Is CBL p.Glu699Gly (c.2096A>G) pathogenic?

CBL p.Glu699Gly (c.2096A>G) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-15). AlphaMissense: ambiguous (0.3501); Very rare (popmax 0.00223%, eas); Associated with CBL-related disorder.

What condition is associated with CBL p.Glu699Gly (c.2096A>G)?

CBL p.Glu699Gly (c.2096A>G) is associated with CBL-related disorder (ClinVar).

How common is CBL p.Glu699Gly (c.2096A>G) in the general population?

CBL p.Glu699Gly (c.2096A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CBL p.Glu699Gly (c.2096A>G)?

AlphaMissense predicts ambiguous (score 0.3501) — an in-silico prediction, not a clinical call.

CBL p.Glu699Gly

c.2096A>G · rs866325598 · VCV302786

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3501 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.3501	ambiguous
REVEL	0.564	indeterminate
SaProt	LLR -5.87	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	24.2	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 0.00223% East Asian · 1/44,880 alleles

Overall 6.85e-05% 1/1,460,360 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.Glu699Gly
Coding: c.2096A>G
MANE Select: NM_005188
dbSNP: rs866325598
Type: single nucleotide variant
Location: chr11:119296977 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 699: the 'required for ubiquitination of spred2' region; the 'interaction with cd2ap' region; the 'disordered' region

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

Disease context

CBL-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CBL p.Glu699= Likely benign ★★ same residue
CBL p.Glu699Asp Uncertain significance ★★ ⚠ same residue
CBL p.Glu699Lys 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
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-glu699gly (accessed [today's date]).

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