Intellectual disability, autosomal recessive 5

Summary

Intellectual disability, autosomal recessive 5 (MONDO:0012613) is a disease caused by NSUN2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: NSUN2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 111

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal recessive 5
Mondo ID	MONDO:0012613
MeSH	C567018
OMIM	611091
DOID	DOID:0081181
UMLS	C1970199
MedGen	370849
GARD	0022541
Is cancer (heuristic)	no

Also known as: autosomal recessive non-syndromic intellectual disability caused by mutation in NSUN2 · intellectual disability, autosomal recessive 5 · intellectual disability, autosomal recessive type 5 · mental retardation, autosomal recessive 5 · mental retardation, autosomal recessive type 5 · MRT5 · NSUN2 autosomal recessive non-syndromic intellectual disability

Data availability: 111 ClinVar variants · 4 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 5

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 2, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, 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

111 retrieved; paginated sample, class counts are floors:

51 uncertain significance, 13 benign, 12 conflicting classifications of pathogenicity, 11 likely pathogenic, 10 pathogenic, 8 benign/likely benign, 4 pathogenic/likely pathogenic, 1 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030591	NM_017755.6(NSUN2):c.1165C>T (p.Arg389Ter)	NSUN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1690829	NM_017755.6(NSUN2):c.1222C>T (p.Arg408Ter)	NSUN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722540	NM_017755.6(NSUN2):c.953A>C (p.Tyr318Ser)	NSUN2	Pathogenic	no assertion criteria provided
1722581	NM_017755.6(NSUN2):c.97-1G>C	NSUN2	Pathogenic	no assertion criteria provided
31675	NM_017755.6(NSUN2):c.679C>T (p.Gln227Ter)	NSUN2	Pathogenic	criteria provided, single submitter
31676	NM_017755.6(NSUN2):c.1114C>T (p.Gln372Ter)	NSUN2	Pathogenic	no assertion criteria provided
31677	NM_017755.6(NSUN2):c.538-11T>G	NSUN2	Pathogenic	no assertion criteria provided
37005	NM_017755.6(NSUN2):c.538-1G>C	NSUN2	Pathogenic	no assertion criteria provided
4080641	NM_017755.6(NSUN2):c.1478del (p.Asn493fs)	NSUN2	Pathogenic	criteria provided, multiple submitters, no conflicts
4531997	NM_017755.6(NSUN2):c.69del (p.Glu24fs)	NSUN2	Pathogenic	criteria provided, single submitter
828097	NM_017755.6(NSUN2):c.1020del (p.Gly341fs)	NSUN2	Pathogenic	criteria provided, multiple submitters, no conflicts
834323	NM_017755.6(NSUN2):c.1725_1728del (p.Ser575fs)	NSUN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
946605	NM_017755.6(NSUN2):c.62_65dup (p.Ala23fs)	NSUN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430834	NM_006772.3(SYNGAP1):c.403C>T (p.Arg135Ter)	SYNGAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1184813	NM_017755.6(NSUN2):c.1903A>G (p.Asn635Asp)	NSUN2	Likely pathogenic	no assertion criteria provided
1705284	NM_017755.6(NSUN2):c.1566del (p.Phe522fs)	NSUN2	Likely pathogenic	criteria provided, single submitter
2499572	NM_017755.6(NSUN2):c.962_964delinsTTA (p.Cys321_Ser322delinsPheThr)	NSUN2	Likely pathogenic	criteria provided, single submitter
2690657	NM_017755.6(NSUN2):c.1198_1201dup (p.Leu401fs)	NSUN2	Likely pathogenic	criteria provided, single submitter
31678	NM_017755.6(NSUN2):c.2035G>A (p.Gly679Arg)	NSUN2	Likely pathogenic	criteria provided, single submitter
3341387	NM_017755.6(NSUN2):c.1914dup (p.Arg639Ter)	NSUN2	Likely pathogenic	criteria provided, single submitter
3341453	NM_017755.6(NSUN2):c.569dup (p.Thr191fs)	NSUN2	Likely pathogenic	criteria provided, single submitter
3592742	NM_017755.6(NSUN2):c.37C>T (p.Gln13Ter)	NSUN2	Likely pathogenic	criteria provided, single submitter
4796510	NM_017755.6(NSUN2):c.947del (p.Met316fs)	NSUN2	Likely pathogenic	criteria provided, single submitter
800516	NM_017755.6(NSUN2):c.839dup (p.Asn280fs)	NSUN2	Likely pathogenic	criteria provided, single submitter
804451	NM_017755.6(NSUN2):c.430_431del (p.Lys144fs)	NSUN2	Likely pathogenic	criteria provided, single submitter
211757	NM_017755.6(NSUN2):c.2143G>A (p.Val715Ile)	NSUN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211761	NM_017755.6(NSUN2):c.2300G>A (p.Arg767Gln)	NSUN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
354047	NM_017755.6(NSUN2):c.2283G>A (p.Ala761=)	NSUN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
354048	NM_017755.6(NSUN2):c.2188A>G (p.Asn730Asp)	NSUN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
354049	NM_017755.6(NSUN2):c.2060G>A (p.Arg687Gln)	NSUN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 5 · 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
NSUN2	Strong	Autosomal recessive	intellectual disability, autosomal recessive 5	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NSUN2	Orphanet:235	Dubowitz syndrome
NSUN2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
SYNGAP1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SYNGAP1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SYNGAP1	Orphanet:544254	SYNGAP1-related developmental and epileptic encephalopathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NSUN2	HGNC:25994	ENSG00000037474	Q08J23	RNA cytosine C(5)-methyltransferase NSUN2	gencc,clinvar
SYNGAP1	HGNC:11497	ENSG00000197283	Q96PV0	Ras/Rap GTPase-activating protein SynGAP	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NSUN2	RNA cytosine C(5)-methyltransferase NSUN2	RNA cytosine C(5)-methyltransferase that methylates cytosine to 5-methylcytosine (m5C) in various RNAs, such as tRNAs, mRNAs and some long non-coding RNAs (lncRNAs).
SYNGAP1	Ras/Rap GTPase-activating protein SynGAP	Major constituent of the PSD essential for postsynaptic signaling.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Scaffold/PPI	1	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NSUN2	Enzyme (other)	yes	2.1.1.202	MeTrfase_RsmB-F_NOP2_dom, RCMT, RCMT_NCL1
SYNGAP1	Scaffold/PPI	no		C2_dom, PH_domain, RasGAP_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	2
secondary oocyte	1
upper arm skin	1
adenohypophysis	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NSUN2	260	ubiquitous	marker	upper arm skin, right uterine tube, secondary oocyte
SYNGAP1	137	ubiquitous	marker	pituitary gland, right uterine tube, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NSUN2	3,213
SYNGAP1	2,175

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NSUN2	Q08J23	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SYNGAP1	Q96PV0	60.43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
tRNA modification in the nucleus and cytosol	1	146.4×	0.029	NSUN2
Regulation of RAS by GAPs	1	96.8×	0.029	SYNGAP1
MAPK1/MAPK3 signaling	1	65.6×	0.029	SYNGAP1
MAPK family signaling cascades	1	51.4×	0.029	SYNGAP1
RAF/MAP kinase cascade	1	30.5×	0.039	SYNGAP1
Signal Transduction	1	5.1×	0.187	SYNGAP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
meiotic cell cycle checkpoint signaling	1	8426.0×	0.003	NSUN2
maintenance of postsynaptic specialization structure	1	2808.7×	0.004	SYNGAP1
tRNA stabilization	1	2106.5×	0.004	NSUN2
regulation of synapse structure or activity	1	1404.3×	0.004	SYNGAP1
regulation of mRNA export from nucleus	1	1053.2×	0.004	NSUN2
hair follicle maturation	1	1053.2×	0.004	NSUN2
negative regulation of axonogenesis	1	648.1×	0.006	SYNGAP1
regulation of long-term neuronal synaptic plasticity	1	495.6×	0.007	SYNGAP1
regulation of intracellular signal transduction	1	443.5×	0.007	SYNGAP1
regulation of stem cell differentiation	1	383.0×	0.007	NSUN2
negative regulation of Ras protein signal transduction	1	337.0×	0.007	SYNGAP1
receptor clustering	1	312.1×	0.007	SYNGAP1
tRNA modification	1	300.9×	0.007	NSUN2
tRNA methylation	1	290.6×	0.007	NSUN2
pattern specification process	1	234.1×	0.007	SYNGAP1
regulation of MAPK cascade	1	227.7×	0.007	SYNGAP1
dendrite development	1	195.9×	0.008	SYNGAP1
visual learning	1	153.2×	0.010	SYNGAP1
regulation of synaptic plasticity	1	129.6×	0.011	SYNGAP1
Ras protein signal transduction	1	102.8×	0.013	SYNGAP1
neuron apoptotic process	1	92.6×	0.014	SYNGAP1
axonogenesis	1	80.2×	0.015	SYNGAP1
spermatid development	1	72.6×	0.016	NSUN2
negative regulation of neuron apoptotic process	1	55.4×	0.020	SYNGAP1
mRNA processing	1	39.4×	0.027	NSUN2
in utero embryonic development	1	36.0×	0.029	NSUN2
cell division	1	23.1×	0.043	NSUN2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NSUN2	1	2
SYNGAP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	NSUN2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NSUN2	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NSUN2	2.1.1.202, 2.1.1.203	multisite-specific tRNA:(cytosine-C5)-methyltransferase, tRNA (cytosine34-C5)-methyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	NSUN2

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	1	NSUN2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SYNGAP1

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)
SYNGAP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.