ★★ same type
CBX2 p.Arg137His Uncertain significance ★★ ⚠ same type
CBX2 p.Gln349His Uncertain significance ★★ ⚠ same type
CBX2 p.Gly133Ser Uncertain significance ★★ ⚠ same type
CBX2 p.Gly287Arg Uncertain significance ★★ ⚠ same type
CBX2 p.Gly332Asp Uncertain significance ★★ ⚠ same type
CBX2 p.Met260Val 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/cbx2-p-thr348ser (accessed [today's date]).

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