Is CBL p.Pro357= (c.1071C>T) pathogenic?

CBL p.Pro357= (c.1071C>T) is classified Likely benign in CBL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-11). Ultra-rare (popmax 0.0312%, eas); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Pro357= (c.1071C>T)?

CBL p.Pro357= (c.1071C>T) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is CBL p.Pro357= (c.1071C>T) in the general population?

CBL p.Pro357= (c.1071C>T) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

CBL p.Pro357=

c.1071C>T · rs397517075 · VCV45195

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.88	GERP 0.39, phastCons 0.003
Overall
CADD	7.821	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0312% East Asian · 14/44,874 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.000868% 14/1,613,416 alleles · ultra-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.Pro357=
Coding: c.1071C>T
MANE Select: NM_005188
dbSNP: rs397517075
Type: single nucleotide variant
Location: chr11:119277820 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 357: an α-helix; the 'sufficient for interaction with ephb1' region; the 'linker' 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.Pro357Ala Uncertain significance ★ ⚠ same residue
CBL p.Pro357Arg Uncertain significance ★ ⚠ same residue
CBL p.Pro357Ser 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-pro357 (accessed [today's date]).

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