Is CBL p.Pro428Ser (c.1282C>T) pathogenic?

CBL p.Pro428Ser (c.1282C>T) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-06). AlphaMissense: ambiguous (0.5235); Very rare (popmax 0.00439%, sas); Associated with CBL-related disorder.

What condition is associated with CBL p.Pro428Ser (c.1282C>T)?

CBL p.Pro428Ser (c.1282C>T) is associated with CBL-related disorder, juvenile myelomonocytic leukemia, RASopathy (ClinVar).

How common is CBL p.Pro428Ser (c.1282C>T) in the general population?

CBL p.Pro428Ser (c.1282C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about CBL p.Pro428Ser (c.1282C>T)?

AlphaMissense predicts ambiguous (score 0.5235) — an in-silico prediction, not a clinical call.

CBL p.Pro428Ser

c.1282C>T · rs762677807 · VCV1415547

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5235 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.5235	ambiguous
REVEL	0.478	indeterminate
SaProt	LLR -12.14	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.1, 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 0.00439% South Asian · 4/91,082 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000248% 4/1,614,126 alleles · very rare exomes 4/1,461,880 · genomes 0/152,246 · joint denominator

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.Pro428Ser
Coding: c.1282C>T
MANE Select: NM_005188
dbSNP: rs762677807
Type: single nucleotide variant
Location: chr11:119278564 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 428: the 'required for ubiquitination of spred2' region; a β-strand

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

Disease context

Also linked: juvenile myelomonocytic leukemia RASopathy

Similar variants

CBL p.Pro428= 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-pro428ser (accessed [today's date]).

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