Is CBL p.Ser452Phe (c.1355C>T) pathogenic?

CBL p.Ser452Phe (c.1355C>T) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-02). AlphaMissense: ambiguous (0.3564); Very rare (popmax 0.00133%, afr); Associated with RASopathy.

What condition is associated with CBL p.Ser452Phe (c.1355C>T)?

CBL p.Ser452Phe (c.1355C>T) is associated with RASopathy (ClinVar).

How common is CBL p.Ser452Phe (c.1355C>T) in the general population?

CBL p.Ser452Phe (c.1355C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CBL p.Ser452Phe (c.1355C>T)?

AlphaMissense predicts ambiguous (score 0.3564) — an in-silico prediction, not a clinical call.

CBL p.Ser452Phe

c.1355C>T · VCV4219885

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3564 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.3564	ambiguous
REVEL	0.374	indeterminate
SaProt	LLR -7.52	tolerated
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	28.5	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 0.00133% African / African-American · 1/74,990 alleles

Overall 6.84e-05% 1/1,461,818 alleles · very 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.Ser452Phe
Coding: c.1355C>T
MANE Select: NM_005188
Type: single nucleotide variant
Location: chr11:119278637 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 452: the 'required for ubiquitination of spred2' region; the 'disordered' region; a modified residue (phosphoserine)

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.Ser452= 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
CBL p.Gln367Pro 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-ser452phe (accessed [today's date]).

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