Is CBL p.Pro543= (c.1629A>G) pathogenic?

CBL p.Pro543= (c.1629A>G) is classified Benign/Likely benign in CBL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-29). Rare (popmax 0.113%, sas); Associated with juvenile myelomonocytic leukemia.

What condition is associated with CBL p.Pro543= (c.1629A>G)?

CBL p.Pro543= (c.1629A>G) is associated with juvenile myelomonocytic leukemia, CBL-related disorder, RASopathy (ClinVar).

How common is CBL p.Pro543= (c.1629A>G) in the general population?

CBL p.Pro543= (c.1629A>G) is rare (popmax 0.113%, sas) (gnomAD).

How is Juvenile myelomonocytic leukemia inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

CBL p.Pro543=

c.1629A>G · rs558577411 · VCV302782

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.113%, sas)

Conditions

juvenile myelomonocytic leukemia

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 0.09	GERP -3.1, phastCons 0.2
Overall
CADD	5.998	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.113% South Asian · 103/91,064 alleles

Filtering AF 0.0953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0888%

Overall 0.00663% 107/1,614,012 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.113%	884
Remaining individualsnot grpmax-eligible	0.0064%	15,627

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.Pro543=
Coding: c.1629A>G
MANE Select: NM_005188
dbSNP: rs558577411
Type: single nucleotide variant
Location: chr11:119285254 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 543: the 'required for ubiquitination of spred2' region; the 'disordered' region

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

Disease context

juvenile myelomonocytic leukemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: CBL-related disorder RASopathy

For Juvenile myelomonocytic leukemia (Orphanet):

Inheritance: Not applicable
Onset: Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

CBL p.Pro543Leu 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
CBL p.Arg420Leu Likely pathogenic ★★ same condition
CBL p.Gln367Arg 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-pro543 (accessed [today's date]).

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