Is CBL p.Arg343Ter (c.1027C>T) pathogenic?

CBL p.Arg343Ter (c.1027C>T) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-04-01). Very rare (popmax 0.0011%, sas); Associated with CBL-related disorder.

What condition is associated with CBL p.Arg343Ter (c.1027C>T)?

CBL p.Arg343Ter (c.1027C>T) is associated with CBL-related disorder, juvenile myelomonocytic leukemia, RASopathy (ClinVar).

How common is CBL p.Arg343Ter (c.1027C>T) in the general population?

CBL p.Arg343Ter (c.1027C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

CBL p.Arg343Ter

c.1027C>T · rs765471101 · VCV1421913

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

CBL-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 16
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -0.98, phastCons 0.96
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,068 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,422 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,068
European (non-Finnish)	0.000339%	294,882

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.Arg343Ter
Coding: c.1027C>T
MANE Select: NM_005188
dbSNP: rs765471101
Type: single nucleotide variant
Location: chr11:119277776 (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

Also linked: juvenile myelomonocytic leukemia RASopathy

Similar variants

CBL p.Arg343Gly Uncertain significance ★★ ⚠ same residue
CBL p.Arg343Gln 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-arg343ter (accessed [today's date]).

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