Is CBL p.Arg550Trp (c.1648C>T) pathogenic?

CBL p.Arg550Trp (c.1648C>T) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-03). AlphaMissense: likely pathogenic (0.7171); Very rare (popmax 0.005%, amr); Associated with RASopathy.

What condition is associated with CBL p.Arg550Trp (c.1648C>T)?

CBL p.Arg550Trp (c.1648C>T) is associated with RASopathy, CBL-related disorder (ClinVar).

How common is CBL p.Arg550Trp (c.1648C>T) in the general population?

CBL p.Arg550Trp (c.1648C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CBL p.Arg550Trp (c.1648C>T)?

AlphaMissense predicts likely pathogenic (score 0.7171) — an in-silico prediction, not a clinical call.

CBL p.Arg550Trp

c.1648C>T · rs202065722 · VCV918146

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7171 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.7171	likely pathogenic
REVEL	0.513	indeterminate
SaProt	LLR -10.39	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.22, phastCons 0.99
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.005% Admixed American · 3/60,002 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00316% 51/1,614,034 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,623
Admixed Americangrpmax	0.005%	20,001
European (non-Finnish)	0.00356%	28,096
East Asian	0.00223%	44,896
South Asian	0.0011%	91,082

Remaining individuals 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.Arg550Trp
Coding: c.1648C>T
MANE Select: NM_005188
dbSNP: rs202065722
Type: single nucleotide variant
Location: chr11:119285273 (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

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

Also linked: CBL-related disorder

Similar variants

CBL p.Arg550Gln 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.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-arg550trp (accessed [today's date]).

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