Is CBL p.Arg499Ter (c.1495C>T) pathogenic?

CBL p.Arg499Ter (c.1495C>T) is classified Uncertain significance in CBL (ClinVar, Single submitter, 2 submitters; last evaluated 2025-02-06). Very rare (popmax 0.000254%, nfe); Associated with RASopathy.

What condition is associated with CBL p.Arg499Ter (c.1495C>T)?

CBL p.Arg499Ter (c.1495C>T) is associated with RASopathy, rhabdomyosarcoma (ClinVar).

How common is CBL p.Arg499Ter (c.1495C>T) in the general population?

CBL p.Arg499Ter (c.1495C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

CBL p.Arg499Ter

c.1495C>T · rs778927765 · VCV978807

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 16
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
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,028 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,086 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.Arg499Ter
Coding: c.1495C>T
MANE Select: NM_005188
dbSNP: rs778927765
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

Also linked: rhabdomyosarcoma

Similar variants

CBL p.Arg499Gln Uncertain significance ★★ ⚠ same residue
CBL p.Arg499= Likely benign ★★ same residue
CBL p.Arg499Gly 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-arg499ter (accessed [today's date]).

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