Is CBL p.Arg280Gln (c.839G>A) pathogenic?

CBL p.Arg280Gln (c.839G>A) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.9931); Ultra-rare (popmax 0.0111%, eas); Associated with CBL-related disorder.

What condition is associated with CBL p.Arg280Gln (c.839G>A)?

CBL p.Arg280Gln (c.839G>A) is associated with CBL-related disorder, RASopathy (ClinVar).

How common is CBL p.Arg280Gln (c.839G>A) in the general population?

CBL p.Arg280Gln (c.839G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about CBL p.Arg280Gln (c.839G>A)?

AlphaMissense predicts likely pathogenic (score 0.9931) — an in-silico prediction, not a clinical call.

CBL p.Arg280Gln

c.839G>A · rs145155035 · VCV279922

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9931 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.9931	likely pathogenic
REVEL	0.826	moderately pathogenic-leaning
SaProt	LLR -14.18	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 0.60	unconstrained · MANE · 45 kb · p 4.6e-13 · regional, not allelic
Overall
CADD	33.0	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 0.0111% East Asian · 5/44,886 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00112% 18/1,613,874 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,977
African / African-American	0.00401%	24,963
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
Finnishnot grpmax-eligible	0.00156%	63,992
South Asian	0.0011%	91,064
European (non-Finnish)	0.000593%	168,566

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.Arg280Gln
Coding: c.839G>A
MANE Select: NM_005188
dbSNP: rs145155035
Type: single nucleotide variant
Location: chr11:119274923 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 280: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the 'sh2-like' region; an α-helix

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

Disease context

Also linked: RASopathy

Similar variants

CBL p.Arg280Gly Uncertain significance ★ ⚠ same residue
CBL p.Arg280Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
CBL p.Arg280= 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
CBL c.1228-2A>G Pathogenic/Likely pathogenic ★★ same condition
CBL p.Arg420Gln 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-arg280gln (accessed [today's date]).

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