Is CBX7 p.Arg140Cys (c.418C>T) pathogenic?

CBX7 p.Arg140Cys (c.418C>T) is classified Uncertain significance in CBX7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-21). AlphaMissense: likely benign (0.0824); Ultra-rare (popmax 0.0113%, eas).

How common is CBX7 p.Arg140Cys (c.418C>T) in the general population?

CBX7 p.Arg140Cys (c.418C>T) is ultra-rare (popmax 0.0113%, eas) (gnomAD).

What do computational predictors say about CBX7 p.Arg140Cys (c.418C>T)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

CBX7 p.Arg140Cys

c.418C>T · VCV4220082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -8.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.47	GERP -2.4, phastCons 0.34
Regional constraint	o/e 0.92	unconstrained · MANE · 858 bp · p 0.23 · regional, not allelic
Overall
CADD	20.1	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 0.0113% East Asian · 5/44,178 alleles

Filtering AF 0.0044% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0028%

Overall 0.00106% 17/1,597,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0113%	8,836
Admixed American	0.00349%	28,638
African / African-American	0.00267%	37,413
Remaining individualsnot grpmax-eligible	0.00162%	61,862
European (non-Finnish)	0.000597%	167,543

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: CBX7
Protein: p.Arg140Cys
Coding: c.418C>T
MANE Select: NM_175709
Type: single nucleotide variant
Location: chr22:39134581 (GRCh38)
Gene constraint: LOEUF 0.767 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 67.01 · 9 PDB

Full CBX7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBX7 p.Ala179Ser Uncertain significance ★ ⚠ same type
CBX7 p.Ala185Val Uncertain significance ★ ⚠ same type
CBX7 p.Ala202Val Uncertain significance ★ ⚠ same type
CBX7 p.Ala214Pro Uncertain significance ★ ⚠ same type
CBX7 p.Ala214Val Uncertain significance ★ ⚠ same type
CBX7 p.Arg159Cys Uncertain significance ★ ⚠ same type
CBX7 p.Arg170Gln Uncertain significance ★ ⚠ same type
CBX7 p.Arg235Cys 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/cbx7-p-arg140cys (accessed [today's date]).

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