Is CBL p.Gln367Pro (c.1100A>C) pathogenic?

CBL p.Gln367Pro (c.1100A>C) is classified Pathogenic/Likely pathogenic in CBL (ClinVar, Multiple submitters, 14 submitters; last evaluated 2023-10-18). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with CBL-related disorder.

What condition is associated with CBL p.Gln367Pro (c.1100A>C)?

CBL p.Gln367Pro (c.1100A>C) is associated with CBL-related disorder, Noonan syndrome, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is CBL p.Gln367Pro (c.1100A>C) in the general population?

CBL p.Gln367Pro (c.1100A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBL p.Gln367Pro (c.1100A>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

CBL p.Gln367Pro

c.1100A>C · rs267606704 · VCV13807

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 8% in CBL
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -14.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	29.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CBL
Protein: p.Gln367Pro
Coding: c.1100A>C
MANE Select: NM_005188
dbSNP: rs267606704
Type: single nucleotide variant
Location: chr11:119278170 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 367: the 'required for ubiquitination of spred2' region; an α-helix; a UniProt-annotated variant site (in nsll); the 'linker' region

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

Disease context

Also linked: Noonan syndrome Noonan syndrome and Noonan-related syndrome RASopathy

Similar variants

CBL p.Gln367Arg Likely pathogenic ★★ same residue
CBL p.Gln367Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
CBL p.Gln367del Pathogenic/Likely pathogenic ★★ 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

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-gln367pro (accessed [today's date]).

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