Is CBL p.Ser407fs (c.1220_1221del) pathogenic?

CBL p.Ser407fs (c.12201221del) is classified Uncertain significance in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-22). Associated with RASopathy.

What condition is associated with CBL p.Ser407fs (c.1220_1221del)?

CBL p.Ser407fs (c.1220_1221del) is associated with RASopathy (ClinVar).

CBL p.Ser407fs

c.1220_1221del · VCV3647325

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.3	GERP 2.1, phastCons 1

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

Variant & gene context

Gene: CBL
Protein: p.Ser407fs
Coding: c.1220_1221del
MANE Select: NM_005188
Type: Deletion
Location: chr11:119278290 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 407: the 'required for ubiquitination of spred2' 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.Ser407Phe Uncertain significance ★★ ⚠ same residue
CBL p.Ser407= Likely benign ★★ same residue
CBL p.Ser407Pro Uncertain significance ★ ⚠ same residue
CBL p.Ser407Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
CBL c.1096-4_1096-1del Pathogenic/Likely pathogenic ★★ same condition
CBL c.2435-1_2435del Uncertain significance ★★ same condition
CBL p.Ile664fs Uncertain significance ★★ same condition
CBL c.1096-9del Likely benign ★★ 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-ser407fs (accessed [today's date]).

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