Is CBL p.Gln367Arg (c.1100A>G) pathogenic?

CBL p.Gln367Arg (c.1100A>G) is classified Likely pathogenic in CBL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-13). AlphaMissense: likely pathogenic (0.9986); Very rare (popmax 8.59e-05%, nfe); Associated with RASopathy.

What condition is associated with CBL p.Gln367Arg (c.1100A>G)?

CBL p.Gln367Arg (c.1100A>G) is associated with RASopathy, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is CBL p.Gln367Arg (c.1100A>G) in the general population?

CBL p.Gln367Arg (c.1100A>G) is very rare (popmax 8.59e-05%, nfe) (gnomAD).

What do computational predictors say about CBL p.Gln367Arg (c.1100A>G)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

CBL p.Gln367Arg

c.1100A>G · rs267606704 · VCV1053208

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.59e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic ✓ concordant with ClinVar
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -12.46	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	27.6	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 8.59e-05% European (non-Finnish) · 1/1,164,286 alleles

Overall 0.000125% 2/1,596,622 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,502
European (non-Finnish)grpmax	8.59e-05%	1,164,287

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gln367Arg
Coding: c.1100A>G
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

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

Also linked: Noonan syndrome and Noonan-related syndrome

Similar variants

CBL p.Gln367Pro Pathogenic/Likely pathogenic ★★ same residue
CBL p.Gln367Lys Conflicting classifications of pathogenicity ★ ⚠ 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.Gln367del Pathogenic/Likely pathogenic ★★ same residue

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-gln367arg (accessed [today's date]).

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