UCHL1

Chr 4ADAR

ubiquitin C-terminal hydrolase L1

Also known as: HEL-117, HEL-S-53, NDGOA, PARK5, PGP 9.5, PGP9.5, PGP95, SPG79

NCBI Gene: 7345 ENSG00000154277 UniProt: P09936 OMIM: 191342

The protein is a deubiquitinase that hydrolyzes peptide bonds at the C-terminal glycine of ubiquitin and regulates multiple cellular processes including synaptic function and protein degradation pathways. Mutations cause spastic paraplegia 79A (autosomal dominant) and spastic paraplegia 79B (autosomal recessive), with potential susceptibility to Parkinson disease. The gene is highly constrained against loss-of-function mutations (pLI 0.99, LOEUF 0.21), indicating that complete loss of protein function is likely not tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the peptidase C12 family. This enzyme is a thiol protease that hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. This gene is specifically expressed in the neurons and in cells of the diffuse neuroendocrine system. Mutations in this gene may be associated with Parkinson disease.[provided by RefSeq, Sep 2009]

OMIM ResearchGenerating clinical summary…

AD/ARLOEUF 0.213 OMIM phenotypes

Clinical Summary— UCHL1

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Gene-Disease Validity (ClinGen)

hereditary spastic paraplegia · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

26 unique Pathogenic / Likely Pathogenic· 81 VUS of 237 total submissions

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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

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.21LOEUF

pLI 0.991

Z-score 3.48

OE 0.00 (0.00–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.70Z-score

OE missense 0.82 (0.70–0.97)

102 obs / 123.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.21)

0≤0.351.4

Missense OE?0.82 (0.70–0.97)

0≤0.61.4

Synonymous OE?1.42

0≤1.21.6

LoF obs/exp: 0 / 14.1Missense obs/exp: 102 / 123.9Syn Z: -2.27

ClinVar Variant Classifications

237 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic14

VUS81

Likely Benign91

Benign25

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	2	0	0	12
Likely Pathogenic	12	2	0	0	14
VUS	5	55	21	0	81
Likely Benign	0	2	53	36	91
Benign	0	1	24	0	25
Conflicting	—				4
Total	27	62	98	36	227

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

17 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap UCHL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →