Is CBL p.Asp772Glu (c.2316T>G) pathogenic?

CBL p.Asp772Glu (c.2316T>G) is classified Benign/Likely benign in CBL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-30). AlphaMissense: likely benign (0.0969); Ultra-rare (popmax 0.0646%, eas); Associated with CBL-related disorder.

What condition is associated with CBL p.Asp772Glu (c.2316T>G)?

CBL p.Asp772Glu (c.2316T>G) is associated with CBL-related disorder, RASopathy (ClinVar).

How common is CBL p.Asp772Glu (c.2316T>G) in the general population?

CBL p.Asp772Glu (c.2316T>G) is ultra-rare (popmax 0.0646%, eas) (gnomAD).

What do computational predictors say about CBL p.Asp772Glu (c.2316T>G)?

AlphaMissense predicts likely benign (score 0.0969) — an in-silico prediction, not a clinical call.

CBL p.Asp772Glu

c.2316T>G · rs774428573 · VCV477707

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0969 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0646%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.0969	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -6.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.3	GERP -2.1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	12.43	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 0.0646% East Asian · 29/44,894 alleles

Filtering AF 0.0461% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0399%

Overall 0.0018% 29/1,614,064 alleles · ultra-rare

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.Asp772Glu
Coding: c.2316T>G
MANE Select: NM_005188
dbSNP: rs774428573
Type: single nucleotide variant
Location: chr11:119298422 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 772: 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.Asp772Val Uncertain significance ★★ ⚠ same residue
CBL p.Asp772Asn Uncertain significance ★ ⚠ same residue
CBL p.Asp772= 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

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-asp772glu (accessed [today's date]).

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