Is CBL p.Arg829Gln (c.2486G>A) pathogenic?

CBL p.Arg829Gln (c.2486G>A) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.9207); Very rare (popmax 0.00401%, afr); Associated with CBL-related disorder.

What condition is associated with CBL p.Arg829Gln (c.2486G>A)?

CBL p.Arg829Gln (c.2486G>A) is associated with CBL-related disorder, RASopathy (ClinVar).

How common is CBL p.Arg829Gln (c.2486G>A) in the general population?

CBL p.Arg829Gln (c.2486G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CBL p.Arg829Gln (c.2486G>A)?

AlphaMissense predicts likely pathogenic (score 0.9207) — an in-silico prediction, not a clinical call.

CBL p.Arg829Gln

c.2486G>A · rs374672276 · VCV45205

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9207 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.9207	likely pathogenic
REVEL	0.441	indeterminate
SaProt	LLR -9.97	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	29.6	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 0.00401% African / African-American · 3/74,900 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00304% 49/1,614,000 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,827
African / African-Americangrpmax	0.00401%	24,967
European (non-Finnish)	0.00339%	29,500
East Asian	0.00223%	44,900
Admixed American	0.00167%	60,002
Finnishnot grpmax-eligible	0.00156%	64,010

Remaining individuals 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.Arg829Gln
Coding: c.2486G>A
MANE Select: NM_005188
dbSNP: rs374672276
Type: single nucleotide variant
Location: chr11:119299546 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 829: 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

Also linked: RASopathy

Similar variants

CBL p.Arg829Trp Uncertain significance ★★ ⚠ same residue
CBL p.Arg829= Likely benign ★ 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

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-arg829gln (accessed [today's date]).

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