PRSS56

Summary

PRSS56 (serine protease 56, HGNC:39433) is a protein-coding gene on chromosome 2q37.1, encoding Serine protease 56 (P0CW18). Serine protease required during eye development.

This gene encodes a protein that contains a peptidase S1 domain and possesses trypsin-like serine protease activity. The encoded protein may play a role in eye development, and mutations in this gene are a cause of autosomal recessive posterior microphthalmos.

Source: NCBI Gene 646960 — RefSeq curated summary.

At a glance

• Gene–disease (curated): isolated microphthalmia 6 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 263 total — 16 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 12
• MANE Select transcript: NM_001195129

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:39433
Approved symbol	PRSS56
Name	serine protease 56
Location	2q37.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000237412
Ensembl biotype	protein_coding
OMIM	613858
Entrez	646960

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 retained_intron, 1 protein_coding

ENST00000602410, ENST00000617714

RefSeq mRNA: 2 — MANE Select: NM_001195129 NM_001195129, NM_001369848

CCDS: CCDS74669

Canonical transcript exons

ENST00000617714 — 13 exons

Exon	Start	End
ENSE00001639866	232524039	232524203
ENSE00001728484	232524738	232524844
ENSE00001799622	232524307	232524369
ENSE00003226910	232520388	232520695
ENSE00003266421	232521816	232521866
ENSE00003307876	232523060	232523202
ENSE00003308944	232521321	232521428
ENSE00003331268	232522515	232522614
ENSE00003355800	232522702	232522861
ENSE00003395543	232523416	232523578
ENSE00003400259	232521971	232522160
ENSE00003730158	232525216	232525716
ENSE00003744771	232523772	232523945

Expression profiles

Bgee: expression breadth broad, 47 present calls, max score 79.39.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4034 / max 233.4920, expressed in 82 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25982	0.2049	49
25984	0.0855	15
25983	0.0576	13
25987	0.0555	30

Top tissues by expression

124 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	79.39	gold quality
gastrocnemius	UBERON:0001388	73.63	gold quality
muscle of leg	UBERON:0001383	72.67	gold quality
skeletal muscle tissue	UBERON:0001134	71.26	gold quality
hypothalamus	UBERON:0001898	66.88	gold quality
primary visual cortex	UBERON:0002436	62.26	gold quality
muscle tissue	UBERON:0002385	58.91	gold quality
substantia nigra	UBERON:0002038	57.49	gold quality
putamen	UBERON:0001874	57.09	gold quality
nucleus accumbens	UBERON:0001882	56.85	gold quality
prefrontal cortex	UBERON:0000451	55.48	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	53.95	gold quality
caudate nucleus	UBERON:0001873	53.91	gold quality
frontal cortex	UBERON:0001870	53.63	gold quality
left testis	UBERON:0004533	52.83	gold quality
anterior cingulate cortex	UBERON:0009835	52.75	gold quality
cerebral cortex	UBERON:0000956	51.76	gold quality
right frontal lobe	UBERON:0002810	51.47	gold quality
Brodmann (1909) area 9	UBERON:0013540	51.31	gold quality
testis	UBERON:0000473	51.30	gold quality
right testis	UBERON:0004534	50.77	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	49.74	gold quality
brain	UBERON:0000955	49.54	gold quality
superior frontal gyrus	UBERON:0002661	48.49	silver quality
amygdala	UBERON:0001876	45.76	gold quality
temporal lobe	UBERON:0001871	45.53	gold quality
Ammon’s horn	UBERON:0001954	43.45	gold quality
sural nerve	UBERON:0015488	43.23	gold quality
bone marrow cell	CL:0002092	42.38	gold quality
right hemisphere of cerebellum	UBERON:0014890	41.18	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting PRSS56, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-646	99.68	67.84	1645

Literature-anchored findings (GeneRIF, showing 13)

• Three different mutations in PRSS56, were detected in microphthalmos patients of the Faroese families. (PMID:21397065)
• Together, these data suggest that alterations of this serine protease may contribute to a spectrum of human ocular conditions including reduced ocular size and ACG. (PMID:21532570)
• PRSS56 is a good candidate for the causal gene for nanophthalmos in a Mexican-Canadian family cohort. (PMID:21850159)
• Corneal diameter decreases with decreasing axial length, suggesting posterior microphthalmos and nanophthalmos represent a spectrum of high hyperopia rather than distinct phenotypes. In the Saudi population PRSS56 mutations are the major cause. (PMID:23127749)
• Idenification of a founder mutation in the PRSS56 gene in Tunisian families with posterior microphthalmia and nanophthalmia. (PMID:23820083)
• variations in PRSS56 were evaluated in patients with either primary angle-closure glaucoma (PACG) or high hyperopia. (PMID:24227917)
• This is the first trio-based whole-genome sequencing (WGS), study for nanophthalmos, revealing the potential role of de novo mutations (DNMs) in MYRF and rare inherited genetic variants in PRSS56 and MFRP. (PMID:31266062)
• The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56. (PMID:31992737)
• The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort. (PMID:32052405)
• Novel mutations in MFRP and PRSS56 are associated with posterior microphthalmos. (PMID:32118495)
• Loss of PRSS56 function leads to ocular angle defects and increased susceptibility to high intraocular pressure. (PMID:32152063)
• Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort. (PMID:33203948)
• Pathogenic variants of MFRP and PRSS56 genes are major causes of nanophthalmos in Japanese patients. (PMID:37501562)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	prss56	ENSDARG00000053158
danio_rerio	si:dkey-76d14.2	ENSDARG00000093458
mus_musculus	Prss56	ENSMUSG00000036480
rattus_norvegicus	Prss56	ENSRNOG00000029865
drosophila_melanogaster	CG33458	FBGN0053458
drosophila_melanogaster	CG33459	FBGN0053459

Paralogs (1): LPA (ENSG00000198670)

Protein

Protein identifiers

Serine protease 56 — P0CW18 (reviewed: P0CW18)

All UniProt accessions (1): P0CW18

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease required during eye development.

Tissue specificity. Expressed neural retina, cornea, sclera and optic nerve.

Disease relevance. Microphthalmia, isolated, 6 (MCOP6) [MIM:613517] A developmental ocular disorder characterized by small malformed eyes. Clinical features are extreme hyperopia due to short axial length with essentially normal anterior segment, steep corneal curvatures, shallow anterior chamber, thick lenses, and thickened scleral wall. Palpebral fissures appear narrow because of relatively deep-set eyes, visual acuity is mildly to moderately reduced, and anisometropic or strabismic amblyopia is common. The fundus of the eye shows crowded optical disks, tortuous vessels, and an abnormal foveal avascular zone. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (2): NP_001182058, NP_001356777 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR043504

Pfam: PF00089

UniProt features (22 total): sequence variant 7, disulfide bond 4, region of interest 3, active site 3, signal peptide 1, chain 1, domain 1, sequence conflict 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0CW18-F1	74.35	0.35

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 145 (charge relay system); 191 (charge relay system); 286 (charge relay system)

Disulfide bonds (4): 130–146, 225–292, 256–271, 282–313

Glycosylation sites (1): 97

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 45 (showing top): GOBP_WOUND_HEALING, GOBP_HEMOSTASIS, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_REGULATION_OF_BODY_FLUID_LEVELS, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY, GOBP_SENSORY_SYSTEM_DEVELOPMENT, FOXN3_TARGET_GENES, HP_ABNORMAL_RETINAL_MORPHOLOGY, HP_ABNORMAL_CORNEA_MORPHOLOGY, HP_MICROCORNEA, HP_GLAUCOMA, HP_VISUAL_IMPAIRMENT, HP_ABNORMALITY_OF_REFRACTION, HP_HYPERMETROPIA

GO Biological Process (3): proteolysis (GO:0006508), blood coagulation (GO:0007596), camera-type eye development (GO:0043010)

GO Molecular Function (4): serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	1
hemostasis	1
wound healing	1
coagulation	1
eye development	1
endopeptidase activity	1
serine-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

744 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRSS56	TMEM98	Q9Y2Y6	811
PRSS56	MFRP	Q9BY79	762
PRSS56	RDH5	Q92781	600
PRSS56	KCNQ5	Q9NR82	584
PRSS56	SHISA6	Q6ZSJ9	555
PRSS56	LAMA2	P24043	551
PRSS56	BEST1	O76090	544
PRSS56	GJD2	Q9UKL4	525
PRSS56	SIX6	O95475	513
PRSS56	ZNF644	Q9H582	509
PRSS56	MAIP1	Q8WWC4	496
PRSS56	RMP64	Q6NW34	489
PRSS56	ZC3H11B	A0A1B0GTU1	479
PRSS56	GRIA4	P48058	476
PRSS56	ZMAT4	Q9H898	476

IntAct

6 interactions, top by confidence:

A	B	Type	Score
Smn1	CLNS1A	psi-mi:“MI:0914”(association)	0.350
ATL3	SNX14	psi-mi:“MI:0914”(association)	0.350
Lgals3bp	CS	psi-mi:“MI:0914”(association)	0.350
MOSPD2	FLNA	psi-mi:“MI:0914”(association)	0.350
RMC1	ANXA2P2	psi-mi:“MI:0914”(association)	0.350

BioGRID (16): PRSS56 (Affinity Capture-MS), PRSS56 (Affinity Capture-MS), PRSS56 (Affinity Capture-MS), PRSS56 (Affinity Capture-MS), PRSS56 (Affinity Capture-MS), PRSS56 (Negative Genetic), PRSS56 (Affinity Capture-MS), PRSS56 (Affinity Capture-MS), PRSS56 (Affinity Capture-MS), PRSS56 (Affinity Capture-MS), PRSS56 (Affinity Capture-MS), PRSS56 (Affinity Capture-MS), PRSS56 (Affinity Capture-MS), PRSS56 (Affinity Capture-MS), PRSS56 (Proximity Label-MS)

ESM2 similar proteins: A1YGK1, A2T7E6, A4D1S0, A6NGW2, F2YMG0, H7C350, O15533, O43593, O60304, O70146, O94761, P0CW18, P27106, P59942, P79295, Q15569, Q1JPB9, Q2TBC4, Q3UM83, Q4TUC0, Q5DRQ5, Q5M844, Q5R732, Q5TJE4, Q63572, Q6P0A1, Q6PZD2, Q6ZV89, Q75NR7, Q7RTU9, Q7Z6P3, Q866Y3, Q8BLH5, Q8BWG4, Q8JZW5, Q8N4L8, Q8NBB4, Q8QZY4, Q8TER5, Q8VIM6

Diamond homologs: A0A1S4GMJ4, A6NIE9, A8JUP7, G3V801, O08762, O42207, O60235, P00741, P00745, P00762, P00765, P03951, P05049, P07477, P07478, P0CW18, P15120, P16292, P16295, P19799, P29786, P29787, P35030, P35039, P69525, P79953, Q14B25, Q14BX2, Q14C59, Q1JRP2, Q27081, Q28278, Q28315, Q28412, Q29463, Q2KJ63, Q2VG86, Q5G265, Q5U405, Q6BEA2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

263 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	7
Uncertain significance	137
Likely benign	45
Benign	37

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1324965	NM_001195129.2(PRSS56):c.1066del (p.Gln356fs)	Pathogenic
1333280	NM_001195129.2(PRSS56):c.219del (p.Arg74fs)	Pathogenic
1385526	NM_001195129.2(PRSS56):c.353G>A (p.Trp118Ter)	Pathogenic
1450154	NM_001195129.2(PRSS56):c.1573del (p.Val525fs)	Pathogenic
183172	NM_001195129.2(PRSS56):c.833dup (p.Val279fs)	Pathogenic
183173	NM_001195129.2(PRSS56):c.709G>A (p.Gly237Arg)	Pathogenic
183174	NM_001195129.2(PRSS56):c.1183T>C (p.Cys395Arg)	Pathogenic
2047480	NM_001195129.2(PRSS56):c.1258G>T (p.Gly420Ter)	Pathogenic
2855573	NM_001195129.2(PRSS56):c.896dup (p.Pro299_Arg300insTer)	Pathogenic
31079	NM_001195129.2(PRSS56):c.926G>C (p.Trp309Ser)	Pathogenic
31080	NM_001195129.2(PRSS56):c.526C>G (p.Arg176Gly)	Pathogenic
3631009	NM_001195129.2(PRSS56):c.849+1G>T	Pathogenic
3641485	NM_001195129.2(PRSS56):c.849+1G>C	Pathogenic
4750585	NM_001195129.2(PRSS56):c.649del (p.Gln217fs)	Pathogenic
4796015	NM_001195129.2(PRSS56):c.69C>A (p.Tyr23Ter)	Pathogenic
915448	NM_001195129.2(PRSS56):c.1202C>A (p.Ala401Glu)	Pathogenic
183170	NM_001195129.2(PRSS56):c.958G>A (p.Gly320Arg)	Likely pathogenic
183175	NM_001195129.2(PRSS56):c.1555G>A (p.Gly519Arg)	Likely pathogenic
4277282	NM_001195129.2(PRSS56):c.320G>T (p.Gly107Val)	Likely pathogenic
4277283	NM_001195129.2(PRSS56):c.632G>C (p.Cys211Ser)	Likely pathogenic
4277285	NM_001195129.2(PRSS56):c.1186G>A (p.Glu396Lys)	Likely pathogenic
4686564	NM_001195129.2(PRSS56):c.970C>T (p.Arg324Cys)	Likely pathogenic
932138	NM_001195129.2(PRSS56):c.94del (p.Gln32fs)	Likely pathogenic

SpliceAI

1437 predictions. Top by Δscore:

Variant	Effect	Δscore
2:232520691:GCAAG:G	donor_gain	1.0000
2:232520695:GGT:G	donor_loss	1.0000
2:232520696:G:GG	donor_gain	1.0000
2:232520696:GTAA:G	donor_loss	1.0000
2:232520697:T:A	donor_loss	1.0000
2:232521455:G:GG	donor_gain	1.0000
2:232521812:GCAG:G	acceptor_loss	1.0000
2:232521813:CAGG:C	acceptor_loss	1.0000
2:232521814:AG:A	acceptor_gain	1.0000
2:232521814:AGGAT:A	acceptor_loss	1.0000
2:232521815:G:T	acceptor_loss	1.0000
2:232521815:GG:G	acceptor_gain	1.0000
2:232521965:TTCTA:T	acceptor_loss	1.0000
2:232521966:TCTA:T	acceptor_loss	1.0000
2:232521967:CTAGG:C	acceptor_loss	1.0000
2:232521968:TA:T	acceptor_loss	1.0000
2:232521969:A:AG	acceptor_gain	1.0000
2:232521969:AG:A	acceptor_gain	1.0000
2:232521970:G:GG	acceptor_gain	1.0000
2:232521970:GG:G	acceptor_gain	1.0000
2:232521970:GGGCC:G	acceptor_gain	1.0000
2:232522156:GTAGG:G	donor_gain	1.0000
2:232522157:TAGG:T	donor_gain	1.0000
2:232522159:GG:G	donor_gain	1.0000
2:232522160:GG:G	donor_gain	1.0000
2:232522161:GTAA:G	donor_loss	1.0000
2:232522613:AGGTG:A	donor_loss	1.0000
2:232522614:GGTGA:G	donor_loss	1.0000
2:232522615:GTGAG:G	donor_loss	1.0000
2:232522616:T:G	donor_loss	1.0000

AlphaMissense

3775 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:232522727:A:T	D191V	0.997
2:232523493:G:C	W309C	0.997
2:232523493:G:T	W309C	0.997
2:232522152:C:G	C146W	0.996
2:232523164:T:A	C271S	0.996
2:232523165:G:C	C271S	0.996
2:232523559:G:C	W331C	0.996
2:232523559:G:T	W331C	0.996
2:232522151:G:A	C146Y	0.995
2:232522702:T:C	F183L	0.995
2:232522704:T:A	F183L	0.995
2:232522704:T:G	F183L	0.995
2:232522727:A:C	D191A	0.995
2:232523503:T:A	C313S	0.995
2:232523504:G:C	C313S	0.995
2:232522595:G:C	R176P	0.994
2:232523197:T:A	C282S	0.994
2:232523198:G:A	C282Y	0.994
2:232523198:G:C	C282S	0.994
2:232523480:G:A	G305E	0.994
2:232523530:T:G	Y322D	0.994
2:232522068:G:C	W118C	0.993
2:232522068:G:T	W118C	0.993
2:232522703:T:G	F183C	0.993
2:232522726:G:C	D191H	0.993
2:232522845:G:C	W230C	0.993
2:232522845:G:T	W230C	0.993
2:232523165:G:A	C271Y	0.993
2:232523426:G:A	G287E	0.993
2:232523426:G:T	G287V	0.993

dbSNP variants (sampled 300 via entrez): RS1000014767 (2:232523989 G>A), RS1000384330 (2:232524283 T>G), RS1000445247 (2:232519525 T>G), RS1001944020 (2:232523367 G>A,T), RS1002204599 (2:232524363 G>A), RS1002649672 (2:232519642 C>T), RS1002997267 (2:232520725 G>A,C), RS1003172681 (2:232524131 G>A,C), RS1003362757 (2:232521563 G>A,C), RS1003922268 (2:232526097 CG>C), RS1003994517 (2:232522233 C>A,G,T), RS1004113883 (2:232522407 C>A,T), RS1004762895 (2:232522273 C>A,T), RS1004833636 (2:232521214 T>C), RS1005242029 (2:232522140 G>A,T)

Disease associations

OMIM: gene MIM:613858 | disease phenotypes: MIM:613517, MIM:600165

GenCC curated gene-disease

Disease	Classification	Inheritance
isolated microphthalmia 6	Definitive	Autosomal recessive
nanophthalmia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
isolated microphthalmia 6	Definitive	AR

Mondo (2): isolated microphthalmia 6 (MONDO:0013293), nanophthalmia (MONDO:0005514)

Orphanet (2): Isolated microphthalmia-anophthalmia-coloboma (Orphanet:2542), Nanophthalmos (Orphanet:35612)

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000568	Microphthalmia
HP:0000610	Abnormal choroid morphology
HP:0000646	Amblyopia
HP:0007703	Abnormal retinal pigmentation
HP:0007906	Ocular hypertension
HP:0008052	Retinal fold
HP:0008499	High hypermetropia
HP:0030823	Scleral thickening

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001858_1	Refractive error	8.000000e-11
GCST001858_8	Refractive error	5.000000e-11
GCST003997_22	Myopia	9.000000e-35
GCST006291_134	Spherical equivalent or myopia (age of diagnosis)	4.000000e-37
GCST009462_42	Optic disc size	5.000000e-13
GCST009962_1	High myopia	4.000000e-16
GCST010002_411	Refractive error	1.000000e-123
GCST012400_76	Low myopia vs hyperopia	3.000000e-11
GCST012403_143	High myopia	1.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Rotenone	increases expression	2
propionaldehyde	increases expression	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
(+)-JQ1 compound	decreases expression	1
Aldehydes	increases expression	1
Ivermectin	decreases expression	1
Phthalic Acids	increases methylation	1
Ziram	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.