Is CBL p.Met487Thr (c.1460T>C) pathogenic?

CBL p.Met487Thr (c.1460T>C) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-09). AlphaMissense: likely benign (0.0876); Very rare (popmax 0.00167%, amr); Associated with RASopathy.

What condition is associated with CBL p.Met487Thr (c.1460T>C)?

CBL p.Met487Thr (c.1460T>C) is associated with RASopathy (ClinVar).

How common is CBL p.Met487Thr (c.1460T>C) in the general population?

CBL p.Met487Thr (c.1460T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CBL p.Met487Thr (c.1460T>C)?

AlphaMissense predicts likely benign (score 0.0876) — an in-silico prediction, not a clinical call.

CBL p.Met487Thr

c.1460T>C · rs995860476 · VCV570675

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.0876	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -5.10	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 0.92	GERP 0.81, phastCons 0.78
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	14.71	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,996 alleles

Overall 0.000124% 2/1,614,064 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,996
African / African-American	0.00133%	74,928

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.Met487Thr
Coding: c.1460T>C
MANE Select: NM_005188
dbSNP: rs995860476
Type: single nucleotide variant
Location: chr11:119284997 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 487: 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

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

Similar variants

CBL p.Met487Val Benign/Likely benign ★★ 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
CBL p.Gln367Arg Likely pathogenic ★★ same condition
CBL p.Gln367Pro Pathogenic/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-met487thr (accessed [today's date]).

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