Is CBL p.Gln691= (c.2073A>G) pathogenic?

CBL p.Gln691= (c.2073A>G) is classified Likely benign in CBL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-01). Very rare (popmax 0.00892%, eas); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Gln691= (c.2073A>G)?

CBL p.Gln691= (c.2073A>G) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is CBL p.Gln691= (c.2073A>G) in the general population?

CBL p.Gln691= (c.2073A>G) is very rare (popmax 0.00892%, eas) (gnomAD).

CBL p.Gln691=

c.2073A>G · rs140298671 · VCV705117

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -0.4, phastCons 1
Overall
CADD	7.858	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00892% East Asian · 4/44,856 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00106% 17/1,611,200 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,214
African / African-American	0.00267%	37,417
Admixed American	0.00167%	59,996
South Asian	0.0011%	91,030
European (non-Finnish)	0.000764%	130,836

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.Gln691=
Coding: c.2073A>G
MANE Select: NM_005188
dbSNP: rs140298671
Type: single nucleotide variant
Location: chr11:119296954 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 691: the 'required for ubiquitination of spred2' region; the 'interaction with cd2ap' region; the 'disordered' 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

Also linked: RASopathy

Similar variants

CBL p.Gln691Pro Uncertain significance ★ ⚠ 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-gln691 (accessed [today's date]).

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