Is CBL p.Pro828= (c.2484G>A) pathogenic?

CBL p.Pro828= (c.2484G>A) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-05-01). Rare (popmax 0.576%, afr); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Pro828= (c.2484G>A)?

CBL p.Pro828= (c.2484G>A) is associated with Cardiovascular phenotype, juvenile myelomonocytic leukemia, CBL-related disorder (ClinVar).

How common is CBL p.Pro828= (c.2484G>A) in the general population?

CBL p.Pro828= (c.2484G>A) is rare (popmax 0.576%, afr) (gnomAD).

CBL p.Pro828=

c.2484G>A · rs149533467 · VCV40424

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

rare (popmax 0.576%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.28	GERP -3.1, phastCons 1
Overall
CADD	9.699	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.576% African / African-American · 432/75,000 alleles

Filtering AF 0.531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.513%

Overall 0.0304% 490/1,614,068 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.576%	174
Remaining individualsnot grpmax-eligible	0.0384%	2,604
Middle Eastern	0.033%	3,031
Admixed American	0.02%	5,001
East Asian	0.00223%	44,886
European (non-Finnish)	0.00161%	62,106

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.Pro828=
Coding: c.2484G>A
MANE Select: NM_005188
dbSNP: rs149533467
Type: single nucleotide variant
Location: chr11:119299544 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 828: 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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: juvenile myelomonocytic leukemia CBL-related disorder Noonan syndrome and Noonan-related syndrome RASopathy

Similar variants

CBL p.Pro828Ala Uncertain significance ★ ⚠ same residue
CBL p.Pro828Leu Uncertain significance ★ ⚠ same residue
CBL p.Pro828Ser 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.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-pro828 (accessed [today's date]).

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