Is CBL p.Lys382Glu (c.1144A>G) pathogenic?

CBL p.Lys382Glu (c.1144A>G) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-02-05). AlphaMissense: likely pathogenic (0.9999); Very rare (popmax 8.49e-05%, nfe); Associated with CBL-related disorder.

What condition is associated with CBL p.Lys382Glu (c.1144A>G)?

CBL p.Lys382Glu (c.1144A>G) is associated with CBL-related disorder, RASopathy (ClinVar).

How common is CBL p.Lys382Glu (c.1144A>G) in the general population?

CBL p.Lys382Glu (c.1144A>G) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about CBL p.Lys382Glu (c.1144A>G)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

CBL p.Lys382Glu

c.1144A>G · rs267606705 · VCV13808

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 8% in CBL
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -14.75	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	30.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,800 alleles

Overall 6.85e-05% 1/1,459,442 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.Lys382Glu
Coding: c.1144A>G
MANE Select: NM_005188
dbSNP: rs267606705
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

Also linked: RASopathy

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.Lys382Gln Uncertain significance ★ ⚠ same residue
CBL c.1096-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBL c.1096-1G>T Pathogenic ★★ same condition
CBL c.1096-2A>T Pathogenic ★★ same condition
CBL c.1228-2A>G 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-lys382glu (accessed [today's date]).

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