CASK

Chr XXLRX-linked

calcium/calmodulin dependent serine protein kinase

Also known as: CAGH39, CAMGUK, CMG, FGS4, LIN2, MICPCH, MRXSNA, TNRC8

NCBI Gene: 8573 ENSG00000147044 OMIM: 300172

The protein functions as a calcium/calmodulin-dependent serine protein kinase and MAGUK scaffold protein located at brain synapses. Mutations cause X-linked intellectual disability with variable features including FG syndrome 4, microcephaly with pontine and cerebellar hypoplasia, and nystagmus, predominantly through loss-of-function mechanisms. The gene shows extreme intolerance to loss-of-function variants, consistent with haploinsufficiency being pathogenic in hemizygous males.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a calcium/calmodulin-dependent serine protein kinase. The encoded protein is a MAGUK (membrane-associated guanylate kinase) protein family member. These proteins are scaffold proteins and the encoded protein is located at synapses in the brain. Mutations in this gene are associated with FG syndrome 4, intellectual disability and microcephaly with pontine and cerebellar hypoplasia, and a form of X-linked intellectual disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismXLR/X-linkedLOEUF 0.073 OMIM phenotypes

Clinical Summary— CASK

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Gene-Disease Validity (ClinGen)

X-linked syndromic intellectual disability · XLDefinitive

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

72 unique Pathogenic / Likely Pathogenic· 205 VUS of 574 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 →

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GeneReview available — CASK

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.07LOEUF

pLI 1.000

Z-score 5.93

OE 0.00 (0.00–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.25Z-score

OE missense 0.37 (0.32–0.43)

133 obs / 359.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.07)

0≤0.351.4

Missense OE?0.37 (0.32–0.43)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 0 / 41.0Missense obs/exp: 133 / 359.9Syn Z: 0.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCASK-related intellectual developmental disorder, with or without nystagmusOTHERXLR

definitiveCASK-related intellectual developmental disorderLOFmonoallelic_X_heterozygous

This gene — mechanism propensity

0.3594th %ile

GOF

0.5563th %ile

LOF

0.73top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 81% of P/LP variants are LoF · LOEUF 0.07

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

ClinVar Variant Classifications

574 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35

Likely Pathogenic37

VUS205

Likely Benign164

Benign33

Conflicting2

Pathogenic

Likely Pathogenic

205

VUS

164

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	26	2	7	0	35
Likely Pathogenic	32	1	4	0	37
VUS	6	172	26	1	205
Likely Benign	0	7	82	75	164
Benign	0	3	18	12	33
Conflicting	—				2
Total	64	185	137	88	476

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap CASK — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →