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

The product of this gene belongs to the serine/threonine protein kinases family, and to the Ca(2+)/calmodulin-dependent protein kinases subfamily. Calcium signaling is crucial for several aspects of plasticity at glutamatergic synapses. This calcium calmodulin-dependent protein kinase is composed of four different chains: alpha, beta, gamma, and delta. The alpha chain encoded by this gene is required for hippocampal long-term potentiation (LTP) and spatial learning. In addition to its calcium-calmodulin (CaM)-dependent activity, this protein can undergo autophosphorylation, resulting in CaM-independent activity. Several transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2018]

OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.252 OMIM phenotypes

Clinical Summary— CAMK2A

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

29 unique Pathogenic / Likely Pathogenic· 96 VUS of 191 total submissions

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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 OE?0.11 (0.05–0.25)

0≤0.351.4

Missense OE?0.24 (0.20–0.29)

0≤0.61.4

Synonymous OE?0.91

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

This gene — mechanism propensity

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.

LOF28% of P/LP variants are LoF · LOEUF 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 CaMK1

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 re2

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

References

ClinVar Variant Classifications

191 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic16

VUS96

Likely Benign44

Benign7

Conflicting9

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	9	0	0	13
Likely Pathogenic	4	11	1	0	16
VUS	10	70	11	5	96
Likely Benign	0	7	18	19	44
Benign	0	0	5	2	7
Conflicting	—				9
Total	18	97	35	26	185

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

10 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap CAMK2A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →