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…

Primary Disease Associations & Inheritance

{?Parkinson disease 5, susceptibility to}MIM #613643

Spastic paraplegia 79A, autosomal dominantMIM #620221

Spastic paraplegia 79B, autosomal recessiveMIM #615491

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · hereditary spastic paraplegia · AD · ClinGen 2025

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

149

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.21

LOEUF· LoF intol.

—

Mechanism

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

Background carrier burden — how many people carry a rare variant somewhere in UCHL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 320

284 rare PASS variants

Rare truncating (LoF)

1 in 5,400

35 rare PASS variants

Rare synonymous (reference)

1 in 250

125 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for UCHL1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 580	1 in 4,400
South Asian	~43k	1 in 220	≈ 1 in 11,000
Remaining (unassigned)	~30k	1 in 200	1 in 4,300
European (Finnish)	~27k	1 in 670	≈ 1 in 23,000
Admixed American	~22k	1 in 360	≈ 1 in 7,500
African / African American	~21k	1 in 240	≈ 1 in 5,600
East Asian	~20k	1 in 380	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 1,600	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 160	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓