Is CBL p.Glu746Lys (c.2236G>A) pathogenic?

CBL p.Glu746Lys (c.2236G>A) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-08). AlphaMissense: likely benign (0.1004); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Glu746Lys (c.2236G>A)?

CBL p.Glu746Lys (c.2236G>A) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is CBL p.Glu746Lys (c.2236G>A) in the general population?

CBL p.Glu746Lys (c.2236G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CBL p.Glu746Lys (c.2236G>A)?

AlphaMissense predicts likely benign (score 0.1004) — an in-silico prediction, not a clinical call.

CBL p.Glu746Lys

c.2236G>A · rs369050822 · VCV2104658

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1004 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1004	likely benign
REVEL	0.386	indeterminate
SaProt	LLR -7.05	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	22.8	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 0.00167% Admixed American · 1/59,996 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000745% 12/1,611,238 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,996
African / African-American	0.00134%	74,812
European (non-Finnish)	0.000849%	117,812

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.Glu746Lys
Coding: c.2236G>A
MANE Select: NM_005188
dbSNP: rs369050822
Type: single nucleotide variant
Location: chr11:119297466 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 746: the 'required for ubiquitination of spred2' region; the 'interaction with cd2ap' region; the 'disordered' region

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: RASopathy

Similar variants

CBL p.Glu746Asp Uncertain significance ★★ ⚠ same residue
CBL p.Glu746Ala Uncertain significance ★ ⚠ same residue
CBL p.Glu746Ter Uncertain significance ★ same residue
CBL c.1096-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBL c.1096-1G>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

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-glu746lys (accessed [today's date]).

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