Is CBL p.Ile157Val (c.469A>G) pathogenic?

CBL p.Ile157Val (c.469A>G) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-24). AlphaMissense: ambiguous (0.5451); Very rare (popmax 0.000508%, nfe); Associated with CBL-related disorder.

What condition is associated with CBL p.Ile157Val (c.469A>G)?

CBL p.Ile157Val (c.469A>G) is associated with CBL-related disorder, RASopathy (ClinVar).

How common is CBL p.Ile157Val (c.469A>G) in the general population?

CBL p.Ile157Val (c.469A>G) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about CBL p.Ile157Val (c.469A>G)?

AlphaMissense predicts ambiguous (score 0.5451) — an in-silico prediction, not a clinical call.

CBL p.Ile157Val

c.469A>G · rs730880430 · VCV180812

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5451 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.5451	ambiguous
REVEL	0.281	benign-leaning
SaProt	LLR -6.08	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.49 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 45 kb · p 4.6e-13 · regional, not allelic
Overall
CADD	23.5	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 0.000508% European (non-Finnish) · 6/1,179,944 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,966 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.Ile157Val
Coding: c.469A>G
MANE Select: NM_005188
dbSNP: rs730880430
Type: single nucleotide variant
Location: chr11:119271760 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 157: 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

Also linked: RASopathy

Similar variants

CBL p.Ile157Met Uncertain significance ★★ ⚠ same residue
CBL p.Ile157= Uncertain significance ★ 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
CBL p.Arg420Leu 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-ile157val (accessed [today's date]).

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