CNKSR2

Chr XX-linked

connector enhancer of kinase suppressor of Ras 2

Also known as: CNK2, KSR2, MAGUIN, MRXSHG

This protein functions as a scaffold protein that mediates mitogen-activated protein kinase pathways downstream from Ras and may regulate synaptic protein assembly at the postsynaptic membrane. Mutations cause X-linked syndromic intellectual developmental disorder (Houge type), inherited in an X-linked pattern. The gene is highly constrained against loss-of-function variants, indicating intolerance to protein-disrupting mutations.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismX-linkedLOEUF 0.181 OMIM phenotype
Clinical SummaryCNKSR2
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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

Dual constrained — LoF & missense intolerant
LoF Constraint
0.18LOEUF
pLI 1.000
Z-score 5.57
OE 0.07 (0.030.18)
Highly constrained

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

Missense Constraint
3.61Z-score
OE missense 0.47 (0.420.54)
177 obs / 372.9 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.07 (0.030.18)
00.351.4
Missense OE0.47 (0.420.54)
00.61.4
Synonymous OE0.83
01.21.6
LoF obs/exp: 3 / 41.9Missense obs/exp: 177 / 372.9Syn Z: 1.52
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongCNKSR2-related intellectual disability with epilepsyLOFXLR
DN
0.3793th %ile
GOF
0.5367th %ile
LOF
0.80top 5%

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

LOFprediction above median · LOEUF 0.18

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

0 submitted variants in 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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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