Is CBL p.Ala905Asp (c.2714C>A) pathogenic?

CBL p.Ala905Asp (c.2714C>A) is classified Uncertain significance in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-06). AlphaMissense: likely pathogenic (0.5754); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with CBL p.Ala905Asp (c.2714C>A)?

CBL p.Ala905Asp (c.2714C>A) is associated with RASopathy (ClinVar).

How common is CBL p.Ala905Asp (c.2714C>A) in the general population?

CBL p.Ala905Asp (c.2714C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBL p.Ala905Asp (c.2714C>A)?

AlphaMissense predicts likely pathogenic (score 0.5754) — an in-silico prediction, not a clinical call.

CBL p.Ala905Asp

c.2714C>A · rs1248988094 · VCV1930478

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5754 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.5754	likely pathogenic
REVEL	0.367	indeterminate
SaProt	LLR -6.34	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.88 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 99 bp · p 0.0026 · regional, not allelic
Overall
CADD	24.8	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.Ala905Asp
Coding: c.2714C>A
MANE Select: NM_005188
dbSNP: rs1248988094
Type: single nucleotide variant
Location: chr11:119299774 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 905: 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

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

Similar variants

CBL p.Ala905= Likely benign ★ 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-ala905asp (accessed [today's date]).

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