CNKSR2

Chr XX-linked

connector enhancer of kinase suppressor of Ras 2

Also known as: CNK2, KSR2, MAGUIN, MRXSHG

NCBI Gene: 22866 ENSG00000149970 UniProt: Q8WXI2 OMIM: 300724

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismX-linkedLOEUF 0.181 OMIM phenotype

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.

📋

ClinVar Variants

56 unique Pathogenic / Likely Pathogenic· 169 VUS of 381 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.07 (0.03–0.18)

0≤0.351.4

Missense OE?0.47 (0.42–0.54)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

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

This gene — mechanism propensity

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 · 95% of P/LP variants are LoF · LOEUF 0.18 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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

381 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35

Likely Pathogenic21

VUS169

Likely Benign33

Benign6

Conflicting6

Pathogenic

Likely Pathogenic

169

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	35	0	0	0	35
Likely Pathogenic	18	3	0	0	21
VUS	6	153	7	3	169
Likely Benign	0	10	6	17	33
Benign	0	2	1	3	6
Conflicting	—				6
Total	59	168	14	23	270

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

View in ClinVar →

108 pathogenic / likely-pathogenic (of 119) ClinVar copy-number / structural variants overlap CNKSR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →