Intellectual disability, autosomal recessive 1

Summary

Intellectual disability, autosomal recessive 1 (MONDO:0009580) is a disease caused by PRSS12 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PRSS12 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 114

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal recessive 1
Mondo ID	MONDO:0009580
MeSH	C565406
OMIM	249500
DOID	DOID:0081177
UMLS	C1855304
MedGen	344468
GARD	0022537
Is cancer (heuristic)	no

Also known as: autosomal recessive non-syndromic intellectual disability caused by mutation in PRSS12 · intellectual disability, autosomal recessive 1 · intellectual disability, autosomal recessive type 1 · mental retardation, autosomal recessive 1 · mental retardation, autosomal recessive type 1 · MRT1 · PRSS12 autosomal recessive non-syndromic intellectual disability

Data availability: 114 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal recessive non-syndromic intellectual disability › intellectual disability, autosomal recessive 1

Related subtypes (67): intellectual disability, autosomal recessive 2, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, intellectual disability, autosomal recessive 5, intellectual disability, autosomal recessive 6, intellectual disability, autosomal recessive 7, intellectual disability, autosomal recessive 9, intellectual disability, autosomal recessive 10, intellectual disability, autosomal recessive 11, intellectual disability, autosomal recessive 4, intellectual disability, autosomal recessive 13, intellectual disability, autosomal recessive 14, Rafiq syndrome, intellectual disability, autosomal recessive 16, intellectual disability, autosomal recessive 18, intellectual disability, autosomal recessive 31, intellectual disability, autosomal recessive 29, intellectual disability, autosomal recessive 27, intellectual disability, autosomal recessive 33, intellectual disability, autosomal recessive 30, intellectual disability, autosomal recessive 19, intellectual disability, autosomal recessive 23, intellectual disability, autosomal recessive 24, intellectual disability, autosomal recessive 25, intellectual disability, autosomal recessive 28, intellectual disability, autosomal recessive 34, intellectual disability, autosomal recessive 42, intellectual disability, autosomal recessive 43, intellectual disability, autosomal recessive 44, intellectual disability, autosomal recessive 45, intellectual disability, autosomal recessive 46, intellectual disability, autosomal recessive 47, Al-Raqad syndrome, intellectual disability, autosomal recessive 50, intellectual disability, autosomal recessive 51, intellectual disability, autosomal recessive 52, intellectual disability, autosomal recessive 54, intellectual disability, autosomal recessive 56, intellectual developmental disorder, autosomal recessive 74, intellectual disability, autosomal recessive 57, intellectual disability, autosomal recessive 58, intellectual disability, autosomal recessive 59, pontocerebellar hypoplasia type 1, intellectual disability, autosomal recessive 64, intellectual disability, autosomal recessive 65, intellectual developmental disorder, autosomal recessive 73, intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, intellectual disability, autosomal recessive 61, intellectual developmental disorder, autosomal recessive 76, intellectual developmental disorder, autosomal recessive 77, intellectual disability, autosomal recessive 66, intellectual developmental disorder, autosomal recessive 67, intellectual developmental disorder, autosomal recessive 68, intellectual developmental disorder, autosomal recessive 69, intellectual developmental disorder, autosomal recessive 70, intellectual developmental disorder, autosomal recessive 71, intellectual developmental disorder, autosomal recessive 72, glycosylphosphatidylinositol biosynthesis defect 16, intellectual disability, autosomal recessive 60, intellectual disability, autosomal recessive 63, adenosine kinase deficiency, intellectual developmental disorder, autosomal recessive 78, intellectual developmental disorder, autosomal recessive 79, intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, intellectual developmental disorder, autosomal recessive 81, intellectual developmental disorder, autosomal recessive 82, intellectual developmental disorder, autosomal recessive 83

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

114 retrieved; paginated sample, class counts are floors:

84 uncertain significance, 8 benign, 7 likely benign, 5 conflicting classifications of pathogenicity, 5 benign/likely benign, 3 likely pathogenic, 2 no classifications from unflagged records

ClinVar	Variant (HGVS)	Gene	Classification	Review
1676513	NM_003619.4(PRSS12):c.441_442del (p.Trp148fs)	PRSS12	Likely pathogenic	criteria provided, single submitter
3780493	NM_003619.4(PRSS12):c.1586G>A (p.Trp529Ter)	PRSS12	Likely pathogenic	criteria provided, single submitter
4849491	NM_003619.4(PRSS12):c.1022del (p.Pro341fs)	PRSS12	Likely pathogenic	criteria provided, single submitter
1031345	NM_003619.4(PRSS12):c.910G>A (p.Val304Ile)	PRSS12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211964	NM_003619.4(PRSS12):c.523G>A (p.Gly175Ser)	PRSS12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436431	NM_003619.4(PRSS12):c.936C>T (p.Ala312=)	PRSS12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
632426	NM_003619.4(PRSS12):c.2488_2489del (p.Met830fs)	PRSS12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
736046	NM_003619.4(PRSS12):c.966C>T (p.Gly322=)	PRSS12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029729	NM_003619.4(PRSS12):c.121C>T (p.Pro41Ser)	PRSS12	Uncertain significance	criteria provided, single submitter
1029730	NM_003619.4(PRSS12):c.2040-1G>C	PRSS12	Uncertain significance	criteria provided, single submitter
1029732	NM_003619.4(PRSS12):c.235G>C (p.Ala79Pro)	PRSS12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031342	NM_003619.4(PRSS12):c.1238A>G (p.Asp413Gly)	PRSS12	Uncertain significance	criteria provided, single submitter
1031344	NM_003619.4(PRSS12):c.254C>A (p.Thr85Lys)	PRSS12	Uncertain significance	criteria provided, single submitter
130044	NM_003619.4(PRSS12):c.19G>A (p.Val7Met)	PRSS12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1336195	NM_003619.4(PRSS12):c.821-1G>A	PRSS12	Uncertain significance	criteria provided, multiple submitters, no conflicts
211960	NM_003619.4(PRSS12):c.2320+6G>C	PRSS12	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435266	NM_003619.4(PRSS12):c.2268_2274delinsAC (p.Arg757fs)	PRSS12	Uncertain significance	criteria provided, single submitter
2435267	NM_003619.4(PRSS12):c.1918G>C (p.Gly640Arg)	PRSS12	Uncertain significance	criteria provided, multiple submitters, no conflicts
2500692	NM_003619.4(PRSS12):c.359A>C (p.Glu120Ala)	PRSS12	Uncertain significance	criteria provided, multiple submitters, no conflicts
2502342	NM_003619.4(PRSS12):c.1501A>T (p.Arg501Ter)	PRSS12	no classifications from unflagged records	no classifications from unflagged records
2581017	NM_003619.4(PRSS12):c.113C>T (p.Pro38Leu)	PRSS12	Uncertain significance	criteria provided, single submitter
2689833	NM_003619.4(PRSS12):c.1402C>T (p.Arg468Ter)	PRSS12	Uncertain significance	criteria provided, single submitter
3219808	NM_003619.4(PRSS12):c.874C>T (p.Arg292Trp)	PRSS12	Uncertain significance	criteria provided, multiple submitters, no conflicts
347370	NM_003619.4(PRSS12):c.*1699T>C	PRSS12	Uncertain significance	criteria provided, single submitter
347371	NM_003619.4(PRSS12):c.*1660T>C	PRSS12	Uncertain significance	criteria provided, single submitter
347372	NM_003619.4(PRSS12):c.*1615C>T	PRSS12	Uncertain significance	criteria provided, multiple submitters, no conflicts
347375	NM_003619.4(PRSS12):c.*920G>C	PRSS12	Uncertain significance	criteria provided, single submitter
347376	NM_003619.4(PRSS12):c.*842C>G	PRSS12	Uncertain significance	criteria provided, single submitter
347377	NM_003619.4(PRSS12):c.*830C>T	PRSS12	Uncertain significance	criteria provided, single submitter
347382	NM_003619.4(PRSS12):c.*531C>A	PRSS12	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PRSS12	Definitive	Autosomal recessive	intellectual disability, autosomal recessive 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRSS12	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRSS12	HGNC:9477	ENSG00000164099	P56730	Neurotrypsin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRSS12	Neurotrypsin	Plays a role in neuronal plasticity and the proteolytic action may subserve structural reorganizations associated with learning and memory operations.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRSS12	Protease	yes		Kringle, SRCR, Trypsin_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
epithelium of bronchus	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRSS12	199	ubiquitous	marker	bronchial epithelial cell, stromal cell of endometrium, epithelium of bronchus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRSS12	921

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRSS12	P56730	77.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
zymogen activation	1	674.1×	0.003	PRSS12
exocytosis	1	151.8×	0.007	PRSS12

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRSS12	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PRSS12	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PRSS12
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PRSS12	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.