CNKSR2

Summary

CNKSR2 (connector enhancer of kinase suppressor of Ras 2, HGNC:19701) is a protein-coding gene on chromosome Xp22.12, encoding Connector enhancer of kinase suppressor of ras 2 (Q8WXI2). May function as an adapter protein or regulator of Ras signaling pathways. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 22866 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 392 total — 41 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 57
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_014927

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19701
Approved symbol	CNKSR2
Name	connector enhancer of kinase suppressor of Ras 2
Location	Xp22.12
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0902, CNK2, KSR2
Ensembl gene	ENSG00000149970
Ensembl biotype	protein_coding
OMIM	300724
Entrez	22866

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 15 protein_coding, 14 retained_intron, 7 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay

ENST00000279451, ENST00000379510, ENST00000425654, ENST00000479158, ENST00000480138, ENST00000485012, ENST00000543067, ENST00000642359, ENST00000642460, ENST00000642501, ENST00000642565, ENST00000642853, ENST00000643156, ENST00000643171, ENST00000643220, ENST00000643309, ENST00000643313, ENST00000643484, ENST00000643841, ENST00000644075, ENST00000644095, ENST00000644295, ENST00000644585, ENST00000644789, ENST00000644798, ENST00000644832, ENST00000645038, ENST00000645074, ENST00000645238, ENST00000645245, ENST00000645539, ENST00000645679, ENST00000645791, ENST00000646175, ENST00000646690, ENST00000646697, ENST00000647058, ENST00000647349, ENST00000647423, ENST00000647532

RefSeq mRNA: 8 — MANE Select: NM_014927 NM_001168647, NM_001168648, NM_001168649, NM_001330770, NM_001330771, NM_001330772, NM_001330773, NM_014927

CCDS: CCDS14198, CCDS55387, CCDS55388, CCDS55389, CCDS87728, CCDS87729, CCDS87730, CCDS87731

Canonical transcript exons

ENST00000379510 — 22 exons

Exon	Start	End
ENSE00001146953	21601282	21601349
ENSE00001146961	21595324	21595395
ENSE00001146970	21594974	21595047
ENSE00001198920	21606779	21606879
ENSE00001198942	21591022	21591194
ENSE00001229010	21561471	21561560
ENSE00001630949	21432612	21432814
ENSE00001690112	21648831	21649027
ENSE00001726580	21426497	21426660
ENSE00001767832	21470766	21470807
ENSE00001771932	21516485	21516631
ENSE00002230874	21609071	21609617
ENSE00002241786	21374418	21374961
ENSE00003462155	21563238	21563452
ENSE00003507268	21490459	21490578
ENSE00003574784	21497787	21497846
ENSE00003578771	21526867	21527000
ENSE00003581375	21590572	21590620
ENSE00003617203	21501520	21501588
ENSE00003644498	21531856	21532067
ENSE00003680331	21440694	21440781
ENSE00003814830	21652306	21654689

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 96.14.

FANTOM5 (CAGE): breadth broad, TPM avg 8.1589 / max 402.0314, expressed in 716 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195714	3.7584	531
195715	3.1884	554
195717	0.3285	109
195710	0.1718	82
195721	0.1523	43
195716	0.1299	60
195709	0.1082	48
195712	0.1081	56
195718	0.0655	24
195711	0.0652	22

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	96.14	gold quality
cerebellar cortex	UBERON:0002129	94.92	gold quality
cerebellar hemisphere	UBERON:0002245	94.89	gold quality
superior frontal gyrus	UBERON:0002661	94.80	gold quality
primary visual cortex	UBERON:0002436	94.79	gold quality
postcentral gyrus	UBERON:0002581	94.66	gold quality
middle temporal gyrus	UBERON:0002771	94.35	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.19	gold quality
buccal mucosa cell	CL:0002336	94.15	gold quality
cerebellum	UBERON:0002037	93.98	gold quality
parietal lobe	UBERON:0001872	93.44	gold quality
entorhinal cortex	UBERON:0002728	93.32	gold quality
biceps brachii	UBERON:0001507	93.17	gold quality
cerebellar vermis	UBERON:0004720	93.01	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.53	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.43	gold quality
prefrontal cortex	UBERON:0000451	92.24	gold quality
occipital lobe	UBERON:0002021	92.00	gold quality
cortical plate	UBERON:0005343	91.90	gold quality
ventricular zone	UBERON:0003053	91.85	gold quality
endothelial cell	CL:0000115	91.61	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.55	gold quality
frontal cortex	UBERON:0001870	91.53	gold quality
frontal lobe	UBERON:0016525	91.52	gold quality
neocortex	UBERON:0001950	90.86	gold quality
cerebral cortex	UBERON:0000956	90.62	gold quality
right frontal lobe	UBERON:0002810	90.28	gold quality
nucleus accumbens	UBERON:0001882	89.60	gold quality
telencephalon	UBERON:0001893	89.59	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.56	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	94.10
E-HCAD-25	yes	85.28
E-ANND-3	yes	7.74
E-MTAB-8060	no	29.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

183 targeting CNKSR2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 10)

• CNK2 through interaction with Raf and Rlf may function as a regulator of Ras signaling. (PMID:14597674)
• CNK and HYP form a discrete dimer by their SAM domains to mediate RAF kinase signaling. (PMID:18287031)
• This study describes the phenotype of CNKSR2 deficiency and its involvement in systems underlying common neurological (PMID:25223753)
• CNKSR2 deletions: a novel cause of X-linked intellectual disability and seizures. (PMID:25754917)
• High CNKSR2 expression is associated with breast cancer progression. (PMID:29534682)
• Expanding the clinical and EEG spectrum of CNKSR2-related encephalopathy with status epilepticus during slow sleep (ESES). (PMID:32197126)
• This study enhances our knowledge of the CNKSR2 gene mutation spectrum and provides further information about the phenotypic characteristics of X-linked syndromic intellectual disability. (PMID:32245427)
• Psychomotor development and attention problems caused by a splicing variant of CNKSR2. (PMID:33298018)
• Finding underlying genetic mechanisms of two patients with autism spectrum disorder carrying familial apparently balanced chromosomal translocations. (PMID:33591602)
• Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders. (PMID:35053419)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnksr2b	ENSDARG00000073707
danio_rerio	cnksr2a	ENSDARG00000074480
mus_musculus	Cnksr2	ENSMUSG00000025658
rattus_norvegicus	Cnksr2	ENSRNOG00000007014
drosophila_melanogaster	cnk	FBGN0286070
caenorhabditis_elegans		WBGENE00000564

Paralogs (4): IPCEF1 (ENSG00000074706), CNKSR1 (ENSG00000142675), CNKSR3 (ENSG00000153721), SAMD3 (ENSG00000164483)

Protein

Protein identifiers

Connector enhancer of kinase suppressor of ras 2 — Q8WXI2 (reviewed: Q8WXI2)

Alternative names: CNK homolog protein 2

All UniProt accessions (16): Q8WXI2, A0A2R8Y5R2, A0A2R8Y5S6, A0A2R8Y604, A0A2R8Y622, A0A2R8Y700, A0A2R8Y7A1, A0A2R8Y7K8, A0A2R8YDB6, A0A2R8YE27, A0A2R8YE65, A0A2R8YE71, A0A2R8YED7, A0A2R8YFM1, A0A2R8YGJ7, A0A2U3TZH5

UniProt curated annotations — full annotation on UniProt →

Function. May function as an adapter protein or regulator of Ras signaling pathways.

Subunit / interactions. Interacts with RAF1, RAB2L and RAL GTPase proteins.

Subcellular location. Cytoplasm. Membrane.

Post-translational modifications. Phosphorylated on tyrosine.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Houge type (MRXSHG) [MIM:301008] A disorder characterized by delayed development, intellectual disability, speech and language delay, and early-onset seizures. Carrier females may be mildly affected. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the CNKSR family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8WXI2-1	1, CNK2A, KSR2A	yes
Q8WXI2-2	2, CNK2B, KSR2B
Q8WXI2-4	3
Q8WXI2-5	4

RefSeq proteins (8): NP_001162118, NP_001162119, NP_001162120, NP_001317699, NP_001317700, NP_001317701, NP_001317702, NP_055742* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR001660	SAM	Domain
IPR001849	PH_domain	Domain
IPR010599	CNK2/3_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR017874	CRIC_domain	Domain
IPR036034	PDZ_sf	Homologous_superfamily
IPR049628	CNK1-3_SAM	Domain
IPR051566	CNKSR	Family

Pfam: PF00169, PF00536, PF00595, PF06663, PF10534

UniProt features (40 total): modified residue 9, compositionally biased region 7, helix 7, domain 5, region of interest 5, splice variant 3, sequence variant 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3BS5	X-RAY DIFFRACTION	2
2EAN	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WXI2-F1	57.67	0.03

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (9): 12, 338, 390, 683, 685, 687, 756, 767, 908

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-5674135	MAP2K and MAPK activation
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants
R-HSA-6802948	Signaling by high-kinase activity BRAF mutants
R-HSA-6802952	Signaling by BRAF and RAF1 fusions
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF
R-HSA-9649948	Signaling downstream of RAS mutants
R-HSA-9656223	Signaling by RAF1 mutants

MSigDB gene sets: 475 (showing top): TGCGCANK_UNKNOWN, LFA1_Q6, GCANCTGNY_MYOD_Q6, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, AP4_Q6, CAGCTG_AP4_Q5, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, KIM_GERMINAL_CENTER_T_HELPER_UP, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, AACTTT_UNKNOWN, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, FIRESTEIN_CTNNB1_PATHWAY, LEF1_Q6, GCM_MAPK10

GO Biological Process (4): regulation of signal transduction (GO:0009966), intracellular signal transduction (GO:0035556), postsynaptic specialization organization (GO:0099084), postsynapse organization (GO:0099173)

GO Molecular Function (3): protein kinase binding (GO:0019901), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (9): cytoplasm (GO:0005737), plasma membrane (GO:0005886), neuronal cell body (GO:0043025), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), extrinsic component of postsynaptic density membrane (GO:0099147), postsynaptic density (GO:0014069), membrane (GO:0016020), postsynaptic membrane (GO:0045211)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Oncogenic MAPK signaling	5
RAF/MAP kinase cascade	1
Signaling by RAS mutants	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
intracellular anatomical structure	2
cellular anatomical structure	2
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
organelle organization	1
postsynapse organization	1
cellular component organization	1
synapse organization	1
kinase binding	1
protein binding	1
binding	1
membrane	1
cell periphery	1
somatodendritic compartment	1
cell body	1
extracellular vesicle	1
synapse	1
postsynaptic density membrane	1
extrinsic component of postsynaptic specialization membrane	1
asymmetric synapse	1
postsynaptic specialization	1
synaptic membrane	1
postsynapse	1

Protein interactions and networks

STRING

1028 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNKSR2	KSR1	Q8IVT5	840
CNKSR2	RALA	P11233	742
CNKSR2	ARHGAP39	Q9C0H5	678
CNKSR2	RAF1	P04049	673
CNKSR2	MAGEC3	Q8TD91	647
CNKSR2	SMURF2	Q9HAU4	578
CNKSR2	LRRC7	Q96NW7	572
CNKSR2	ARHGEF6	Q15052	561
CNKSR2	DLG4	P78352	538
CNKSR2	BRAF	P15056	516
CNKSR2	MOB3B	Q86TA1	505
CNKSR2	KDM5C	P41229	490
CNKSR2	MAGI2	Q86UL8	489
CNKSR2	SUSD1	Q6UWL2	460
CNKSR2	ATRX	P46100	453

IntAct

140 interactions, top by confidence:

A	B	Type	Score
CNKSR2	ave	psi-mi:“MI:0407”(direct interaction)	0.650
CNKSR2	LRRC7	psi-mi:“MI:0407”(direct interaction)	0.590
CNKSR2	LRRC7	psi-mi:“MI:0915”(physical association)	0.590
EGFR	CNKSR2	psi-mi:“MI:0915”(physical association)	0.510
CNKSR2	EGFR	psi-mi:“MI:0915”(physical association)	0.510
YAP1	CNKSR2	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	ERBIN	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
PDZK1	CNKSR2	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	SNTG1	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI3	CNKSR2	psi-mi:“MI:0407”(direct interaction)	0.440
CNKSR2	SNTG2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (26): MOB3B (Affinity Capture-MS), RAF1 (Affinity Capture-Western), CNKSR2 (Affinity Capture-Western), RALA (Affinity Capture-Western), RLF (Affinity Capture-Western), SMURF2 (Affinity Capture-Western), CNKSR2 (Affinity Capture-Western), CNKSR2 (Reconstituted Complex), CNKSR2 (Proximity Label-MS), CNKSR2 (Proximity Label-MS), CNKSR2 (Reconstituted Complex), CNKSR2 (Affinity Capture-Western), CNKSR2 (Affinity Capture-MS), CNKSR2 (Two-hybrid), CNKSR2 (Negative Genetic)

ESM2 similar proteins: A1A5G2, A2AFR3, A7MBL8, B9EJ86, E1C1R4, E1C3P4, F1LXF1, O94806, O94967, P0C6S7, P0CAX5, P11274, P22682, Q0V9G5, Q14161, Q14CM0, Q15139, Q16513, Q1RMU2, Q3KR37, Q3LAC4, Q3UGM2, Q5RED8, Q5T6S3, Q5U252, Q62101, Q66H62, Q6DFZ1, Q6P5G6, Q6PAJ1, Q70Z35, Q7Z6G8, Q80TI0, Q80TQ2, Q80YA9, Q8BIZ1, Q8BWW9, Q8BY87, Q8K1Y2, Q8NEL9

Diamond homologs: A0JN54, A8JQ65, B3LXF2, B3NYS4, B4I4Y1, B4JHJ7, B4K6T8, B4PRE2, B4R0A5, D3YWQ0, D3YXJ0, D3YZU1, D3ZEY4, E9PUQ8, F1MAB7, F4JKI3, F4JQ95, G9CGD6, O08560, O75912, O88673, P09216, P10830, P16054, P20192, P23298, P23743, P34885, P49619, P49620, P49621, P51556, P52429, P52824, P90980, Q01583, Q02156, Q03603, Q05655, Q09103

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CNKSR2	up-regulates	RAF1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	44.6×	7e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	42.5×	7e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	42.5×	7e-06
Long-term potentiation	5	37.2×	1e-05
Assembly and cell surface presentation of NMDA receptors	9	35.7×	4e-10
Neurexins and neuroligins	10	30.8×	2e-10
Protein-protein interactions at synapses	6	24.9×	8e-06
RHOB GTPase cycle	5	12.1×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	71.0×	1e-15
receptor clustering	8	55.5×	3e-10
protein localization to synapse	6	51.1×	2e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	7	38.5×	1e-07
protein-containing complex assembly	10	12.7×	6e-07
cell-cell adhesion	11	12.4×	2e-07
chemical synaptic transmission	7	6.0×	5e-03
intracellular signal transduction	10	4.2×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

392 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	41
Likely pathogenic	17
Uncertain significance	174
Likely benign	30
Benign	7

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013357	NM_014927.5(CNKSR2):c.1280del (p.Arg427fs)	Pathogenic
1065349	NM_014927.5(CNKSR2):c.1235T>A (p.Leu412Ter)	Pathogenic
1069804	NM_014927.5(CNKSR2):c.1652del (p.Asn551fs)	Pathogenic
1071289	NM_014927.5(CNKSR2):c.2349T>G (p.Tyr783Ter)	Pathogenic
1072522	NM_014927.5(CNKSR2):c.1735A>T (p.Lys579Ter)	Pathogenic
1076481	NM_014927.5(CNKSR2):c.847C>T (p.Arg283Ter)	Pathogenic
1194118	NM_014927.5(CNKSR2):c.1905-2A>G	Pathogenic
1236202	NM_014927.5(CNKSR2):c.2041C>T (p.Gln681Ter)	Pathogenic
1275787	NM_014927.5(CNKSR2):c.1295dup (p.Thr433fs)	Pathogenic
1299341	NM_014927.5(CNKSR2):c.2336C>G (p.Ser779Ter)	Pathogenic
1340807	GRCh37/hg19 Xp22.12(chrX:21606718-21780720)x0	Pathogenic
149741	GRCh38/hg38 Xp22.12(chrX:21356600-21624363)x0	Pathogenic
1526770	GRCh37/hg19 Xp22.12(chrX:21606718-21773954)	Pathogenic
157605	NM_014927.5(CNKSR2):c.453dup (p.Asp152fs)	Pathogenic
1697306	NM_014927.5(CNKSR2):c.548_551del (p.Lys183fs)	Pathogenic
1805928	NM_014927.5(CNKSR2):c.2024_2027del (p.Glu675fs)	Pathogenic
1807717	GRCh37/hg19 Xp22.12(chrX:21606719-21774071)x1	Pathogenic
1810182	NM_014927.5(CNKSR2):c.1902dup (p.Tyr635fs)	Pathogenic
2661881	GRCh37/hg19 Xp22.12(chrX:21393016-21675906)x0	Pathogenic
2685443	GRCh37/hg19 Xp22.12(chrX:21500494-21574694)x0	Pathogenic
280521	NM_014927.5(CNKSR2):c.114del (p.Ile39fs)	Pathogenic
280628	NM_014927.5(CNKSR2):c.2340_2344del (p.His782fs)	Pathogenic
3146485	NM_014927.5(CNKSR2):c.2250_2256del (p.Gly751fs)	Pathogenic
3340931	NM_014927.5(CNKSR2):c.2693-43_2703del	Pathogenic
3341078	NM_014927.5(CNKSR2):c.187C>T (p.Gln63Ter)	Pathogenic
3359078	NM_014927.5(CNKSR2):c.1979G>A (p.Trp660Ter)	Pathogenic
3370293	NM_014927.5(CNKSR2):c.573_576del (p.Ser192fs)	Pathogenic
3370477	NM_014927.5(CNKSR2):c.1684C>T (p.Arg562Ter)	Pathogenic
3376274	NM_014927.5(CNKSR2):c.423G>A (p.Trp141Ter)	Pathogenic
3773734	NM_014927.5(CNKSR2):c.742-1G>A	Pathogenic

SpliceAI

4236 predictions. Top by Δscore:

Variant	Effect	Δscore
X:21426488:A:AG	acceptor_gain	1.0000
X:21426489:T:G	acceptor_gain	1.0000
X:21426495:A:AG	acceptor_gain	1.0000
X:21426495:AG:A	acceptor_gain	1.0000
X:21426496:G:GC	acceptor_gain	1.0000
X:21426496:GG:G	acceptor_gain	1.0000
X:21426496:GGT:G	acceptor_gain	1.0000
X:21426496:GGTC:G	acceptor_gain	1.0000
X:21426496:GGTCT:G	acceptor_gain	1.0000
X:21426622:G:GT	donor_gain	1.0000
X:21426634:G:GT	donor_gain	1.0000
X:21426658:TTGG:T	donor_loss	1.0000
X:21426659:TGGTA:T	donor_loss	1.0000
X:21426661:G:C	donor_loss	1.0000
X:21426661:G:GG	donor_gain	1.0000
X:21426662:T:G	donor_loss	1.0000
X:21432603:A:AG	acceptor_gain	1.0000
X:21432604:T:G	acceptor_gain	1.0000
X:21432605:A:AG	acceptor_gain	1.0000
X:21432606:A:G	acceptor_gain	1.0000
X:21432608:TCAG:T	acceptor_loss	1.0000
X:21432609:CAG:C	acceptor_loss	1.0000
X:21432610:A:AG	acceptor_gain	1.0000
X:21432610:AGAAT:A	acceptor_loss	1.0000
X:21432611:G:GA	acceptor_gain	1.0000
X:21432611:G:T	acceptor_loss	1.0000
X:21432611:GA:G	acceptor_gain	1.0000
X:21432611:GAA:G	acceptor_gain	1.0000
X:21432611:GAAT:G	acceptor_gain	1.0000
X:21432611:GAATT:G	acceptor_gain	1.0000

AlphaMissense

6818 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:21374928:T:A	W11R	1.000
X:21374928:T:C	W11R	1.000
X:21374930:G:C	W11C	1.000
X:21374930:G:T	W11C	1.000
X:21374952:T:A	W19R	1.000
X:21374952:T:C	W19R	1.000
X:21374953:G:C	W19S	1.000
X:21374954:G:C	W19C	1.000
X:21374954:G:T	W19C	1.000
X:21426500:T:C	L23P	1.000
X:21426503:A:T	D24V	1.000
X:21426533:T:C	F34S	1.000
X:21426553:G:A	G41R	1.000
X:21426553:G:C	G41R	1.000
X:21426553:G:T	G41W	1.000
X:21426554:G:A	G41E	1.000
X:21426563:T:A	L44Q	1.000
X:21426563:T:C	L44P	1.000
X:21426566:T:C	L45P	1.000
X:21426587:T:A	L52Q	1.000
X:21426587:T:C	L52P	1.000
X:21426602:T:A	V57D	1.000
X:21426621:G:C	Q63H	1.000
X:21426621:G:T	Q63H	1.000
X:21426622:G:A	E64K	1.000
X:21426623:A:T	E64V	1.000
X:21426626:T:C	L65P	1.000
X:21426632:T:C	L67S	1.000
X:21426634:G:A	E68K	1.000
X:21426635:A:T	E68V	1.000

dbSNP variants (sampled 300 via entrez): RS1000027775 (X:21584994 C>T), RS1000041901 (X:21631872 A>C), RS1000052648 (X:21398777 GAA>G), RS1000082682 (X:21489653 G>A), RS1000104532 (X:21400922 A>AT), RS1000110883 (X:21388292 A>G), RS1000120864 (X:21570511 T>C), RS1000126671 (X:21480770 G>A), RS1000157020 (X:21392874 C>T), RS1000158942 (X:21564125 G>A), RS1000176164 (X:21545080 G>A), RS1000176893 (X:21410304 G>A,C), RS1000194026 (X:21484106 A>G), RS1000209380 (X:21409797 C>T), RS1000225444 (X:21646346 C>A)

Disease associations

OMIM: gene MIM:300724 | disease phenotypes: MIM:301008

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	X-linked
intellectual disability, X-linked, syndromic, Houge type	Strong	X-linked
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	XL

Mondo (6): intellectual disability, X-linked, syndromic, Houge type (MONDO:0030909), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092), X-linked complex neurodevelopmental disorder (MONDO:0100148), undetermined early-onset epileptic encephalopathy (MONDO:0018614), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001315	Reduced tendon reflexes
HP:0001328	Specific learning disability
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001417	X-linked inheritance

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002539_97	Schizophrenia	2.000000e-12
GCST006442_460	Educational attainment (years of education)	8.000000e-09
GCST007847_123	Type 2 diabetes	3.000000e-08
GCST008103_166	Bipolar disorder	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1938216 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

51 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, decreases expression, affects expression, increases expression	8
trichostatin A	affects cotreatment, decreases expression, increases expression	3
potassium chromate(VI)	affects cotreatment, decreases expression, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	affects cotreatment, decreases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	increases expression	1
methyleugenol	decreases expression	1
kojic acid	decreases expression	1
sodium arsenite	decreases expression, increases abundance, affects cotreatment	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	affects expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
belinostat	affects cotreatment, decreases expression	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
jinfukang	affects cotreatment, decreases expression	1
NSC 689534	decreases expression, affects binding	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Arbutin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118376	Binding	Inhibition of KSR2 in human SKCO1 cells at 1 uM after 4 hrs using biotin labeled SKNVFYDNGK probe by mass-spectrometric analysis relative to control	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SJ38	HAP1 CNKSR2 (-) 1	Cancer cell line	Male
CVCL_SJ39	HAP1 CNKSR2 (-) 2	Cancer cell line	Male
CVCL_SJ40	HAP1 CNKSR2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

197 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders