Is CBL p.Pro742Ser (c.2224C>T) pathogenic?

CBL p.Pro742Ser (c.2224C>T) is classified Uncertain significance in CBL (ClinVar, Single submitter, 2 submitters; last evaluated 2025-04-18). AlphaMissense: likely benign (0.0664); No allele count reported in gnomAD v4.1 (AN 1,612,964); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Pro742Ser (c.2224C>T)?

CBL p.Pro742Ser (c.2224C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is CBL p.Pro742Ser (c.2224C>T) in the general population?

CBL p.Pro742Ser (c.2224C>T) is no allele count reported in gnomAD v4.1 (AN 1,612,964) (gnomAD).

What do computational predictors say about CBL p.Pro742Ser (c.2224C>T)?

AlphaMissense predicts likely benign (score 0.0664) — an in-silico prediction, not a clinical call.

CBL p.Pro742Ser

c.2224C>T · rs587778157 · VCV133810

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0664 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,612,964)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0664	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -4.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.1	GERP -3.3, phastCons 0.001
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	7.347	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

No allele count reported in gnomAD v4.1 (AN 1,612,964). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CBL
Protein: p.Pro742Ser
Coding: c.2224C>T
MANE Select: NM_005188
dbSNP: rs587778157
Type: single nucleotide variant
Location: chr11:119297454 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 742: the 'required for ubiquitination of spred2' region; the 'interaction with cd2ap' 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

Similar variants

CBL p.Pro742= Likely benign ★ same residue
CBL p.Ala187Ser Uncertain significance ★★ ⚠ same condition
CBL p.Ala187Val Uncertain significance ★★ ⚠ same condition
CBL p.Ala208Thr Uncertain significance ★★ ⚠ same condition
CBL p.Ala385Gly Uncertain significance ★★ ⚠ same condition
CBL p.Ala450Val Uncertain significance ★★ ⚠ same condition
CBL p.Ala513Thr Uncertain significance ★★ ⚠ same condition
CBL p.Ala556Gly Uncertain significance ★★ ⚠ 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-pro742ser (accessed [today's date]).

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