Is CBL p.Tyr371Phe (c.1112A>T) pathogenic?

CBL p.Tyr371Phe (c.1112A>T) is classified Likely pathogenic in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-29). AlphaMissense: likely pathogenic (0.9486); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with CBL p.Tyr371Phe (c.1112A>T)?

CBL p.Tyr371Phe (c.1112A>T) is associated with RASopathy (ClinVar).

How common is CBL p.Tyr371Phe (c.1112A>T) in the general population?

CBL p.Tyr371Phe (c.1112A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBL p.Tyr371Phe (c.1112A>T)?

AlphaMissense predicts likely pathogenic (score 0.9486) — an in-silico prediction, not a clinical call.

CBL p.Tyr371Phe

c.1112A>T · rs387906666 · VCV949693

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9486 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.9486	likely pathogenic ✓ concordant with ClinVar
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -10.49	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 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	28.0	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

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.Tyr371Phe
Coding: c.1112A>T
MANE Select: NM_005188
dbSNP: rs387906666
Type: single nucleotide variant
Location: chr11:119278182 (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

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

Similar variants

CBL p.Tyr371Asn Pathogenic/Likely pathogenic ★★ same residue
CBL p.Tyr371Asp 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.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-tyr371phe (accessed [today's date]).

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