STUB1

Chr 16ADAR

STIP1 homology and U-box containing protein 1

Also known as: CHIP, HSPABP2, NY-CO-7, SCA48, SCAR16, SDCCAG7, UBOX1

NCBI Gene: 10273 ENSG00000103266 UniProt: Q9UNE7 OMIM: 607207

The STUB1 protein functions as an E3 ubiquitin ligase and cochaperone that targets misfolded proteins for proteasomal degradation and maintains mitochondrial quality control. Mutations cause spinocerebellar ataxia with both autosomal recessive (SCA16) and autosomal dominant (SCA48) inheritance patterns. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.68), and the ataxias primarily affect the cerebellum and result in progressive movement disorders.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein containing tetratricopeptide repeat and a U-box that functions as a ubiquitin ligase/cochaperone. The encoded protein binds to and ubiquitinates shock cognate 71 kDa protein (Hspa8) and DNA polymerase beta (Polb), among other targets. Mutations in this gene cause spinocerebellar ataxia, autosomal recessive 16. Alternative splicing results in multiple transcript variants. There is a pseudogene for this gene on chromosome 2. [provided by RefSeq, Jun 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.682 OMIM phenotypes

Clinical Summary— STUB1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.68LOEUF

pLI 0.019

Z-score 2.54

OE 0.34 (0.19–0.68)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.16Z-score

OE missense 0.76 (0.66–0.87)

143 obs / 187.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.19–0.68)

0≤0.351.4

Missense OE?0.76 (0.66–0.87)

0≤0.61.4

Synonymous OE?1.40

0≤1.21.6

LoF obs/exp: 6 / 17.4Missense obs/exp: 143 / 187.9Syn Z: -2.79

This gene — mechanism propensity

0.6936th %ile

GOF

0.74top 25%

LOF

0.2871th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNFurther in vitro experiments demonstrated that this novel heterozygous STUB1 frameshift variant impairs the CHIP protein's activity and its interaction with the E2 ubiquitin ligase, UbE2D1, leading to neuronal accumulation of tau and ÃÂ±-synuclein, caspase-3 activation, and promoting cellular apopt1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References