PRSS21

Chr 16

serine protease 21

Also known as: ESP-1, ESP1, TEST1, TESTISIN

NCBI Gene: 10942 ENSG00000007038 UniProt: Q9Y6M0 OMIM: 608159

The protein is a cell-surface anchored serine protease of the trypsin family that cleaves peptide bonds at lysine or arginine residues and may regulate proteolytic events during testicular germ cell maturation. This gene is highly constrained against loss-of-function variants (pLI ~0, LOEUF 1.32), but no established Mendelian diseases have been associated with PRSS21 mutations in current medical literature. The protein localizes to premeiotic testicular germ cells and may be involved in testicular tumor progression.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a cell-surface anchored serine protease, which is a member of the trypsin family of serine proteases. The encoded protein is predicted to be active on peptide linkages involving the carboxyl group of lysine or arginine. The encoded protein localizes to the cytoplasm and the plasma membrane of premeiotic testicular germ cells and may be involved in progression of testicular tumors of germ cell origin. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.32

Clinical Summary— PRSS21

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

54 VUS of 67 total submissions

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?

1.32LOEUF

pLI 0.000

Z-score 0.66

OE 0.81 (0.52–1.32)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.64Z-score

OE missense 1.13 (1.01–1.26)

224 obs / 198.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.81 (0.52–1.32)

0≤0.351.4

Missense OE?1.13 (1.01–1.26)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 12 / 14.7Missense obs/exp: 224 / 198.5Syn Z: 0.48

This gene — mechanism propensity

0.6939th %ile

GOF

0.6931th %ile

LOF

0.3065th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction 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.

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

ClinVar Variant Classifications

67 submitted variants in ClinVar

ClinVar

Classification Summary

VUS54

Likely Benign6

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	54	54
Likely Benign	6	6
Benign	0	0
Total	60	60

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap PRSS21 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →