Intellectual disability, autosomal dominant 6

Summary

Intellectual disability, autosomal dominant 6 (MONDO:0013509) is a disease caused by GRIN2B (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GRIN2B (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,368

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		98	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 6
Mondo ID	MONDO:0013509
OMIM	613970
Orphanet	589547
DOID	DOID:0070036
UMLS	C3151411
MedGen	462761
GARD	0012851
Is cancer (heuristic)	no

Also known as: autosomal dominant non-syndromic intellectual disability caused by mutation in GRIN2B · GRIN2B autosomal dominant non-syndromic intellectual disability · GRIN2B encephalopathy · GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder · GRIN2B-related neurodevelopmental disorder · intellectual developmental disorder, autosomal dominant 6, with or without seizures · intellectual disability, autosomal dominant 6 · intellectual disability, autosomal dominant type 6 · mental retardation, autosomal dominant 6 · mental retardation, autosomal dominant 6, with or without seizures · mental retardation, autosomal dominant type 6 · MRD6

Data availability: 1,368 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › intellectual disability, autosomal dominant › intellectual disability, autosomal dominant 6

Related subtypes (28): intellectual disability, autosomal dominant 1, intellectual disability, autosomal dominant 3, intellectual disability, autosomal dominant 4, intellectual disability, autosomal dominant 5, intellectual disability, autosomal dominant 2, neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, intellectual disability, autosomal dominant 9, intellectual disability, autosomal dominant 10, intellectual disability, autosomal dominant 11, intellectual disability, autosomal dominant 24, intellectual disability, autosomal dominant 38, intellectual disability, autosomal dominant 39, intellectual disability, autosomal dominant 40, intellectual disability, autosomal dominant 42, autosomal dominant non-syndromic intellectual disability, intellectual developmental disorder, autosomal dominant 65, intellectual developmental disorder, autosomal dominant 69, intellectual developmental disorder, autosomal dominant 66, intellectual developmental disorder, autosomal dominant 64, intellectual developmental disorder, autosomal dominant 67, intellectual developmental disorder, autosomal dominant 68, autosomal dominant syndromic intellectual disability, intellectual developmental disorder, autosomal dominant 70, intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities, intellectual developmental disorder, autosomal dominant 72, intellectual developmental disorder, autosomal dominant 74, intellectual developmental disorder, autosomal dominant 75, intellectual developmental disorder, autosomal dominant 76

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

600 retrieved; paginated sample, class counts are floors:

259 likely benign, 137 uncertain significance, 60 benign, 56 conflicting classifications of pathogenicity, 28 benign/likely benign, 23 likely pathogenic, 20 pathogenic, 17 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1164046	NM_000834.5(GRIN2B):c.1928T>C (p.Leu643Pro)	GRIN2B	Pathogenic	criteria provided, multiple submitters, no conflicts
1299652	NM_000834.5(GRIN2B):c.1606G>A (p.Val536Ile)	GRIN2B	Pathogenic	criteria provided, single submitter
1364424	NC_000012.11:g.(?13906231)(13906869_?)del	GRIN2B	Pathogenic	criteria provided, single submitter
1401421	NM_000834.5(GRIN2B):c.2150C>T (p.Ala717Val)	GRIN2B	Pathogenic	criteria provided, single submitter
1408815	NM_000834.5(GRIN2B):c.2410G>A (p.Glu804Lys)	GRIN2B	Pathogenic	criteria provided, single submitter
1421943	NM_000834.5(GRIN2B):c.3789_3837dup (p.Lys1280delinsGlyProAlaGlyCysProSerGlyGlyAspValLysArgLeuHisHisTer)	GRIN2B	Pathogenic	criteria provided, single submitter
143189	NM_000834.5(GRIN2B):c.1238A>G (p.Glu413Gly)	GRIN2B	Pathogenic	criteria provided, single submitter
1458907	NM_000834.5(GRIN2B):c.1628G>A (p.Gly543Glu)	GRIN2B	Pathogenic	criteria provided, single submitter
1467695	NM_000834.5(GRIN2B):c.2056G>A (p.Val686Met)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162087	NM_000834.5(GRIN2B):c.1619G>A (p.Arg540His)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685342	NM_000834.5(GRIN2B):c.2216T>C (p.Met739Thr)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685866	NM_000834.5(GRIN2B):c.2402G>A (p.Cys801Tyr)	GRIN2B	Pathogenic	criteria provided, single submitter
1685867	NM_000834.5(GRIN2B):c.2192A>G (p.Tyr731Cys)	GRIN2B	Pathogenic	criteria provided, single submitter
1685868	NM_000834.5(GRIN2B):c.2072C>G (p.Thr691Arg)	GRIN2B	Pathogenic	criteria provided, single submitter
1685869	NM_000834.5(GRIN2B):c.1849T>A (p.Ser617Thr)	GRIN2B	Pathogenic	criteria provided, single submitter
1685870	NM_000834.5(GRIN2B):c.1477_1499dup (p.Glu500_Val501insProGlyMetValTer)	GRIN2B	Pathogenic	criteria provided, single submitter
1687537	NM_000834.5(GRIN2B):c.3912C>G (p.Tyr1304Ter)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1696671	NM_000834.5(GRIN2B):c.2117T>A (p.Met706Lys)	GRIN2B	Pathogenic	criteria provided, single submitter
1800708	NM_000834.5(GRIN2B):c.1931C>A (p.Ala644Asp)	GRIN2B	Pathogenic	criteria provided, multiple submitters, no conflicts
1803124	NM_000834.5(GRIN2B):c.3937_3940del (p.Glu1313fs)	GRIN2B	Pathogenic	criteria provided, single submitter
1805847	NM_000834.5(GRIN2B):c.1844A>G (p.Asn615Ser)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
205730	NM_000834.5(GRIN2B):c.1832G>T (p.Gly611Val)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208643	NM_000834.5(GRIN2B):c.2459G>C (p.Gly820Ala)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208749	NM_000834.5(GRIN2B):c.1916C>T (p.Ala639Val)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2118872	NM_000834.5(GRIN2B):c.1623C>A (p.Ser541Arg)	GRIN2B	Pathogenic	criteria provided, multiple submitters, no conflicts
2133232	NM_000834.5(GRIN2B):c.1011-1G>C	GRIN2B	Pathogenic	criteria provided, single submitter
218471	NM_000834.5(GRIN2B):c.2430C>A (p.Ser810Arg)	GRIN2B	Pathogenic	criteria provided, multiple submitters, no conflicts
224818	NM_000834.5(GRIN2B):c.2065G>A (p.Gly689Ser)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
234479	NM_000834.5(GRIN2B):c.1970A>G (p.Glu657Gly)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
234500	NM_000834.5(GRIN2B):c.2252T>C (p.Ile751Thr)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
GRIN2B	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 6	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRIN2B	Orphanet:589547	GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder
GRIN2B	Orphanet:697160	Infantile epileptic spasms syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GRIN2B	HGNC:4586	ENSG00000273079	Q13224	Glutamate receptor ionotropic, NMDA 2B	gencc,clinvar
HEBP1	HGNC:17176	ENSG00000013583	Q9NRV9	Heme-binding protein 1	clinvar
DDX47	HGNC:18682	ENSG00000213782	Q9H0S4	Probable ATP-dependent RNA helicase DDX47	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRIN2B	Glutamate receptor ionotropic, NMDA 2B	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).
HEBP1	Heme-binding protein 1	May bind free porphyrinogens that may be present in the cell and thus facilitate removal of these potentially toxic compound.
DDX47	Probable ATP-dependent RNA helicase DDX47	Required for efficient ribosome biogenesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GRIN2B	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
HEBP1	Other/Unknown	no		SOUL_heme-bd, Reg_factor_effector_dom_sf
DDX47	Other/Unknown	no		RNA-helicase_DEAD-box_CS, Helicase_C-like, DEAD/DEAH_box_helicase_dom

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
buccal mucosa cell	1
cortical plate	1
duodenum	1
ileal mucosa	1
jejunal mucosa	1
islet of Langerhans	1
smooth muscle tissue	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRIN2B	138	broad	marker	buccal mucosa cell, cortical plate, Brodmann (1909) area 23
HEBP1	287	ubiquitous	marker	jejunal mucosa, duodenum, ileal mucosa
DDX47	134	ubiquitous	marker	islet of Langerhans, ventricular zone, smooth muscle tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DDX47	4,190
GRIN2B	3,611
HEBP1	446

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRIN2B	Q13224	36
DDX47	Q9H0S4	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HEBP1	Q9NRV9	84.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Activated NTRK2 signals through FYN	1	634.4×	0.012	GRIN2B
Formyl peptide receptors bind formyl peptides and many other ligands	1	475.8×	0.012	HEBP1
MECP2 regulates neuronal receptors and channels	1	200.3×	0.012	GRIN2B
Ras activation upon Ca2+ influx through NMDA receptor	1	190.3×	0.012	GRIN2B
Unblocking of NMDA receptors, glutamate binding and activation	1	181.3×	0.012	GRIN2B
Synaptic adhesion-like molecules	1	181.3×	0.012	GRIN2B
Negative regulation of NMDA receptor-mediated neuronal transmission	1	181.3×	0.012	GRIN2B
Long-term potentiation	1	158.6×	0.012	GRIN2B
EPHB-mediated forward signaling	1	88.5×	0.018	GRIN2B
Assembly and cell surface presentation of NMDA receptors	1	84.6×	0.018	GRIN2B
Neurexins and neuroligins	1	65.6×	0.020	GRIN2B
rRNA modification in the nucleus and cytosol	1	62.4×	0.020	DDX47
Major pathway of rRNA processing in the nucleolus and cytosol	1	20.6×	0.052	DDX47
RAF/MAP kinase cascade	1	20.4×	0.052	GRIN2B
G alpha (i) signalling events	1	13.0×	0.075	HEBP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of dendritic spine maintenance	1	936.2×	0.011	GRIN2B
regulation of monoatomic cation transmembrane transport	1	702.2×	0.011	GRIN2B
calcium ion transmembrane import into cytosol	1	510.7×	0.011	GRIN2B
ionotropic glutamate receptor signaling pathway	1	432.1×	0.011	GRIN2B
excitatory chemical synaptic transmission	1	432.1×	0.011	GRIN2B
protein heterotetramerization	1	351.1×	0.011	GRIN2B
glutamate receptor signaling pathway	1	312.1×	0.011	GRIN2B
regulation of neuronal synaptic plasticity	1	224.7×	0.012	GRIN2B
positive regulation of synaptic transmission, glutamatergic	1	208.1×	0.012	GRIN2B
monoatomic cation transmembrane transport	1	208.1×	0.012	GRIN2B
positive regulation of excitatory postsynaptic potential	1	175.5×	0.012	GRIN2B
excitatory postsynaptic potential	1	147.8×	0.013	GRIN2B
extrinsic apoptotic signaling pathway via death domain receptors	1	133.8×	0.014	DDX47
synaptic transmission, glutamatergic	1	119.5×	0.014	GRIN2B
long-term synaptic potentiation	1	93.6×	0.017	GRIN2B
regulation of synaptic plasticity	1	86.4×	0.017	GRIN2B
circadian rhythm	1	81.4×	0.017	HEBP1
learning or memory	1	80.2×	0.017	GRIN2B
response to ethanol	1	48.9×	0.025	GRIN2B
rRNA processing	1	47.2×	0.025	DDX47
RNA splicing	1	29.4×	0.038	DDX47
brain development	1	26.5×	0.038	GRIN2B
mRNA processing	1	26.2×	0.038	DDX47
chemical synaptic transmission	1	25.8×	0.038	GRIN2B

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
GRIN2B	HALOPERIDOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GRIN2B	35	4
HEBP1	0	0
DDX47	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
HALOPERIDOL	4	GRIN2B
DEXTROMETHORPHAN	4	GRIN2B
KETAMINE	4	GRIN2B
CYCLOSERINE	4	GRIN2B
MEMANTINE	4	GRIN2B
TACRINE	4	GRIN2B
LEVORPHANOL	4	GRIN2B
AMANTADINE	4	GRIN2B
CHLORPROMAZINE	4	GRIN2B
PROCYCLIDINE	4	GRIN2B
ORPHENADRINE	4	GRIN2B
DALZANEMDOR	3	GRIN2B
LATREPIRDINE	3	GRIN2B
ESMETHADONE	3	GRIN2B
GLUTAMIC ACID	3	GRIN2B
TRAXOPRODIL	2	GRIN2B
ELIPRODIL	2	GRIN2B
IFENPRODIL	2	GRIN2B
EVT-101 FREE BASE	2	GRIN2B
ZELQUISTINEL	2	GRIN2B
DEXTRORPHAN	2	GRIN2B
LEVOMETHADONE	2	GRIN2B
ALPHAMETHADOL	2	GRIN2B
RADIPRODIL	2	GRIN2B
PHENCYCLIDINE	2	GRIN2B
DIZOCILPINE	2	GRIN2B
ONFASPRODIL	2	GRIN2B
TEZAMPANEL ANHYDROUS	2	GRIN2B
RACEMETHORPHAN	2	GRIN2B
LICOSTINEL	2	GRIN2B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GRIN2B	471	Binding:429, Functional:36, ADMET:5, Toxicity:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GRIN2B	471

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
HALOPERIDOL	4	GRIN2B
DEXTROMETHORPHAN	4	GRIN2B
KETAMINE	4	GRIN2B
CYCLOSERINE	4	GRIN2B
MEMANTINE	4	GRIN2B
TACRINE	4	GRIN2B
LEVORPHANOL	4	GRIN2B
AMANTADINE	4	GRIN2B
CHLORPROMAZINE	4	GRIN2B
PROCYCLIDINE	4	GRIN2B
ORPHENADRINE	4	GRIN2B
DALZANEMDOR	3	GRIN2B
LATREPIRDINE	3	GRIN2B
ESMETHADONE	3	GRIN2B
GLUTAMIC ACID	3	GRIN2B
TRAXOPRODIL	2	GRIN2B
ELIPRODIL	2	GRIN2B
IFENPRODIL	2	GRIN2B
EVT-101 FREE BASE	2	GRIN2B
ZELQUISTINEL	2	GRIN2B
DEXTRORPHAN	2	GRIN2B
LEVOMETHADONE	2	GRIN2B
ALPHAMETHADOL	2	GRIN2B
RADIPRODIL	2	GRIN2B
PHENCYCLIDINE	2	GRIN2B
DIZOCILPINE	2	GRIN2B
ONFASPRODIL	2	GRIN2B
TEZAMPANEL ANHYDROUS	2	GRIN2B
RACEMETHORPHAN	2	GRIN2B
LICOSTINEL	2	GRIN2B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GRIN2B
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	HEBP1, DDX47

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HEBP1	0	—
DDX47	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.