PRSS12

protein-coding

serine protease 12, the group of Scavenger receptor cysteine rich domain containing|Serine proteases

Gene summary

This gene encodes a member of the trypsin family of serine proteases and contains a signal peptide, a proline-rich region, a Kringle domain, four scavenger receptor cysteine-rich domains, and a trypsin-like serine protease domain. The protein, sometimes referred to as neurotrypsin or motopsin, is secreted from neuronal cells and localizes to the synaptic cleft. Studies in mice show that this protein cleaves a protein, agrin, that is important for the formation and maintenance of exitatory synapses. Defects in this gene cause a form of autosomal recessive cognitive impairment (MRT1). [provided by RefSeq, Jul 2017]

MANE transcript

NM_003619.4

Inheritance

ClinVar variants

P:6U:222B:40

Top phenotype

Intellectual developmental disorder, autosomal recessive 1

gnomAD constraint

pLI —, LoF o/e 0.96

Max pathogenic AF

—

Genomic locus

chr4:118,280,038-118,353,003

External References & Databases

Ensembl (ENSG00000164099)

Transcript & Mutation Effects

hg38 • Region Span ~73.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

non-syndromic intellectual disabilityLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0000509

Submitter: Illumina

intellectual developmental disorder, autosomal recessive 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009580

Submitter: G2P

non-syndromic intellectual disabilityLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0000509

Submitter: ClinGen

*PRSS12* is located at chromosome 4q26 and encodes a synaptic serine protease expressed in the brain. *PRSS12* was first reported in relation to non-syndromic intellectual disability in 2002 (Molinari et al., PMID: 12459588) in two consanguineous families. Only one proband with a homozygous frameshift variant was scored. A second proband also carried the same homozygous frameshift variant, but both families originated from the same region of Eastern Algeria and were found to carry the variant on the same haplotype, so this individual was not scored. Segregation data was scored in Family 1, in which the variant was identified in a homozygous state in four affected siblings and in a heterozygous state in three unaffected siblings (PMID: 12459588). *Prss12* knockout mice showed no deficits in long-term memory, but had altered social interaction compared to wild-type mice (PMID: 20092579). In addition, knockout mice had reduced hippocampal apical spine density, reduced phosphorylated CREB expression after behavioral stimulation, and reduced activity-dependent formation of dendritic filopodia in the hippocampus (PMIDs: 19303856, 20092579). The evidence from knockout mouse models was not scored as there is very limited genetic data, so the implication for a human phenotype is currently unclear. In summary, there is limited evidence to support the relationship between *PRSS12* and non-syndromic intellectual disability. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 4, 2021. It was reevaluated on August 21, 2026. As a result of this reevaluation, no additional patients were identified and the classification did not change. The scoring was updated to be consistent with SOP Version 12.

intellectual developmental disorder, autosomal recessive 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009580

Submitter: PanelApp Australia

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 1LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0009580

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 1AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 12459588; 12925575

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRSS12 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 192

Intellectual disability, autosomal recessive 1Total: 75

not providedTotal: 42

PRSS12-related disorderTotal: 9

Long QT syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003619.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			11 clinvar	27 clinvar	2 clinvar	40
missense			188 clinvar	10 clinvar		198
nonsense		2 clinvar	9 clinvar			11
start loss						0
frameshift		3 clinvar	9 clinvar	1 clinvar		13
splice donor/acceptor (+/-2bp)		1 clinvar	5 clinvar			6
Total	0	6	222	38	2	268

Highest pathogenic variant AF is 0.000039653773

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003619.4	RefSeq	NP_003610.2	13	MANE Select
ENST00000296498.3	Ensembl	ENSP00000296498.3	13	MANE Select
NM_001440549.1	RefSeq	NP_001427478.1	13	Standard
NM_001440550.1	RefSeq	NP_001427479.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

exocytosis
receptor-mediated endocytosis
zymogen activation

Molecular Function

serine-type endopeptidase activity
scavenger receptor activity
serine-type peptidase activity

Cellular Component

plasma membrane
axon
dendrite
cytoplasmic vesicle
synaptic cleft

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296498
Coding exons: 13
Length: 72966
Individuals with no LoFs: 125006
Homozygous LoFs: 2
Heterozygous LoFs: 740
Defined: 125748
p: 0.00295

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.387	460	484	0.951	0.0000260	5628
Missense (PolyPhen)		165	175.14	0.94208		2074
Synonymous	0.402	175	182	0.962	0.00000952	1727
Loss of Function	0.221	44	45.6	0.965	0.00000249	503

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.0024	0.0024	notable
Ashkenazi Jewish	0.0026	0.0026	notable
East Asian	0.0023	0.0023	notable
Finnish	0.0099	0.0098	notable
European (Non-Finnish)	0.0018	0.0017	notable
South Asian	0.0050	0.0050	notable
Other	0.0016	0.0016	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in neuronal plasticity and the proteolytic action may subserve structural reorganizations associated with learning and memory operations. {ECO:0000250}.;

Recessive Scores

pRec: 0.136

Intolerance Scores

LoFtool: 0.310
RVIS EVS: 0.07
RVIS percentile EVS: 59.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.247

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium