Is CBL p.Lys382Gln (c.1144A>C) pathogenic?

CBL p.Lys382Gln (c.1144A>C) is classified Uncertain significance in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-03). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with CBL p.Lys382Gln (c.1144A>C)?

CBL p.Lys382Gln (c.1144A>C) is associated with RASopathy (ClinVar).

How common is CBL p.Lys382Gln (c.1144A>C) in the general population?

CBL p.Lys382Gln (c.1144A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBL p.Lys382Gln (c.1144A>C)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

CBL p.Lys382Gln

c.1144A>C · VCV3689520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic · top 8% in CBL
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -14.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CBL
Protein: p.Lys382Gln
Coding: c.1144A>C
MANE Select: NM_005188
Type: single nucleotide variant
Location: chr11:119278214 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 382: the 'required for ubiquitination of spred2' region; a turn; a UniProt-annotated variant site (in nsll; dominant-negative; impairs cbl-mediated ubiquitination, internalization and degradation of the egf receptor/egfr; decreases the ability to negatively regulate egfr signaling)

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.Lys382= Likely benign ★★ same residue
CBL p.Lys382Arg Uncertain significance ★ ⚠ same residue
CBL p.Lys382Asn Uncertain significance ★ ⚠ same residue
CBL p.Lys382Glu Conflicting classifications of pathogenicity ★ ⚠ 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

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-lys382gln (accessed [today's date]).

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