Intellectual disability, autosomal dominant 53

Summary

Intellectual disability, autosomal dominant 53 (MONDO:0030919) is a disease caused by CAMK2A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CAMK2A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 41

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 53
Mondo ID	MONDO:0030919
EFO	EFO:0009165
OMIM	617798
DOID	DOID:0080228
UMLS	C4540481
MedGen	1623344
GARD	0016473
Is cancer (heuristic)	no

Also known as: autosomal dominant mental retardation 53 · intellectual disability, autosomal dominant 53 · mental retardation, autosomal dominant 53 · MRD53

Data availability: 41 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 dominant non-syndromic intellectual disability › intellectual disability, autosomal dominant 53

Related subtypes (25): intellectual disability, autosomal dominant 22, neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language, intellectual disability, autosomal dominant 33, intellectual disability, autosomal dominant 34, intellectual disability, autosomal dominant 41, intellectual disability, autosomal dominant 43, intellectual disability, autosomal dominant 58, intellectual disability, autosomal dominant 45, intellectual disability, autosomal dominant 46, intellectual disability, autosomal dominant 47, Clark-Baraitser syndrome, intellectual disability, autosomal dominant 50, intellectual disability, autosomal dominant 51, intellectual disability, autosomal dominant 52, intellectual disability, autosomal dominant 54, intellectual disability, autosomal dominant 55, with seizures, intellectual disability, autosomal dominant 56, intellectual developmental disorder 61, intellectual developmental disorder 59, intellectual developmental disorder 60 with seizures, intellectual developmental disorder 62, intellectual developmental disorder, autosomal dominant 63, with macrocephaly, Coffin-Siris syndrome 6, intellectual disability, autosomal dominant 57, intellectual developmental disorder, autosomal dominant 73

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

41 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 10 pathogenic, 7 likely pathogenic, 6 conflicting classifications of pathogenicity, 5 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1804079	NM_015981.4(CAMK2A):c.666C>A (p.Tyr222Ter)	CAMK2A	Pathogenic	criteria provided, single submitter
2920686	NM_015981.4(CAMK2A):c.775C>T (p.Arg259Cys)	CAMK2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430912	NM_015981.4(CAMK2A):c.293T>C (p.Phe98Ser)	CAMK2A	Pathogenic	no assertion criteria provided
430913	NM_015981.4(CAMK2A):c.327G>C (p.Glu109Asp)	CAMK2A	Pathogenic	no assertion criteria provided
430914	NM_015981.4(CAMK2A):c.548A>T (p.Glu183Val)	CAMK2A	Pathogenic	no assertion criteria provided
430916	NM_015981.4(CAMK2A):c.635C>T (p.Pro212Leu)	CAMK2A	Pathogenic	criteria provided, multiple submitters, no conflicts
430917	NM_015981.4(CAMK2A):c.845A>G (p.His282Arg)	CAMK2A	Pathogenic	no assertion criteria provided
430918	NM_015981.4(CAMK2A):c.856A>C (p.Thr286Pro)	CAMK2A	Pathogenic	no assertion criteria provided
560171	NM_015981.4(CAMK2A):c.635C>A (p.Pro212Gln)	CAMK2A	Pathogenic	no assertion criteria provided
560173	NM_015981.4(CAMK2A):c.817-1G>A	CAMK2A	Pathogenic	no assertion criteria provided
988756	NM_015981.4(CAMK2A):c.220C>T (p.Arg74Ter)	CAMK2A	Pathogenic	criteria provided, single submitter
1162321	NM_015981.4(CAMK2A):c.524G>C (p.Gly175Ala)	CAMK2A	Likely pathogenic	criteria provided, single submitter
1285567	NM_015981.4(CAMK2A):c.59G>A (p.Gly20Asp)	CAMK2A	Likely pathogenic	criteria provided, single submitter
1700224	NM_015981.4(CAMK2A):c.785_790del (p.Ala262_Ala263del)	CAMK2A	Likely pathogenic	criteria provided, single submitter
2442355	NM_015981.4(CAMK2A):c.415G>C (p.Glu139Gln)	CAMK2A	Likely pathogenic	criteria provided, single submitter
2442356	NM_015981.4(CAMK2A):c.755T>C (p.Leu252Pro)	CAMK2A	Likely pathogenic	criteria provided, single submitter
4814056	NM_015981.4(CAMK2A):c.325G>A (p.Glu109Lys)	CAMK2A	Likely pathogenic	criteria provided, single submitter
666572	NM_015981.4(CAMK2A):c.49G>A (p.Glu17Lys)	CAMK2A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709169	NM_015981.4(CAMK2A):c.82C>T (p.Arg28Ter)	CAMK2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803780	NM_015981.4(CAMK2A):c.884C>A (p.Ala295Asp)	CAMK2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218729	NM_015981.4(CAMK2A):c.704C>T (p.Pro235Leu)	CAMK2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2211805	NM_015981.4(CAMK2A):c.235A>G (p.Ile79Val)	CAMK2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3258078	NM_015981.4(CAMK2A):c.74C>T (p.Ser25Leu)	CAMK2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4526542	NM_015981.4(CAMK2A):c.310C>T (p.Arg104Trp)	CAMK2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1342475	NM_015981.4(CAMK2A):c.270C>T (p.Asp90=)	CAMK2A	Uncertain significance	criteria provided, single submitter
1420622	NM_015981.4(CAMK2A):c.1029G>C (p.Glu343Asp)	CAMK2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1696674	NM_015981.4(CAMK2A):c.712G>C (p.Asp238His)	CAMK2A	Uncertain significance	criteria provided, single submitter
1805031	NM_015981.4(CAMK2A):c.271C>T (p.Leu91=)	CAMK2A	Uncertain significance	criteria provided, single submitter
2506989	NM_015981.4(CAMK2A):c.1419G>A (p.Trp473Ter)	CAMK2A	Uncertain significance	criteria provided, single submitter
3251933	NM_015981.4(CAMK2A):c.545C>T (p.Pro182Leu)	CAMK2A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
CAMK2A	Strong	Autosomal dominant	intellectual disability, autosomal dominant 53	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CAMK2A	Orphanet:178469	Autosomal dominant 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
CAMK2A	HGNC:1460	ENSG00000070808	Q9UQM7	Calcium/calmodulin-dependent protein kinase type II subunit alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CAMK2A	Calcium/calmodulin-dependent protein kinase type II subunit alpha	Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in various processes, such as synaptic plasticity, neurotransmitter release and long-term pote…

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CAMK2A	Kinase	yes	2.7.11.17	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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
amygdala	1
prefrontal cortex	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CAMK2A	184	broad	marker	amygdala, prefrontal cortex, right frontal lobe

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CAMK2A	3,914

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CAMK2A	Q9UQM7	22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 63. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
CaMK IV-mediated phosphorylation of CREB	1	1142.0×	0.009	CAMK2A
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1	878.5×	0.009	CAMK2A
Glutamate binding, activation of AMPA receptors and synaptic plasticity	1	761.3×	0.009	CAMK2A
Ras activation upon Ca2+ influx through NMDA receptor	1	571.0×	0.009	CAMK2A
Trafficking of AMPA receptors	1	543.8×	0.009	CAMK2A
Unblocking of NMDA receptors, glutamate binding and activation	1	543.8×	0.009	CAMK2A
Negative regulation of NMDA receptor-mediated neuronal transmission	1	543.8×	0.009	CAMK2A
Long-term potentiation	1	475.8×	0.009	CAMK2A
Signaling by RAS mutants	1	423.0×	0.009	CAMK2A
Cellular response to heat stress	1	393.8×	0.009	CAMK2A
Calmodulin induced events	1	380.7×	0.009	CAMK2A
CaM pathway	1	380.7×	0.009	CAMK2A
Ca-dependent events	1	368.4×	0.009	CAMK2A
Regulation of MECP2 expression and activity	1	368.4×	0.009	CAMK2A
Phase 0 - rapid depolarisation	1	346.1×	0.009	CAMK2A
RAF activation	1	335.9×	0.009	CAMK2A
G-protein mediated events	1	326.3×	0.009	CAMK2A
DAG and IP3 signaling	1	317.2×	0.009	CAMK2A
HSF1-dependent transactivation	1	317.2×	0.009	CAMK2A
Transcriptional Regulation by MECP2	1	317.2×	0.009	CAMK2A
Beta-catenin independent WNT signaling	1	292.8×	0.009	CAMK2A
Signaling by RAF1 mutants	1	278.5×	0.009	CAMK2A
Opioid Signalling	1	265.6×	0.009	CAMK2A
PLC beta mediated events	1	265.6×	0.009	CAMK2A
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.009	CAMK2A
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.009	CAMK2A
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.009	CAMK2A
Signaling downstream of RAS mutants	1	253.8×	0.009	CAMK2A
Oncogenic MAPK signaling	1	248.3×	0.009	CAMK2A
Ion transport by P-type ATPases	1	207.6×	0.010	CAMK2A

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
peptidyl-threonine autophosphorylation	1	16852.0×	0.001	CAMK2A
negative regulation of hydrolase activity	1	8426.0×	0.001	CAMK2A
regulation of endocannabinoid signaling pathway	1	5617.3×	0.001	CAMK2A
regulation of mitochondrial membrane permeability involved in apoptotic process	1	2808.7×	0.002	CAMK2A
angiotensin-activated signaling pathway	1	1532.0×	0.003	CAMK2A
positive regulation of cardiac muscle cell apoptotic process	1	1203.7×	0.003	CAMK2A
dendritic spine development	1	1203.7×	0.003	CAMK2A
negative regulation of ferroptosis	1	802.5×	0.003	CAMK2A
regulation of neurotransmitter secretion	1	766.0×	0.003	CAMK2A
regulation of neuronal synaptic plasticity	1	674.1×	0.003	CAMK2A
regulation of protein localization to plasma membrane	1	648.1×	0.003	CAMK2A
regulation of neuron migration	1	624.1×	0.003	CAMK2A
positive regulation of calcium ion transport	1	581.1×	0.003	CAMK2A
cellular response to interferon-beta	1	526.6×	0.003	CAMK2A
positive regulation of receptor signaling pathway via JAK-STAT	1	432.1×	0.003	CAMK2A
long-term synaptic potentiation	1	280.9×	0.005	CAMK2A
response to ischemia	1	251.5×	0.005	CAMK2A
cellular response to type II interferon	1	208.1×	0.005	CAMK2A
obsolete positive regulation of NF-kappaB transcription factor activity	1	205.5×	0.005	CAMK2A
G1/S transition of mitotic cell cycle	1	200.6×	0.005	CAMK2A
calcium ion transport	1	181.2×	0.006	CAMK2A
protein phosphorylation	1	68.0×	0.015	CAMK2A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
CAMK2A	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CAMK2A	25	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	CAMK2A
OXYBATE	4	CAMK2A
RUXOLITINIB	4	CAMK2A
TOFACITINIB CITRATE	4	CAMK2A
TOFACITINIB	4	CAMK2A
BOSUTINIB	4	CAMK2A
NINTEDANIB	4	CAMK2A
SUNITINIB	4	CAMK2A
MIDOSTAURIN	4	CAMK2A
ENZASTAURIN	3	CAMK2A
CURCUMIN	3	CAMK2A
ALVOCIDIB	3	CAMK2A
LESTAURTINIB	3	CAMK2A
RUBOXISTAURIN	3	CAMK2A
CI-1040	2	CAMK2A
SU-014813	2	CAMK2A
CENISERTIB	2	CAMK2A
RG-547	2	CAMK2A
R-406	2	CAMK2A
BI-2536	2	CAMK2A
SOTRASTAURIN	2	CAMK2A
GSK-461364	1	CAMK2A
KW-2449	1	CAMK2A
AZD-1080	1	CAMK2A
CYC-116	1	CAMK2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CAMK2A	341	Binding:340, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CAMK2A	2.7.11.17	Ca2+/calmodulin-dependent protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CAMK2A	341

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

25 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)
FEDRATINIB	4	CAMK2A
OXYBATE	4	CAMK2A
RUXOLITINIB	4	CAMK2A
TOFACITINIB CITRATE	4	CAMK2A
TOFACITINIB	4	CAMK2A
BOSUTINIB	4	CAMK2A
NINTEDANIB	4	CAMK2A
SUNITINIB	4	CAMK2A
MIDOSTAURIN	4	CAMK2A
ENZASTAURIN	3	CAMK2A
CURCUMIN	3	CAMK2A
ALVOCIDIB	3	CAMK2A
LESTAURTINIB	3	CAMK2A
RUBOXISTAURIN	3	CAMK2A
CI-1040	2	CAMK2A
SU-014813	2	CAMK2A
CENISERTIB	2	CAMK2A
RG-547	2	CAMK2A
R-406	2	CAMK2A
BI-2536	2	CAMK2A
SOTRASTAURIN	2	CAMK2A
GSK-461364	1	CAMK2A
KW-2449	1	CAMK2A
AZD-1080	1	CAMK2A
CYC-116	1	CAMK2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CAMK2A
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.