Is CBL p.Arg506Ter (c.1516C>T) pathogenic?

CBL p.Arg506Ter (c.1516C>T) is classified Likely pathogenic in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-01). Ultra-rare (popmax 0.0165%, mid); Associated with Noonan syndrome and Noonan-related syndrome.

What condition is associated with CBL p.Arg506Ter (c.1516C>T)?

CBL p.Arg506Ter (c.1516C>T) is associated with Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is CBL p.Arg506Ter (c.1516C>T) in the general population?

CBL p.Arg506Ter (c.1516C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

CBL p.Arg506Ter

c.1516C>T · rs886041500 · VCV1334208

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Noonan syndrome and Noonan-related syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 16
Splicing
SpliceAI	Δ0.44	donor gain · deltas
Pangolin	Δ0.37	gain · loss 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.3	GERP -1.4, phastCons 1
Overall
CADD	40.0	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.84e-05% 1/1,461,884 alleles · ultra-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.Arg506Ter
Coding: c.1516C>T
MANE Select: NM_005188
dbSNP: rs886041500
Type: single nucleotide variant
Location: chr11:119285053 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 506: the 'required for ubiquitination of spred2' region

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

Disease context

Noonan syndrome and Noonan-related syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CBL p.Arg506Gly Uncertain significance ★★ ⚠ same residue
CBL p.Arg506Leu Uncertain significance ★★ ⚠ same residue
CBL p.Arg506Gln Uncertain significance ★ ⚠ same residue
CBL p.Gln367Arg Likely pathogenic ★★ same condition
CBL p.Gln367Pro Pathogenic/Likely pathogenic ★★ same condition
CBL p.Arg563Cys Uncertain significance ★★ ⚠ same condition
CBL p.Arg718Gln Uncertain significance ★★ ⚠ same condition
CBL p.Arg829Trp Uncertain significance ★★ ⚠ 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-arg506ter (accessed [today's date]).

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