Is CBL p.Tyr291= (c.873T>C) pathogenic?

CBL p.Tyr291= (c.873T>C) is classified Likely benign in CBL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0367%, amr); Associated with juvenile myelomonocytic leukemia.

What condition is associated with CBL p.Tyr291= (c.873T>C)?

CBL p.Tyr291= (c.873T>C) is associated with juvenile myelomonocytic leukemia, RASopathy (ClinVar).

How common is CBL p.Tyr291= (c.873T>C) in the general population?

CBL p.Tyr291= (c.873T>C) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

How is Juvenile myelomonocytic leukemia inherited?

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

CBL p.Tyr291=

c.873T>C · rs756526812 · VCV383007

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Conditions

juvenile myelomonocytic leukemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.62 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.034	GERP -1.5, phastCons 0.82
Overall
CADD	8.119	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0367% Admixed American · 22/60,010 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00235% 38/1,614,088 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,728
Middle Eastern	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
African / African-American	0.00133%	74,946
South Asian	0.0011%	91,096
European (non-Finnish)	0.000593%	168,572

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.Tyr291=
Coding: c.873T>C
MANE Select: NM_005188
dbSNP: rs756526812
Type: single nucleotide variant
Location: chr11:119276000 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 291: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the 'sh2-like' region; a β-strand

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: RASopathy

For Juvenile myelomonocytic leukemia (Orphanet):

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

Similar variants

CBL p.Tyr291Cys Uncertain significance ★ ⚠ 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
CBL p.Arg420Leu Likely pathogenic ★★ same condition
CBL p.Gln367Arg Likely pathogenic ★★ same condition
CBL p.Gln367Pro 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-tyr291 (accessed [today's date]).

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