Is CBL p.Arg343Gln (c.1028G>A) pathogenic?

CBL p.Arg343Gln (c.1028G>A) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-03). AlphaMissense: ambiguous (0.5573); Very rare (popmax 0.00267%, afr); Associated with juvenile myelomonocytic leukemia.

What condition is associated with CBL p.Arg343Gln (c.1028G>A)?

CBL p.Arg343Gln (c.1028G>A) is associated with juvenile myelomonocytic leukemia, CBL-related disorder, RASopathy (ClinVar).

How common is CBL p.Arg343Gln (c.1028G>A) in the general population?

CBL p.Arg343Gln (c.1028G>A) is very rare (popmax 0.00267%, afr) (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.Arg343Gln (c.1028G>A)?

AlphaMissense predicts ambiguous (score 0.5573) — an in-silico prediction, not a clinical call.

CBL p.Arg343Gln

c.1028G>A · rs759585425 · VCV1396535

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5573 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

juvenile myelomonocytic leukemia

Computational evidence

Protein change
AlphaMissense	0.5573	ambiguous
REVEL	0.657	pathogenic-leaning
SaProt	LLR -11.28	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.9, 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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,898 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00031% 5/1,613,486 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,449
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.00017%	589,797

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.Arg343Gln
Coding: c.1028G>A
MANE Select: NM_005188
dbSNP: rs759585425
Type: single nucleotide variant
Location: chr11:119277777 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 343: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the 'sh2-like' 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.Arg343Gly Uncertain significance ★★ ⚠ same residue
CBL p.Arg343Ter Conflicting classifications of pathogenicity ★ same residue
CBL p.Arg343Pro Uncertain significance ★ same residue
CBL p.Arg343= 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

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-arg343gln (accessed [today's date]).

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