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…

Primary Disease Associations & Inheritance

?Intellectual developmental disorder, autosomal recessive 63MIM #618095

Intellectual developmental disorder, autosomal dominant 53MIM #617798

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · complex neurodevelopmental disorder · AD · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.25

LOEUF· LoF intol.

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in CAMK2A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

397 rare PASS variants

Rare truncating (LoF)

1 in 1,200

42 rare PASS variants

Rare synonymous (reference)

1 in 110

258 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CAMK2A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 1,100
South Asian	~43k	1 in 110	1 in 1,700
Remaining (unassigned)	~30k	1 in 150	1 in 1,900
European (Finnish)	~27k	1 in 300	1 in 4,200
Admixed American	~22k	1 in 110	≈ 1 in 7,000
African / African American	~21k	1 in 140	1 in 2,500
East Asian	~20k	1 in 220	1 in 1,100
Ashkenazi Jewish	~13k	1 in 680	none seen
Middle Eastern	~2,884	1 in 180	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 18 of 19 coding exons well covered in gnomAD exomes; exon 16 marginal. Genomes: all 19.? see exons ↓