Is CBL p.Arg280Gly (c.838C>G) pathogenic?

CBL p.Arg280Gly (c.838C>G) is classified Uncertain significance in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-02). AlphaMissense: likely pathogenic (0.9991); Very rare (popmax 0.000169%, nfe); Associated with RASopathy.

What condition is associated with CBL p.Arg280Gly (c.838C>G)?

CBL p.Arg280Gly (c.838C>G) is associated with RASopathy (ClinVar).

How common is CBL p.Arg280Gly (c.838C>G) in the general population?

CBL p.Arg280Gly (c.838C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CBL p.Arg280Gly (c.838C>G)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

CBL p.Arg280Gly

c.838C>G · rs730880432 · VCV2814048

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic · top 8% in CBL
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -15.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.1, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 45 kb · p 4.6e-13 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000169% European (non-Finnish) · 2/1,179,964 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,738 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: CBL
Protein: p.Arg280Gly
Coding: c.838C>G
MANE Select: NM_005188
dbSNP: rs730880432
Type: single nucleotide variant
Location: chr11:119274922 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 280: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the 'sh2-like' region; an α-helix

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

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CBL p.Arg280Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CBL p.Arg280Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
CBL p.Arg280= Likely benign ★ same residue
CBL c.1096-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBL c.1096-1G>T Pathogenic ★★ same condition
CBL c.1228-2A>G Pathogenic/Likely pathogenic ★★ same condition
CBL p.Arg420Gln Pathogenic/Likely pathogenic ★★ same condition
CBL p.Arg420Leu Likely pathogenic ★★ same condition

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/cbl-p-arg280gly (accessed [today's date]).

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