Is CBL p.Ser252Phe (c.755C>T) pathogenic?

CBL p.Ser252Phe (c.755C>T) is classified Uncertain significance in CBL (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-14). AlphaMissense: likely pathogenic (0.6036); Very rare (popmax 8.48e-05%, nfe); Associated with CBL-related disorder.

What condition is associated with CBL p.Ser252Phe (c.755C>T)?

CBL p.Ser252Phe (c.755C>T) is associated with CBL-related disorder (ClinVar).

How common is CBL p.Ser252Phe (c.755C>T) in the general population?

CBL p.Ser252Phe (c.755C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CBL p.Ser252Phe (c.755C>T)?

AlphaMissense predicts likely pathogenic (score 0.6036) — an in-silico prediction, not a clinical call.

CBL p.Ser252Phe

c.755C>T · rs1477764968 · VCV3054207

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6036 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.6036	likely pathogenic
REVEL	0.679	pathogenic-leaning
SaProt	LLR -14.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.24	acceptor gain · deltas
Pangolin	Δ0.48	gain · loss 0.41 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 45 kb · p 4.6e-13 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,266 alleles

Overall 6.2e-05% 1/1,612,434 alleles · very rare exomes 1/1,460,576 · genomes 0/151,858 · joint denominator

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.Ser252Phe
Coding: c.755C>T
MANE Select: NM_005188
dbSNP: rs1477764968
Type: single nucleotide variant
Location: chr11:119274839 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 252: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the 'sh2-like' region; an α-helix

Full CBL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CBL-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CBL p.Ser252Cys Uncertain significance ★★ ⚠ same residue
CBL c.1096-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBL c.1096-1G>T Pathogenic ★★ same condition
CBL c.1096-2A>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.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-ser252phe (accessed [today's date]).

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