Is CBL p.Arg593Trp (c.1777C>T) pathogenic?

CBL p.Arg593Trp (c.1777C>T) is classified Benign/Likely benign in CBL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-14). AlphaMissense: ambiguous (0.429); Ultra-rare (popmax 0.0624%, eas); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Arg593Trp (c.1777C>T)?

CBL p.Arg593Trp (c.1777C>T) is associated with Cardiovascular phenotype, CBL-related disorder, RASopathy (ClinVar).

How common is CBL p.Arg593Trp (c.1777C>T) in the general population?

CBL p.Arg593Trp (c.1777C>T) is ultra-rare (popmax 0.0624%, eas) (gnomAD).

What do computational predictors say about CBL p.Arg593Trp (c.1777C>T)?

AlphaMissense predicts ambiguous (score 0.429) — an in-silico prediction, not a clinical call.

CBL p.Arg593Trp

c.1777C>T · rs776999573 · VCV1653003

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.429 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0624%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.429	ambiguous
REVEL	0.506	indeterminate
SaProt	LLR -10.06	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	28.5	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 0.0624% East Asian · 28/44,878 alleles

Filtering AF 0.0443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0382%

Overall 0.00229% 37/1,614,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0624%	1,603
Finnishnot grpmax-eligible	0.00156%	64,040
African / African-American	0.00133%	75,040
European (non-Finnish)	0.000593%	168,577

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.Arg593Trp
Coding: c.1777C>T
MANE Select: NM_005188
dbSNP: rs776999573
Type: single nucleotide variant
Location: chr11:119285402 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 593: 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: CBL-related disorder RASopathy

Similar variants

CBL p.Arg593Gln Uncertain significance ★★ ⚠ same residue
CBL p.Arg593Pro 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
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-arg593trp (accessed [today's date]).

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