Non-syndromic intellectual disability

Summary

Non-syndromic intellectual disability (MONDO:0000509) is a disease with 8 cohort genes.

At a glance

• Cohort genes: 8
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	non-syndromic intellectual disability
Mondo ID	MONDO:0000509
DOID	DOID:0050889
Is cancer (heuristic)	no

Also known as: isolated intellectual disability · nonsyndromic intellectual disability

Data availability: 9 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (9): syndromic intellectual disability, intellectual developmental disorder and retinitis pigmentosa; IDDRP, PPP2R1A-related intellectual disability, intellectual disability, autosomal dominant, X-linked intellectual disability, intellectual disability, autosomal recessive, NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability, SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth, intellectual developmental disorder with polymicrogyria and seizures

Subtypes (3): autosomal dominant non-syndromic intellectual disability, non-syndromic X-linked intellectual disability, autosomal recessive non-syndromic intellectual disability

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

9 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 not provided, 1 no classifications from unflagged records, 1 pathogenic, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
585059	NM_000827.4(GRIA1):c.2234G>A (p.Gly745Asp)	GRIA1	Pathogenic/Likely pathogenic	no assertion criteria provided
1803059	NM_001040142.2(SCN2A):c.183_184insA (p.Leu62fs)	SCN2A	Pathogenic	criteria provided, single submitter
431152	NM_001032221.6(STXBP1):c.1706C>T (p.Ser569Phe)	MIR3911	Likely pathogenic	criteria provided, single submitter
3773780	NM_031407.7(HUWE1):c.4885A>G (p.Ser1629Gly)	HUWE1	Uncertain significance	criteria provided, single submitter
1803049	NM_001382637.1(OTUD7A):c.1251G>A (p.Trp417Ter)	OTUD7A	no classifications from unflagged records	no classifications from unflagged records
2444809	NM_001040142.2(SCN2A):c.208C>G (p.Pro70Ala)	SCN2A	Uncertain significance	criteria provided, single submitter
3773796	NM_006662.3(SRCAP):c.3710A>G (p.Asn1237Ser)	SRCAP	Uncertain significance	criteria provided, single submitter
2505111	NM_001040142.2(SCN2A):c.3671_3674dup (p.Ala1226fs)	SCN2A	not provided	no classification provided
1345027	NM_001080517.3(SETD5):c.2305del (p.Arg769fs)	SETD5	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 16 · 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
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome
SRCAP	Orphanet:2044	Floating-Harbor syndrome
SRCAP	Orphanet:528084	Non-specific syndromic intellectual disability
SETD5	Orphanet:435638	3p25.3 microdeletion syndrome
SETD5	Orphanet:528084	Non-specific syndromic intellectual disability
HUWE1	Orphanet:528084	Non-specific syndromic intellectual disability
GRIA1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
GRIA1	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability

Cohort genes → proteins

8 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRSS12	HGNC:9477	ENSG00000164099	P56730	Neurotrypsin	gencc
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	clinvar
SRCAP	HGNC:16974	ENSG00000080603	Q6ZRS2	Chromatin remodeling protein SRCAP	clinvar
OTUD7A	HGNC:20718	ENSG00000169918	Q8TE49	OTU domain-containing protein 7A	clinvar
SETD5	HGNC:25566	ENSG00000168137	Q9C0A6	Histone-lysine N-methyltransferase SETD5	clinvar
HUWE1	HGNC:30892	ENSG00000086758	Q7Z6Z7	E3 ubiquitin-protein ligase HUWE1	clinvar
MIR3911	HGNC:38962	ENSG00000283874		microRNA 3911	clinvar
GRIA1	HGNC:4571	ENSG00000155511	P42261	Glutamate receptor 1	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.
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
SRCAP	Chromatin remodeling protein SRCAP	Acts both as a chromatin remodeler and transcription coregulator.
OTUD7A	OTU domain-containing protein 7A	Deubiquitinase, which cleaves ‘Lys-11’-linked polyubiquitin chains.
SETD5	Histone-lysine N-methyltransferase SETD5	Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission.
HUWE1	E3 ubiquitin-protein ligase HUWE1	E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins.
GRIA1	Glutamate receptor 1	Ionotropic glutamate receptor that functions as a ligand-gated cation channel, gated by L-glutamate and glutamatergic agonists such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), quisqualic acid, and kainic acid.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.38

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
Ion channel	1	13.9×	0.348
Protease	1	4.6×	0.497
Enzyme (other)	1	1.5×	0.755
Transcription factor	1	1.0×	0.755
Other/Unknown	4	0.9×	0.755

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRSS12	Protease	yes		Kringle, SRCR, Trypsin_dom
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SRCAP	Other/Unknown	no		SNF2_N, Helicase_C-like, Helicase_ATP-bd
OTUD7A	Transcription factor	no		Znf_A20, OTU_dom, OTU_Deubiquitinase
SETD5	Other/Unknown	no		SET_dom, SETD5_SET, SET_dom_sf
HUWE1	Enzyme (other)	yes	2.3.2.26	HECT_dom, WWE_dom, UBA-like_sf
MIR3911	Other/Unknown	no
GRIA1	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt

Expression context

Cohort genes with no expression data: 0.

5 cohort genes 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	3
stromal cell of endometrium	2
Brodmann (1909) area 23	2
middle temporal gyrus	2
bronchial epithelial cell	1
epithelium of bronchus	1
cerebellar vermis	1
granulocyte	1
endothelial cell	1
adrenal tissue	1
colonic epithelium	1
right lobe of thyroid gland	1
skin of abdomen	1
skin of leg	1
myometrium	1
subcutaneous adipose tissue	1
CA1 field of hippocampus	1
cortical plate	1
cranial nerve II	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
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
SRCAP	167	ubiquitous	yes	sural nerve, stromal cell of endometrium, granulocyte
OTUD7A	178	broad	yes	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
SETD5	284	ubiquitous	marker	adrenal tissue, colonic epithelium, sural nerve
HUWE1	300	ubiquitous	marker	skin of leg, skin of abdomen, right lobe of thyroid gland
MIR3911	50		yes	sural nerve, subcutaneous adipose tissue, myometrium
GRIA1	194	broad	marker	CA1 field of hippocampus, cortical plate, cranial nerve II

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HUWE1	5,793
GRIA1	3,443
SRCAP	2,987
SCN2A	2,810
SETD5	1,865
OTUD7A	1,098
PRSS12	921
MIR3911	0

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HUWE1	Q7Z6Z7	19
SRCAP	Q6ZRS2	10
SCN2A	Q99250	5
OTUD7A	Q8TE49	1
GRIA1	P42261	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRSS12	P56730	77.42
SETD5	Q9C0A6	47.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 8 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Activation of AMPA receptors	1	713.8×	0.026	GRIA1
Trafficking of GluR2-containing AMPA receptors	1	167.9×	0.026	GRIA1
Trafficking of AMPA receptors	1	135.9×	0.026	GRIA1
Unblocking of NMDA receptors, glutamate binding and activation	1	135.9×	0.026	GRIA1
Synaptic adhesion-like molecules	1	135.9×	0.026	GRIA1
Long-term potentiation	1	119.0×	0.026	GRIA1
Interaction between L1 and Ankyrins	1	92.1×	0.026	SCN2A
Phase 0 - rapid depolarisation	1	86.5×	0.026	SCN2A
Cargo concentration in the ER	1	84.0×	0.026	GRIA1
Sensory perception of taste	1	84.0×	0.026	SCN2A
Ovarian tumor domain proteases	1	69.6×	0.026	OTUD7A
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	69.6×	0.026	SCN2A
COPII-mediated vesicle transport	1	40.8×	0.041	GRIA1
L1CAM interactions	1	30.1×	0.052	SCN2A
Cardiac conduction	1	27.2×	0.053	SCN2A
Sensory Perception	1	23.8×	0.057	SCN2A
Muscle contraction	1	19.3×	0.066	SCN2A
Axon guidance	1	11.3×	0.104	SCN2A
Nervous system development	1	10.7×	0.104	SCN2A
Antigen processing: Ubiquitination & Proteasome degradation	1	9.3×	0.114	HUWE1
Neutrophil degranulation	1	5.8×	0.170	HUWE1
Developmental Biology	1	3.6×	0.249	SCN2A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
neuronal action potential	2	137.6×	0.007	SCN2A, GRIA1
intrinsic apoptotic signaling pathway in response to osmotic stress	1	1203.7×	0.013	SCN2A
response to lithium ion	1	1203.7×	0.013	GRIA1
positive regulation of locomotion involved in locomotory behavior	1	1203.7×	0.013	GRIA1
cellular response to amine stimulus	1	802.5×	0.013	GRIA1
response to sucrose	1	481.5×	0.013	GRIA1
negative regulation of transcription by RNA polymerase III	1	481.5×	0.013	SETD5
cellular response to ammonium ion	1	481.5×	0.013	GRIA1
cellular response to dsRNA	1	481.5×	0.013	GRIA1
response to psychosocial stress	1	481.5×	0.013	GRIA1
regulation of receptor recycling	1	401.2×	0.013	GRIA1
regulation of DNA-templated transcription elongation	1	401.2×	0.013	SETD5
negative regulation of peroxisome proliferator activated receptor signaling pathway	1	401.2×	0.013	HUWE1
positive regulation of membrane potential	1	401.2×	0.013	GRIA1
response to fungicide	1	401.2×	0.013	GRIA1
negative regulation of mitochondrial fusion	1	300.9×	0.016	HUWE1
cellular response to brain-derived neurotrophic factor stimulus	1	267.5×	0.016	GRIA1
cellular response to L-glutamate	1	240.7×	0.016	GRIA1
conditioned place preference	1	240.7×	0.016	GRIA1
protein K11-linked deubiquitination	1	218.9×	0.016	OTUD7A
regulation of chromatin organization	1	218.9×	0.016	SETD5
positive regulation of type 2 mitophagy	1	218.9×	0.016	HUWE1
cAMP/PKA signal transduction	1	200.6×	0.017	SRCAP
protein deubiquitination involved in ubiquitin-dependent protein catabolic process	1	185.2×	0.018	OTUD7A
response to morphine	1	172.0×	0.018	GRIA1
response to arsenic-containing substance	1	172.0×	0.018	GRIA1
behavioral response to pain	1	126.7×	0.022	GRIA1
long-term synaptic depression	1	126.7×	0.022	GRIA1
cellular response to peptide hormone stimulus	1	120.4×	0.022	GRIA1
protein branched polyubiquitination	1	120.4×	0.022	HUWE1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 6

Druggability breadth: 4 of 8 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SCN2A	BEPRIDIL
GRIA1	PERAMPANEL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
GRIA1	6	4
PRSS12	0	0
SRCAP	0	0
OTUD7A	0	0
SETD5	0	0
HUWE1	0	0
MIR3911	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
GRIA1	168	Binding:127, Functional:39, ADMET:2
HUWE1	4	Binding:3, Functional:1
PRSS12	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HUWE1	2.3.2.26	HECT-type E3 ubiquitin transferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SCN2A	203
GRIA1	168

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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.

Compound	Max phase	Cohort target (bioactivity)
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SCN2A, GRIA1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HUWE1
D	Druggable family + AlphaFold only, no drug	1	PRSS12
E	Difficult family or no structure, no drug	4	SRCAP, OTUD7A, SETD5, MIR3911

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRSS12	1	—
SRCAP	0	—
OTUD7A	0	—
SETD5	0	—
HUWE1	4	—
MIR3911	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.