Is CBL p.Leu864= (c.2592C>T) pathogenic?

CBL p.Leu864= (c.2592C>T) is classified Benign in CBL (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). Common (popmax 11.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Noonan syndrome and Noonan-related syndrome.

What condition is associated with CBL p.Leu864= (c.2592C>T)?

CBL p.Leu864= (c.2592C>T) is associated with Noonan syndrome and Noonan-related syndrome, juvenile myelomonocytic leukemia, CBL-related disorder (ClinVar).

CBL p.Leu864=

Q: How common is CBL p.Leu864= (c.2592C>T) in the general population?

CBL p.Leu864= (c.2592C>T) is common (popmax 11.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2592C>T · rs1893177 · VCV45208

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 11.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Noonan syndrome and Noonan-related syndrome

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 1.2	GERP -0.56, phastCons 0.84
Overall
CADD	7.437	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 11.3% African / African-American · 8,464/75,008 alleles

Filtering AF 11.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 11%

Overall 0.593% 9,579/1,614,182 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.3%	9
Remaining individualsnot grpmax-eligible	0.841%	119
Admixed American	0.755%	133
Middle Eastern	0.462%	216
South Asian	0.0318%	3,141
European (non-Finnish)	0.00661%	15,129
East Asian	0.00223%	44,890

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.Leu864=
Coding: c.2592C>T
MANE Select: NM_005188
dbSNP: rs1893177
Type: single nucleotide variant
Location: chr11:119299652 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 864: the 'required for ubiquitination of spred2' region; an α-helix; the 'interaction with cd2ap' region; the uba domain

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

Disease context

Noonan syndrome and Noonan-related syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: juvenile myelomonocytic leukemia CBL-related disorder RASopathy

Similar variants

CBL p.Leu864Val Uncertain significance ★ ⚠ same residue
CBL p.Leu864Phe 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

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-leu864 (accessed [today's date]).

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