Is CBL p.Pro782Leu (c.2345C>T) pathogenic?

CBL p.Pro782Leu (c.2345C>T) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1003); Rare (popmax 0.781%, afr); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Pro782Leu (c.2345C>T)?

CBL p.Pro782Leu (c.2345C>T) is associated with Cardiovascular phenotype, CBL-related disorder, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is CBL p.Pro782Leu (c.2345C>T) in the general population?

CBL p.Pro782Leu (c.2345C>T) is rare (popmax 0.781%, afr) (gnomAD).

What do computational predictors say about CBL p.Pro782Leu (c.2345C>T)?

AlphaMissense predicts likely benign (score 0.1003) — an in-silico prediction, not a clinical call.

CBL p.Pro782Leu

c.2345C>T · rs2229073 · VCV40421

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.1003 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.781%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1003	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -7.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	24.9	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 0.781% African / African-American · 586/75,044 alleles

Filtering AF 0.729% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.708%

Overall 0.058% 936/1,614,116 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.781%	128
Admixed American	0.163%	612
Remaining individualsnot grpmax-eligible	0.104%	962
Middle Eastern	0.066%	1,516
East Asian	0.0446%	2,244
European (non-Finnish)	0.0135%	7,421
South Asian	0.00439%	22,770

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.Pro782Leu
Coding: c.2345C>T
MANE Select: NM_005188
dbSNP: rs2229073
Type: single nucleotide variant
Location: chr11:119298451 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 782: the 'required for ubiquitination of spred2' region; the 'interaction with cd2ap' region; a UniProt-annotated variant site (in)

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: CBL-related disorder Noonan syndrome and Noonan-related syndrome RASopathy

Similar variants

CBL p.Pro782= Likely benign ★★ 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-pro782leu (accessed [today's date]).

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