Is CBL p.Arg499Gly (c.1495C>G) pathogenic?

CBL p.Arg499Gly (c.1495C>G) is classified Uncertain significance in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely pathogenic (0.9901); Very rare (popmax 8.47e-05%, nfe); Associated with RASopathy.

What condition is associated with CBL p.Arg499Gly (c.1495C>G)?

CBL p.Arg499Gly (c.1495C>G) is associated with RASopathy (ClinVar).

How common is CBL p.Arg499Gly (c.1495C>G) in the general population?

CBL p.Arg499Gly (c.1495C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CBL p.Arg499Gly (c.1495C>G)?

AlphaMissense predicts likely pathogenic (score 0.9901) — an in-silico prediction, not a clinical call.

CBL p.Arg499Gly

c.1495C>G · VCV4800616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9901 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.9901	likely pathogenic
REVEL	0.545	indeterminate
SaProt	LLR -8.62	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.28, phastCons 0.99
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,022 alleles

Overall 6.84e-05% 1/1,461,878 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.Arg499Gly
Coding: c.1495C>G
MANE Select: NM_005188
Type: single nucleotide variant
Location: chr11:119285032 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 499: the 'required for ubiquitination of spred2' region; a UniProt-annotated variant site (found in patients with acute myeloid leukemia; uncertain significance)

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.Arg499Gln Uncertain significance ★★ ⚠ same residue
CBL p.Arg499= Likely benign ★★ same residue
CBL p.Arg499Ter Uncertain significance ★ 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-arg499gly (accessed [today's date]).

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