Is CBL p.Pro453Ser (c.1357C>T) pathogenic?

CBL p.Pro453Ser (c.1357C>T) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-16). AlphaMissense: likely benign (0.2028); Ultra-rare (popmax 0.0167%, amr); Associated with RASopathy.

What condition is associated with CBL p.Pro453Ser (c.1357C>T)?

CBL p.Pro453Ser (c.1357C>T) is associated with RASopathy (ClinVar).

How common is CBL p.Pro453Ser (c.1357C>T) in the general population?

CBL p.Pro453Ser (c.1357C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about CBL p.Pro453Ser (c.1357C>T)?

AlphaMissense predicts likely benign (score 0.2028) — an in-silico prediction, not a clinical call.

CBL p.Pro453Ser

c.1357C>T · rs748055961 · VCV1516357

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2028 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.2028	likely benign
REVEL	0.314	indeterminate
SaProt	LLR -5.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	24.1	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 0.0167% Admixed American · 10/59,982 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000821% 12/1,461,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,998
South Asian	0.0011%	91,064
European (non-Finnish)	8.47e-05%	1,179,952

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.Pro453Ser
Coding: c.1357C>T
MANE Select: NM_005188
dbSNP: rs748055961
Type: single nucleotide variant
Location: chr11:119278639 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 453: 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

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CBL p.Pro453Leu Uncertain significance ★★ ⚠ same residue
CBL p.Pro453= Benign/Likely benign ★★ 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-pro453ser (accessed [today's date]).

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