Is CBL p.Arg206Ter (c.616C>T) pathogenic?

CBL p.Arg206Ter (c.616C>T) is classified Uncertain significance in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-26). Very rare (popmax 0.00167%, amr); Associated with RASopathy.

What condition is associated with CBL p.Arg206Ter (c.616C>T)?

CBL p.Arg206Ter (c.616C>T) is associated with RASopathy (ClinVar).

How common is CBL p.Arg206Ter (c.616C>T) in the general population?

CBL p.Arg206Ter (c.616C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

CBL p.Arg206Ter

c.616C>T · VCV3628767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 4 of 16
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 0.17, phastCons 1
Overall
CADD	38.0	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 0.00167% Admixed American · 1/59,998 alleles

Overall 0.000186% 3/1,613,968 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,998
African / African-American	0.00133%	74,920
European (non-Finnish)	8.47e-05%	1,179,966

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.Arg206Ter
Coding: c.616C>T
MANE Select: NM_005188
Type: single nucleotide variant
Location: chr11:119273893 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 206: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the 'ef-hand-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.Arg206= Likely benign ★★ same residue
CBL p.Arg206Gln 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
CBL p.Gln367Arg 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-arg206ter (accessed [today's date]).

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