Is CBL p.Leu28Phe (c.82C>T) pathogenic?

CBL p.Leu28Phe (c.82C>T) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-28). AlphaMissense: ambiguous (0.3474); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with CBL p.Leu28Phe (c.82C>T)?

CBL p.Leu28Phe (c.82C>T) is associated with RASopathy (ClinVar).

How common is CBL p.Leu28Phe (c.82C>T) in the general population?

CBL p.Leu28Phe (c.82C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBL p.Leu28Phe (c.82C>T)?

AlphaMissense predicts ambiguous (score 0.3474) — an in-silico prediction, not a clinical call.

CBL p.Leu28Phe

c.82C>T · rs2496819373 · VCV2188734

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3474 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,569,158)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.3474	ambiguous
REVEL	0.262	benign-leaning
SaProt	LLR -6.65	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 26 kb · p 0.76 · regional, not allelic
Overall
CADD	25.7	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

No allele count reported in gnomAD v4.1 (AN 1,569,158). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CBL
Protein: p.Leu28Phe
Coding: c.82C>T
MANE Select: NM_005188
dbSNP: rs2496819373
Type: single nucleotide variant
Location: chr11:119206499 (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.Leu28Pro 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-leu28phe (accessed [today's date]).

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