Is CBL p.Lys389Thr (c.1166A>C) pathogenic?

CBL p.Lys389Thr (c.1166A>C) is classified Pathogenic/Likely pathogenic in CBL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-07). AlphaMissense: likely pathogenic (0.9991); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CBL p.Lys389Thr (c.1166A>C)?

CBL p.Lys389Thr (c.1166A>C) is associated with Inborn genetic diseases (ClinVar).

How common is CBL p.Lys389Thr (c.1166A>C) in the general population?

CBL p.Lys389Thr (c.1166A>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CBL p.Lys389Thr (c.1166A>C)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

CBL p.Lys389Thr

c.1166A>C · rs1949904868 · VCV985899

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic ✓ concordant with ClinVar · top 8% in CBL
REVEL	0.862	moderately pathogenic-leaning
SaProt	LLR -15.78	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	29.8	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 8.48e-05% European (non-Finnish) · 1/1,179,050 alleles

Overall 6.85e-05% 1/1,460,796 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.Lys389Thr
Coding: c.1166A>C
MANE Select: NM_005188
dbSNP: rs1949904868
Type: single nucleotide variant
Location: chr11:119278236 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 389: the 'required for ubiquitination of spred2' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CBL p.Lys389Arg Uncertain significance ★ ⚠ same residue
CBL p.Lys389Asn Uncertain significance ★ ⚠ same residue
CBL p.Lys389Gln Uncertain significance ★ ⚠ same residue
CBL p.Lys389Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
CBL p.Thr377Ala Uncertain significance ★★ ⚠ same condition
CBL p.Gln367Lys Conflicting classifications of pathogenicity ★ ⚠ same condition
CBL p.Leu892fs Uncertain significance ★ same condition
CBL c.1096-1G>C Pathogenic/Likely pathogenic ★★ same type

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-lys389thr (accessed [today's date]).

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