Is CBL p.Ala488Val (c.1463C>T) pathogenic?

CBL p.Ala488Val (c.1463C>T) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0909); Very rare (popmax 0.00246%, nfe); Associated with Noonan syndrome and Noonan-related syndrome.

What condition is associated with CBL p.Ala488Val (c.1463C>T)?

CBL p.Ala488Val (c.1463C>T) is associated with Noonan syndrome and Noonan-related syndrome, juvenile myelomonocytic leukemia, CBL-related disorder (ClinVar).

How common is CBL p.Ala488Val (c.1463C>T) in the general population?

CBL p.Ala488Val (c.1463C>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about CBL p.Ala488Val (c.1463C>T)?

AlphaMissense predicts likely benign (score 0.0909) — an in-silico prediction, not a clinical call.

CBL p.Ala488Val

c.1463C>T · rs377502790 · VCV120247

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Noonan syndrome and Noonan-related syndrome

Computational evidence

Protein change
AlphaMissense	0.0909	likely benign
REVEL	0.322	indeterminate
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	23.3	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 0.00246% European (non-Finnish) · 29/1,180,002 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00192% 31/1,614,020 alleles · very rare exomes 28/1,461,868 · genomes 3/152,152 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00246%	40,690
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00134%	74,906

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.Ala488Val
Coding: c.1463C>T
MANE Select: NM_005188
dbSNP: rs377502790
Type: single nucleotide variant
Location: chr11:119285000 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 488: the 'required for ubiquitination of spred2' region; the 'disordered' region

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.Ala488= Likely benign ★★ same residue
CBL p.Ala488Asp 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-ala488val (accessed [today's date]).

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