Is CBL p.Arg68Trp (c.202C>T) pathogenic?

CBL p.Arg68Trp (c.202C>T) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-22). AlphaMissense: likely pathogenic (0.9923); Very rare (popmax 0.00223%, eas); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Arg68Trp (c.202C>T)?

CBL p.Arg68Trp (c.202C>T) is associated with Cardiovascular phenotype, juvenile myelomonocytic leukemia, CBL-related disorder (ClinVar).

How common is CBL p.Arg68Trp (c.202C>T) in the general population?

CBL p.Arg68Trp (c.202C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CBL p.Arg68Trp (c.202C>T)?

AlphaMissense predicts likely pathogenic (score 0.9923) — an in-silico prediction, not a clinical call.

CBL p.Arg68Trp

c.202C>T · rs730880429 · VCV180811

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9923	likely pathogenic
REVEL	0.53	indeterminate
SaProt	LLR -14.43	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 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 26 kb · p 0.76 · regional, not allelic
Overall
CADD	32.0	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 0.00223% East Asian · 1/44,882 alleles

Overall 0.000205% 3/1,461,206 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
South Asian	0.0011%	91,072
European (non-Finnish)	8.47e-05%	1,179,962

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.Arg68Trp
Coding: c.202C>T
MANE Select: NM_005188
dbSNP: rs730880429
Type: single nucleotide variant
Location: chr11:119232454 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 68: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the '4h' region; an α-helix

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: juvenile myelomonocytic leukemia CBL-related disorder RASopathy

Similar variants

CBL p.Arg68Gln Uncertain significance ★★ ⚠ same residue
CBL p.Arg68Pro Uncertain significance ★ ⚠ same residue
CBL p.Arg68= Likely benign ★ 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-arg68trp (accessed [today's date]).

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