Is CBL p.Ala522= (c.1566T>C) pathogenic?

CBL p.Ala522= (c.1566T>C) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-24). Ultra-rare (popmax 0.04%, afr); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Ala522= (c.1566T>C)?

CBL p.Ala522= (c.1566T>C) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is CBL p.Ala522= (c.1566T>C) in the general population?

CBL p.Ala522= (c.1566T>C) is ultra-rare (popmax 0.04%, afr) (gnomAD).

CBL p.Ala522=

c.1566T>C · rs371065029 · VCV544007

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.52 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.19	GERP -4.2, phastCons 0.07
Overall
CADD	9.881	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% African / African-American · 30/74,926 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00217% 35/1,614,078 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.04%	2,498
Remaining individualsnot grpmax-eligible	0.0064%	15,623
Admixed American	0.00167%	60,004

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.Ala522=
Coding: c.1566T>C
MANE Select: NM_005188
dbSNP: rs371065029
Type: single nucleotide variant
Location: chr11:119285191 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 522: the 'required for ubiquitination of spred2' 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.Ala522Val Uncertain significance ★★ ⚠ same residue
CBL p.Ala522Gly 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
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-ala522 (accessed [today's date]).

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