Is CBL p.Leu28Pro (c.83T>C) pathogenic?

CBL p.Leu28Pro (c.83T>C) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-07). AlphaMissense: likely pathogenic (0.9572); Very rare (popmax 8.63e-05%, nfe); Associated with RASopathy.

What condition is associated with CBL p.Leu28Pro (c.83T>C)?

CBL p.Leu28Pro (c.83T>C) is associated with RASopathy (ClinVar).

How common is CBL p.Leu28Pro (c.83T>C) in the general population?

CBL p.Leu28Pro (c.83T>C) is very rare (popmax 8.63e-05%, nfe) (gnomAD).

What do computational predictors say about CBL p.Leu28Pro (c.83T>C)?

AlphaMissense predicts likely pathogenic (score 0.9572) — an in-silico prediction, not a clinical call.

CBL p.Leu28Pro

c.83T>C · rs2496819377 · VCV2699339

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9572 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.63e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.9572	likely pathogenic
REVEL	0.464	indeterminate
SaProt	LLR -8.89	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 0.29, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 26 kb · p 0.76 · regional, not allelic
Overall
CADD	27.6	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 8.63e-05% European (non-Finnish) · 1/1,158,814 alleles

Overall 7.06e-05% 1/1,417,334 alleles · very rare

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.Leu28Pro
Coding: c.83T>C
MANE Select: NM_005188
dbSNP: rs2496819377
Type: single nucleotide variant
Location: chr11:119206500 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 28: the 'sufficient for interaction with ephb1' region

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

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CBL p.Leu28Phe Uncertain significance ★★ ⚠ same residue
CBL p.Leu28= Likely benign ★★ same residue
CBL p.Leu28Val 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

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-leu28pro (accessed [today's date]).

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