CASK

Chr XXLRX-linked

calcium/calmodulin dependent serine protein kinase

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

NCBI Gene: 8573ENSG00000147044UniProt: P07498

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]

Primary Disease Associations & Inheritance

FG syndrome 4MIM #300422
XLR
Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasiaMIM #300749
X-linked
Intellectual developmental disorder, with or without nystagmusMIM #300422
XLR
423
ClinVar variants
77
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— CASK
🧬
Gene-Disease Validity (ClinGen)
X-linked syndromic intellectual disability · XLDefinitive

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.
📋
ClinVar Variants
77 Pathogenic / Likely Pathogenic· 194 VUS of 423 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.07)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.37 (0.32–0.43)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 0 / 41.0Missense obs/exp: 133 / 359.9Syn Z: 0.08

ClinVar Variant Classifications

423 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44
Likely Pathogenic33
VUS194
Likely Benign124
Benign24
Conflicting4
44
Pathogenic
33
Likely Pathogenic
194
VUS
124
Likely Benign
24
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
1
26
0
44
Likely Pathogenic
24
2
7
0
33
VUS
5
156
33
0
194
Likely Benign
0
6
60
58
124
Benign
0
2
15
7
24
Conflicting
—4
Total4616714165423

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

View in ClinVar →

Protein Context — Lollipop Plot

CASK · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CASK-related intellectual developmental disorder, with or without nystagmus

definitive
Monoallelic X HemizygousUndeterminedAltered Gene Product Structure, Uncertain
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

CASK-related intellectual developmental disorder

definitive
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

FG syndrome 4

MIM #300422

Molecular basis of disorder known

X-linked recessive

Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia

MIM #300749

Molecular basis of disorder known

X-linked

Intellectual developmental disorder, with or without nystagmus

MIM #300422

Molecular basis of disorder known

X-linked recessive
📖
GeneReview available — CASK
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.
Pande S et al.·Eur J Hum Genet
2024Cohort
The neurodevelopmental spectrum of CASK-related disorder.
Martin J et al.·J Neurodev Disord
2025
Dissecting CASK: Novel splice site variant associated with male MICPCH phenotype.
Silveira KC et al.·Clin Genet
2024Case report
Structural constraints and functional divergences in CASK evolution.
LaConte L et al.·Biochem Soc Trans
2013Review
Pathogenic variants in CASK: Expanding the genotype-phenotype correlations.
Dubbs H et al.·Am J Med Genet A
2022
Genetic evidence for splicing-dependent structural and functional plasticity in CASK protein.
Patel PA et al.·J Med Genet
2024Functional
What is circulating factor disease and how is it currently explained?
Hayward S et al.·Pediatr Nephrol
2023Review
Presynaptic dysfunction in CASK-related neurodevelopmental disorders.
Becker M et al.·Transl Psychiatry
2020
Genetic disorders associated with postnatal microcephaly.
Seltzer LE et al.·Am J Med Genet C Semin Med Genet
2014Review
Pontocerebellar Hypoplasia: a Pattern Recognition Approach.
Rüsch CT et al.·Cerebellum
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools