PRSS8

Chr 16

serine protease 8

Also known as: CAP1, PROSTASIN

NCBI Gene: 5652 ENSG00000052344 UniProt: Q16651 OMIM: 600823

This gene encodes a serine protease that cleaves protein substrates at lysine or arginine residues and stimulates epithelial sodium channel activity through proteolytic activation of the gamma subunit. Mutations cause autosomal recessive hypotrichosis simplex, characterized by sparse hair growth from birth. The gene shows moderate constraint against loss-of-function variants, suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the peptidase S1 or chymotrypsin family of serine proteases. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate via a disulfide bond to form the heterodimeric enzyme. This enzyme is highly expressed in prostate epithelia and is one of several proteolytic enzymes found in seminal fluid. This protease exhibits trypsin-like substrate specificity, cleaving protein substrates at the carboxyl terminus of lysine or arginine residues. The encoded protease partially mediates proteolytic activation of the epithelial sodium channel, a regulator of sodium balance, and may also play a role in epithelial barrier formation. [provided by RefSeq, Feb 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.69

Clinical Summary— PRSS8

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

31 VUS of 41 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?

0.69LOEUF

pLI 0.100

Z-score 2.37

OE 0.30 (0.15–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.17Z-score

OE missense 0.77 (0.67–0.88)

154 obs / 200.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.15–0.69)

0≤0.351.4

Missense OE?0.77 (0.67–0.88)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 4 / 13.3Missense obs/exp: 154 / 200.8Syn Z: 0.74

This gene — mechanism propensity

0.6452th %ile

GOF

0.7029th %ile

LOF

0.3067th %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

41 submitted variants in ClinVar

ClinVar

Classification Summary

VUS31

Likely Benign5

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	31	0	31
Likely Benign	4	1	5
Benign	1	0	1
Total	36	1	37

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap PRSS8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →