Is CBL p.Asp31Glu (c.93C>A) pathogenic?

CBL p.Asp31Glu (c.93C>A) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-28). AlphaMissense: likely pathogenic (0.8722); Very rare (popmax 0.00364%, nfe); Associated with juvenile myelomonocytic leukemia.

What condition is associated with CBL p.Asp31Glu (c.93C>A)?

CBL p.Asp31Glu (c.93C>A) is associated with juvenile myelomonocytic leukemia, CBL-related disorder, RASopathy (ClinVar).

How common is CBL p.Asp31Glu (c.93C>A) in the general population?

CBL p.Asp31Glu (c.93C>A) is very rare (popmax 0.00364%, nfe) (gnomAD).

How is Juvenile myelomonocytic leukemia inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CBL p.Asp31Glu (c.93C>A)?

AlphaMissense predicts likely pathogenic (score 0.8722) — an in-silico prediction, not a clinical call.

CBL p.Asp31Glu

c.93C>A · rs376679438 · VCV488171

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

juvenile myelomonocytic leukemia

Computational evidence

Protein change
AlphaMissense	0.8722	likely pathogenic
REVEL	0.232	benign-leaning
SaProt	LLR -5.86	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 0.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 26 kb · p 0.76 · regional, not allelic
Overall
CADD	23.8	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 0.00364% European (non-Finnish) · 42/1,154,790 alleles

Filtering AF 0.00272% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00269% 42/1,562,144 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.Asp31Glu
Coding: c.93C>A
MANE Select: NM_005188
dbSNP: rs376679438
Type: single nucleotide variant
Location: chr11:119206510 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 31: the 'sufficient for interaction with ephb1' region

Full CBL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

juvenile myelomonocytic leukemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: CBL-related disorder RASopathy

For Juvenile myelomonocytic leukemia (Orphanet):

Inheritance: Not applicable
Onset: Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

CBL p.Asp31= 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
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-asp31glu (accessed [today's date]).

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