CNKSR2

Chr XX-linked

connector enhancer of kinase suppressor of Ras 2

Also known as: CNK2, KSR2, MAGUIN, MRXSHG

NCBI Gene: 22866ENSG00000149970UniProt: Q8WXI2

This gene encodes a multidomain protein that functions as a scaffold protein to mediate the mitogen-activated protein kinase pathways downstream from Ras. This gene product is induced by vitamin D and inhibits apoptosis in certain cancer cells. It may also play a role in ternary complex assembly of synaptic proteins at the postsynaptic membrane and coupling of signal transduction to membrane/cytoskeletal remodeling. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked syndromic, Houge typeMIM #301008
X-linked
0
ClinVar variants
0
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CNKSR2
🧬
Gene-Disease Validity (ClinGen)
X-linked complex neurodevelopmental disorder · 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.

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.
0.18LOEUF
pLI 1.000
Z-score 5.57
OE 0.07 (0.03–0.18)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
3.61Z-score
OE missense 0.47 (0.42–0.54)
177 obs / 372.9 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.0.07 (0.03–0.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.47 (0.42–0.54)
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.0.83
0≤1.21.6
LoF obs/exp: 3 / 41.9Missense obs/exp: 177 / 372.9Syn Z: 1.52

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

CNKSR2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CNKSR2-related intellectual disability with epilepsy

strong
Monoallelic X HemizygousLoss 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

Intellectual developmental disorder, X-linked syndromic, Houge type

MIM #301008

Molecular basis of disorder known

X-linked
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.
Hu H et al.·Mol Psychiatry
2016
Chromosome X-wide common variant association study in autism spectrum disorder.
Mendes M et al.·Am J Hum Genet
2025
CNKSR2-Related Developmental and Epileptic Encephalopathy with Spike-Wave Activation in Sleep: A Report of Two Additional Cases and Review of the Literature.
Whitney R et al.·Neurol India
2024Review
Identification of CNKSR2 Pathogenic Variant and Detection of Strong XCI in a Female Patient With Severe DEE-SWAS and Phenotype Expansion in Male Patients.
Katata Y et al.·Clin Genet
2025Case report
CNKSR2-related neurodevelopmental and epilepsy disorder: a cohort of 13 new families and literature review indicating a predominance of loss of function pathogenic variants.
Higa LA et al.·BMC Med Genomics
2021Review
Expanding the clinical and EEG spectrum of CNKSR2-related encephalopathy with status epilepticus during slow sleep (ESES).
Bonardi CM et al.·Clin Neurophysiol
2020Case report
Novel Digital Anomalies, Hippocampal Atrophy, and Mutations Expand the Genotypic and Phenotypic Spectra of CNKSR2 in the Houge Type of X-Linked Syndromic Intellectual Development Disorder (MRXSHG).
Ghasemi MR et al.·Am J Med Genet A
2025
Hemizygous splicing variant in CNKSR2 results in X-linked intellectual developmental disorder.
Lou Y et al.·Mol Genet Genomic Med
2024
Psychomotor development and attention problems caused by a splicing variant of CNKSR2.
Zhang Y et al.·BMC Med Genomics
2020Case report
A de novo variant in the X-linked gene CNKSR2 is associated with seizures and mild intellectual disability in a female patient.
Polla DL et al.·Mol Genet Genomic Med
2019Case report
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools