Is CBL p.Tyr371Asp (c.1111T>G) pathogenic?

CBL p.Tyr371Asp (c.1111T>G) is classified Pathogenic/Likely pathogenic in CBL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-30). AlphaMissense: likely pathogenic (0.9998); Very rare (popmax 8.55e-05%, nfe); Associated with CBL-related disorder.

What condition is associated with CBL p.Tyr371Asp (c.1111T>G)?

CBL p.Tyr371Asp (c.1111T>G) is associated with CBL-related disorder, RASopathy (ClinVar).

How common is CBL p.Tyr371Asp (c.1111T>G) in the general population?

CBL p.Tyr371Asp (c.1111T>G) is very rare (popmax 8.55e-05%, nfe) (gnomAD).

What do computational predictors say about CBL p.Tyr371Asp (c.1111T>G)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

CBL p.Tyr371Asp

c.1111T>G · rs267606706 · VCV2137268

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.55e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 8% in CBL
REVEL	0.973	strongly pathogenic-leaning
SaProt	LLR -16.59	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 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	32.0	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 8.55e-05% European (non-Finnish) · 1/1,169,258 alleles

Overall 6.9e-05% 1/1,450,022 alleles · very 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.Tyr371Asp
Coding: c.1111T>G
MANE Select: NM_005188
dbSNP: rs267606706
Type: single nucleotide variant
Location: chr11:119278181 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 371: the 'required for ubiquitination of spred2' region; an α-helix; a modified residue (phosphotyrosine; by insr); a UniProt-annotated variant site (found in patients with acute myeloid leukemia; uncertain significance; loss of the ability to negatively regulate signaling pathways; promotes cell cycle progression; decreases apoptosis); the 'linker' region

Full CBL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: RASopathy

Similar variants

CBL p.Tyr371Asn Pathogenic/Likely pathogenic ★★ same residue
CBL p.Tyr371Cys Pathogenic ★★ same residue
CBL p.Tyr371His Pathogenic/Likely pathogenic ★★ same residue
CBL p.Tyr371Ser Pathogenic/Likely pathogenic ★★ same residue
CBL p.Tyr371Phe Likely pathogenic ★ same residue
CBL p.Tyr371del Likely pathogenic ★ same residue
CBL p.Tyr371= Likely benign ★ same residue
CBL c.1096-1G>C 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-tyr371asp (accessed [today's date]).

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