CAMK2A

Chr 5ARAD

calcium/calmodulin dependent protein kinase II alpha

Also known as: CAMKA, CaMKIINalpha, CaMKIIalpha, MRD53, MRT63

NCBI Gene: 815 ENSG00000070808 UniProt: Q9UQM7 OMIM: 114078

CAMK2A encodes the alpha subunit of calcium/calmodulin-dependent protein kinase II, which is essential for hippocampal long-term potentiation and spatial learning through calcium-dependent and autophosphorylation-mediated signaling at glutamatergic synapses. Mutations cause intellectual developmental disorder that can be inherited in either autosomal dominant or autosomal recessive patterns. The protein's critical role in synaptic plasticity explains why loss-of-function mutations lead to cognitive impairment.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismAR/ADLOEUF 0.252 OMIM phenotypes

Clinical Summary— CAMK2A

🧬

Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.25LOEUF

pLI 0.998

Z-score 4.98

OE 0.11 (0.05–0.25)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

4.68Z-score

OE missense 0.24 (0.20–0.29)

72 obs / 299.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.11 (0.05–0.25)

0≤0.351.4

Missense OE0.24 (0.20–0.29)

0≤0.61.4

Synonymous OE0.91

0≤1.21.6

LoF obs/exp: 4 / 36.5Missense obs/exp: 72 / 299.8Syn Z: 0.82

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCAMK2A-related intellectual disabilityLOFAD

0.5279th %ile

GOF

0.5856th %ile

LOF

0.63top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.25

GOF1 literature citation

DN1 literature citation

Literature Evidence

DNHere we show that a de novo Glu183 to Val (E183V) mutation in the CaMKIIÎ± catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIÎ± substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKPMID:28130356

GOFCAMK2A autophosphorylation at Thr286 is critical for autonomous (calcium-independent) function. E109D (114078.0002) and H282R caused a significant increase in autophosphorylation at Thr286, consistent with a gain of function, whereas F98S (114078.0001) and E183V (114078.0003) showed a significant rePMID:25363768

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.