Is CBL p.Arg96Cys (c.286C>T) pathogenic?

CBL p.Arg96Cys (c.286C>T) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-23). AlphaMissense: likely pathogenic (0.9035); Very rare (popmax 0.0022%, sas); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Arg96Cys (c.286C>T)?

CBL p.Arg96Cys (c.286C>T) is associated with Cardiovascular phenotype, juvenile myelomonocytic leukemia, CBL-related disorder (ClinVar).

How common is CBL p.Arg96Cys (c.286C>T) in the general population?

CBL p.Arg96Cys (c.286C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CBL p.Arg96Cys (c.286C>T)?

AlphaMissense predicts likely pathogenic (score 0.9035) — an in-silico prediction, not a clinical call.

CBL p.Arg96Cys

c.286C>T · rs147438359 · VCV1018257

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9035 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9035	likely pathogenic
REVEL	0.798	moderately pathogenic-leaning
SaProt	LLR -12.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 45 kb · p 4.6e-13 · regional, not allelic
Overall
CADD	33.0	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 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00112% 18/1,613,918 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,543
Admixed American	0.00167%	59,984
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00133%	74,910
European (non-Finnish)	0.0011%	90,765

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.Arg96Cys
Coding: c.286C>T
MANE Select: NM_005188
dbSNP: rs147438359
Type: single nucleotide variant
Location: chr11:119232538 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 96: 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.Arg96His 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
CBL p.Gln367Arg 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-arg96cys (accessed [today's date]).

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