Is CBL p.Arg787Cys (c.2359C>T) pathogenic?

CBL p.Arg787Cys (c.2359C>T) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-21). AlphaMissense: ambiguous (0.3935); Rare (popmax 0.197%, mid); Associated with RASopathy.

What condition is associated with CBL p.Arg787Cys (c.2359C>T)?

CBL p.Arg787Cys (c.2359C>T) is associated with RASopathy, CBL-related disorder, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is CBL p.Arg787Cys (c.2359C>T) in the general population?

CBL p.Arg787Cys (c.2359C>T) is rare (popmax 0.197%, mid) (gnomAD).

What do computational predictors say about CBL p.Arg787Cys (c.2359C>T)?

AlphaMissense predicts ambiguous (score 0.3935) — an in-silico prediction, not a clinical call.

CBL p.Arg787Cys

c.2359C>T · rs143132980 · VCV178012

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3935 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.197%, mid)

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.3935	ambiguous
REVEL	0.605	indeterminate
SaProt	LLR -9.03	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, 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 0.197% Middle Eastern · 12/6,084 alleles

Filtering AF 0.114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0892%

Overall 0.00768% 124/1,614,022 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.197%	507
Admixed American	0.0783%	1,277
African / African-American	0.0187%	5,352
Remaining individualsnot grpmax-eligible	0.0048%	20,828
European (non-Finnish)	0.00381%	26,222
South Asian	0.0022%	45,542
Finnishnot grpmax-eligible	0.00156%	64,032

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.Arg787Cys
Coding: c.2359C>T
MANE Select: NM_005188
dbSNP: rs143132980
Type: single nucleotide variant
Location: chr11:119298465 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 787: the 'required for ubiquitination of spred2' region; the 'interaction with cd2ap' 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 Noonan syndrome and Noonan-related syndrome

Similar variants

CBL p.Arg787His Conflicting classifications of pathogenicity ★ ⚠ same residue
CBL p.Arg787Leu 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-arg787cys (accessed [today's date]).

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