Is CBL p.Leu75Val (c.223C>G) pathogenic?

CBL p.Leu75Val (c.223C>G) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-13). AlphaMissense: ambiguous (0.3524); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with CBL p.Leu75Val (c.223C>G)?

CBL p.Leu75Val (c.223C>G) is associated with RASopathy (ClinVar).

How common is CBL p.Leu75Val (c.223C>G) in the general population?

CBL p.Leu75Val (c.223C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBL p.Leu75Val (c.223C>G)?

AlphaMissense predicts ambiguous (score 0.3524) — an in-silico prediction, not a clinical call.

CBL p.Leu75Val

c.223C>G · rs2135266146 · VCV1999784

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3524 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.3524	ambiguous
REVEL	0.451	indeterminate
SaProt	LLR -10.12	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 26 kb · p 0.76 · regional, not allelic
Overall
CADD	20.7	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.Leu75Val
Coding: c.223C>G
MANE Select: NM_005188
dbSNP: rs2135266146
Type: single nucleotide variant
Location: chr11:119232475 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 75: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the '4h' region; an α-helix

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 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
CBL p.Tyr371Asn 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-leu75val (accessed [today's date]).

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