Is CBL p.Arg550Gln (c.1649G>A) pathogenic?

CBL p.Arg550Gln (c.1649G>A) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-04). AlphaMissense: ambiguous (0.4171); Very rare (popmax 0.00223%, eas); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Arg550Gln (c.1649G>A)?

CBL p.Arg550Gln (c.1649G>A) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is CBL p.Arg550Gln (c.1649G>A) in the general population?

CBL p.Arg550Gln (c.1649G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CBL p.Arg550Gln (c.1649G>A)?

AlphaMissense predicts ambiguous (score 0.4171) — an in-silico prediction, not a clinical call.

CBL p.Arg550Gln

c.1649G>A · rs1949973841 · VCV1003891

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4171 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4171	ambiguous
REVEL	0.531	indeterminate
SaProt	LLR -8.81	tolerated
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	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 0.00223% East Asian · 1/44,894 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,874 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,894
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000169%	590,005

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.Arg550Gln
Coding: c.1649G>A
MANE Select: NM_005188
dbSNP: rs1949973841
Type: single nucleotide variant
Location: chr11:119285274 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 550: 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

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

Also linked: RASopathy

Similar variants

CBL p.Arg550Trp Uncertain significance ★★ ⚠ same residue
CBL p.Arg550= Likely benign ★★ same residue
CBL p.Arg550Leu Uncertain significance ★ ⚠ 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

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-arg550gln (accessed [today's date]).

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