Is CBL p.Met400Arg (c.1199T>G) pathogenic?

CBL p.Met400Arg (c.1199T>G) is classified Pathogenic in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2012-06-19). AlphaMissense: likely pathogenic (0.9998); Very rare (popmax 8.48e-05%, nfe).

How common is CBL p.Met400Arg (c.1199T>G) in the general population?

CBL p.Met400Arg (c.1199T>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CBL p.Met400Arg (c.1199T>G)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

CBL p.Met400Arg

c.1199T>G · rs397507491 · VCV40405

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 8% in CBL
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -14.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	32.0	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 8.48e-05% European (non-Finnish) · 1/1,179,898 alleles

Overall 6.84e-05% 1/1,461,746 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.Met400Arg
Coding: c.1199T>G
MANE Select: NM_005188
dbSNP: rs397507491
Type: single nucleotide variant
Location: chr11:119278269 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 400: the 'required for ubiquitination of spred2' region; a β-strand

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

Similar variants

CBL p.Met400Leu Uncertain significance ★★ ⚠ same residue
CBL p.Met400Thr Uncertain significance ★★ ⚠ same residue
CBL p.Met400Val Uncertain significance ★ ⚠ same residue
CBL c.1096-1G>C Pathogenic/Likely pathogenic ★★ same type
CBL c.1096-1G>T Pathogenic ★★ same type
CBL c.1096-2A>T Pathogenic ★★ same type
CBL c.1228-2A>G Pathogenic/Likely pathogenic ★★ same type
CBL p.Arg420Gln Pathogenic/Likely pathogenic ★★ same type

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-met400arg (accessed [today's date]).

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