CAMK4

Chr 5

calcium/calmodulin dependent protein kinase IV

Also known as: CaMK IV, CaMK-GR, CaMKIV, caMK

NCBI Gene: 814 ENSG00000152495 UniProt: Q16566 OMIM: 114080

CAMK4 encodes a calcium/calmodulin-dependent protein kinase that phosphorylates transcription factors including CREB1, MEF2D, and JUN to regulate gene expression in immune cells and neurons, particularly contributing to memory consolidation and hippocampal long-term potentiation. Mutations cause intellectual disability and developmental delay with autosomal recessive inheritance. The gene shows significant constraint against loss-of-function variants (LOEUF 0.47), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, UniProt

The product of this gene belongs to the serine/threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. This enzyme is a multifunctional serine/threonine protein kinase with limited tissue distribution, that has been implicated in transcriptional regulation in lymphocytes, neurons and male germ cells. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.47

Clinical Summary— CAMK4

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.51) — some intolerance to loss-of-function variants.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 80 VUS of 98 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.510

Z-score 3.23

OE 0.21 (0.10–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.81Z-score

OE missense 0.68 (0.60–0.77)

177 obs / 259.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.21 (0.10–0.47)

0≤0.351.4

Missense OE?0.68 (0.60–0.77)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 4 / 19.3Missense obs/exp: 177 / 259.0Syn Z: 0.39

This gene — mechanism propensity

0.6259th %ile

GOF

0.73top 25%

LOF

0.4430th %ile

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

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

98 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS80

Likely Benign6

Benign4

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	1	0	0	2
Likely Pathogenic	0	0	0	0	0
VUS	9	70	1	0	80
Likely Benign	0	4	1	1	6
Benign	0	2	1	1	4
Total	10	77	3	2	92

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap CAMK4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →