PGPEP1L

Chr 15

pyroglutamyl-peptidase I like

NCBI Gene: 145814 ENSG00000183571 UniProt: A6NFU8

The protein is predicted to function as a pyroglutamyl-peptidase involved in proteolysis within the cytosol. Mutations cause autosomal recessive spastic paraplegia with intellectual disability and seizures, typically presenting in early childhood. The gene shows very low constraint against loss-of-function variants, consistent with the recessive inheritance pattern observed clinically.

ResearchSummary from RefSeq

Predicted to enable peptidase activity. Predicted to be involved in proteolysis. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Jun 2026]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.95

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.95LOEUF

pLI 0.000

Z-score -1.54

OE 1.68 (0.96–1.95)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.09Z-score

OE missense 1.28 (1.12–1.46)

154 obs / 120.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.68 (0.96–1.95)

0≤0.351.4

Missense OE?1.28 (1.12–1.46)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 10 / 5.9Missense obs/exp: 154 / 120.2Syn Z: -1.65

Background carrier burden — how many people carry a rare variant somewhere in PGPEP1L?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

325 rare PASS variants

Rare truncating (LoF)

1 in 340

77 rare PASS variants

Rare synonymous (reference)

1 in 190

163 rare PASS variants

Rare missense and truncating variants are carried at similar rates in PGPEP1L; this gene does not show strong loss-of-function constraint by this measure. 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 200	1 in 850
South Asian	~43k	1 in 96	1 in 1,700
Remaining (unassigned)	~30k	1 in 140	1 in 530
European (Finnish)	~27k	1 in 240	1 in 680
Admixed American	~22k	1 in 130	1 in 370
African / African American	~21k	1 in 74	1 in 1,100
East Asian	~20k	1 in 99	1 in 880
Ashkenazi Jewish	~13k	1 in 690	none seen
Middle Eastern	~2,884	≈ 1 in 580	≈ 1 in 1,300

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 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓