Is CBL p.Arg420Gln (c.1259G>A) pathogenic?

CBL p.Arg420Gln (c.1259G>A) is classified Pathogenic/Likely pathogenic in CBL (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-04-29). AlphaMissense: likely pathogenic (0.9982); Very rare (popmax 0.00267%, afr); Associated with CBL-related disorder.

What condition is associated with CBL p.Arg420Gln (c.1259G>A)?

CBL p.Arg420Gln (c.1259G>A) is associated with CBL-related disorder, rhabdomyosarcoma, juvenile myelomonocytic leukemia (ClinVar).

How common is CBL p.Arg420Gln (c.1259G>A) in the general population?

CBL p.Arg420Gln (c.1259G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CBL p.Arg420Gln (c.1259G>A)?

AlphaMissense predicts likely pathogenic (score 0.9982) — an in-silico prediction, not a clinical call.

CBL p.Arg420Gln

c.1259G>A · rs267606708 · VCV13810

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

AlphaMissense

likely pathogenic

0.9982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.9982	likely pathogenic ✓ concordant with ClinVar
REVEL	0.858	moderately pathogenic-leaning
SaProt	LLR -11.90	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	34.0	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 0.00267% African / African-American · 2/75,006 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00161% 26/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,007
African / African-Americangrpmax	0.00267%	37,503
South Asian	0.0022%	45,536
Admixed American	0.00167%	60,024
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.00153%	65,554

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg420Gln
Coding: c.1259G>A
MANE Select: NM_005188
dbSNP: rs267606708
Type: single nucleotide variant
Location: chr11:119278541 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 420: the 'required for ubiquitination of spred2' region; a UniProt-annotated variant site (in nsll; dominant-negative; impairs cbl-mediated ubiquitination, internalization and degradation of the egf receptor/egfr; decreases the ability to negatively regulate egfr signaling)

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

Disease context

Also linked: rhabdomyosarcoma juvenile myelomonocytic leukemia RASopathy

Similar variants

CBL p.Arg420Leu Likely pathogenic ★★ same residue
CBL p.Arg420= Likely benign ★★ same residue
CBL p.Arg420Gly Uncertain significance ★ ⚠ same residue
CBL p.Arg420Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
CBL p.Arg420Ter Likely benign ★ 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

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-arg420gln (accessed [today's date]).

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