Is CBL p.Val598= (c.1794A>G) pathogenic?

CBL p.Val598= (c.1794A>G) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-30). Very rare (popmax 0.000254%, nfe); Associated with Noonan syndrome and Noonan-related syndrome.

What condition is associated with CBL p.Val598= (c.1794A>G)?

CBL p.Val598= (c.1794A>G) is associated with Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is CBL p.Val598= (c.1794A>G) in the general population?

CBL p.Val598= (c.1794A>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

CBL p.Val598=

c.1794A>G · rs760865008 · VCV1334234

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

Noonan syndrome and Noonan-related syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -2.9, phastCons 1
Overall
CADD	6.065	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,020 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,890 alleles · very rare

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.Val598=
Coding: c.1794A>G
MANE Select: NM_005188
dbSNP: rs760865008
Type: single nucleotide variant
Location: chr11:119285419 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 598: 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

Noonan syndrome and Noonan-related syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CBL p.Val598Ile Uncertain significance ★★ ⚠ same residue
CBL p.Val598Ala Uncertain significance ★ ⚠ same residue
CBL p.Val598Glu Uncertain significance ★ ⚠ same residue
CBL p.Gln367Arg Likely pathogenic ★★ same condition
CBL p.Gln367Pro Pathogenic/Likely pathogenic ★★ same condition
CBL p.Arg563Cys Uncertain significance ★★ ⚠ same condition
CBL p.Arg718Gln Uncertain significance ★★ ⚠ same condition
CBL p.Arg829Trp Uncertain significance ★★ ⚠ 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-val598 (accessed [today's date]).

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