CASKIN1

Summary

CASKIN1 (CASK interacting protein 1, HGNC:20879) is a protein-coding gene on chromosome 16p13.3, encoding Caskin-1 (Q8WXD9). May link the scaffolding protein CASK to downstream intracellular effectors.

Enables identical protein binding activity. Predicted to be involved in signal transduction. Predicted to be active in cytoplasm; glutamatergic synapse; and postsynapse.

Source: NCBI Gene 57524 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 314 total — 2 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_020764

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20879
Approved symbol	CASKIN1
Name	CASK interacting protein 1
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1306, ANKS5A
Ensembl gene	ENSG00000167971
Ensembl biotype	protein_coding
OMIM	612184
Entrez	57524

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 1 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000343516, ENST00000562055, ENST00000564289

RefSeq mRNA: 1 — MANE Select: NM_020764 NM_020764

CCDS: CCDS42103

Canonical transcript exons

ENST00000343516 — 20 exons

Exon	Start	End
ENSE00001364487	2179593	2181599
ENSE00001365747	2187353	2187461
ENSE00001370386	2186707	2186824
ENSE00001370636	2183646	2183747
ENSE00001371949	2185307	2185408
ENSE00001373773	2186978	2187072
ENSE00001377276	2181791	2181929
ENSE00001377824	2178902	2179325
ENSE00001378151	2187166	2187274
ENSE00001379919	2183831	2183941
ENSE00001380712	2185111	2185199
ENSE00001388841	2184951	2185035
ENSE00001427239	2177180	2178646
ENSE00001611754	2190307	2190358
ENSE00001688354	2190073	2190170
ENSE00001774041	2189419	2189564
ENSE00001799702	2189027	2189157
ENSE00002267057	2196339	2196605
ENSE00003508998	2189238	2189333
ENSE00003621676	2184777	2184868

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 94.93.

FANTOM5 (CAGE): breadth broad, TPM avg 1.8648 / max 71.0697, expressed in 400 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155909	0.7268	225
155911	0.5700	169
155908	0.3719	97
155910	0.1438	79
155905	0.0271	3
207703	0.0105	7
155906	0.0094	3
155907	0.0053	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	94.93	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.32	gold quality
primary visual cortex	UBERON:0002436	94.26	gold quality
endothelial cell	CL:0000115	94.18	gold quality
entorhinal cortex	UBERON:0002728	94.02	gold quality
anterior cingulate cortex	UBERON:0009835	94.01	gold quality
postcentral gyrus	UBERON:0002581	93.70	gold quality
superior frontal gyrus	UBERON:0002661	93.65	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.41	gold quality
cerebellar hemisphere	UBERON:0002245	93.33	gold quality
cerebellar cortex	UBERON:0002129	93.19	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.00	gold quality
temporal lobe	UBERON:0001871	92.98	gold quality
nucleus accumbens	UBERON:0001882	92.98	gold quality
amygdala	UBERON:0001876	92.93	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.88	gold quality
frontal cortex	UBERON:0001870	92.83	gold quality
putamen	UBERON:0001874	92.77	gold quality
cerebellum	UBERON:0002037	92.70	gold quality
parietal lobe	UBERON:0001872	92.62	gold quality
neocortex	UBERON:0001950	92.62	gold quality
caudate nucleus	UBERON:0001873	92.61	gold quality
cerebral cortex	UBERON:0000956	92.29	gold quality
prefrontal cortex	UBERON:0000451	91.90	gold quality
occipital lobe	UBERON:0002021	91.81	gold quality
middle temporal gyrus	UBERON:0002771	91.73	gold quality
Ammon’s horn	UBERON:0001954	91.63	gold quality
hypothalamus	UBERON:0001898	90.85	gold quality
forebrain	UBERON:0001890	90.18	gold quality
brain	UBERON:0000955	90.11	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

83 targeting CASKIN1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-202-3P	99.84	71.41	1290

Literature-anchored findings (GeneRIF, showing 5)

• Study shows that a short linear EEIWVLRK peptide motif from Caskin1 is necessary and sufficient for binding CASK. (PMID:21763699)
• SAM domains of Caskin1 form a new type of SAM helical polymer. (PMID:22153505)
• the SH3 domain of human Caskin1 is a lipid-binding domain rather than a proline-rich motif interacting domain. (PMID:28104445)
• Solution NMR Structure of the SH3 Domain of Human Caskin1 Validates the Lack of a Typical Peptide Binding Groove and Supports a Role in Lipid Mediator Binding. (PMID:33467043)
• A Missense Variant in CASKIN1’s Proline-Rich Region Segregates with Psychosis in a Three-Generation Family. (PMID:36672919)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	caskin1	ENSDARG00000046107
danio_rerio	si:dkeyp-9d4.3	ENSDARG00000100166
mus_musculus	Caskin1	ENSMUSG00000033597
rattus_norvegicus	Caskin1	ENSRNOG00000003195

Paralogs (1): CASKIN2 (ENSG00000177303)

Protein

Protein identifiers

Caskin-1 — Q8WXD9 (reviewed: Q8WXD9)

Alternative names: CASK-interacting protein 1

All UniProt accessions (1): Q8WXD9

UniProt curated annotations — full annotation on UniProt →

Function. May link the scaffolding protein CASK to downstream intracellular effectors.

Subunit / interactions. Binds the CaM kinase domain of CASK. Forms a ternary complex with CASK and LIN7A, LIN7B or LIN7C. Competes with APBA1 that forms a similar complex with CASK and LIN7 proteins. The tripartite complex CASKIN1/CASK/LIN7(A/B/C) binds the cytoplasmic tail of NRXN1. Polymerizes, via the tandem SAM domains, to form long, 8 nM wide fibers, upon which other proteins can assemble.

Subcellular location. Cytoplasm.

RefSeq proteins (1): NP_065815* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR001660	SAM	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR032117	Caskin_C	Domain
IPR032232	Caskin1-CID	Domain
IPR033635	ANKS1/Caskin	Family
IPR035495	Caskin1_SH3	Domain
IPR035497	Caskin1/2_SAM_1	Domain
IPR035498	Caskin1/2_SAM_2	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00536, PF07653, PF12796, PF13637, PF16600, PF16632, PF16907

UniProt features (71 total): modified residue 19, helix 12, compositionally biased region 11, strand 9, region of interest 8, repeat 6, domain 3, chain 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3SEI	X-RAY DIFFRACTION	2.4
3SEN	X-RAY DIFFRACTION	3.1
7ATY	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WXD9-F1	54.22	0.10

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 (19): 253, 358, 398, 423, 432, 633, 646, 719, 724, 737, 787, 889, 891, 987, 1065, 1067, 1257, 1266, 1364

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 92 (showing top): CREL_01, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, CAGCTG_AP4_Q5, GTGCCTT_MIR506, CDP_01, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_ORGANELLE_ASSEMBLY, TGANTCA_AP1_C, GOBP_REGULATION_OF_SYNAPSE_STRUCTURE_OR_ACTIVITY, GOBP_CELL_JUNCTION_ASSEMBLY, RFX1_02

GO Biological Process (2): signal transduction (GO:0007165), regulation of postsynaptic density assembly (GO:0099151)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
synapse	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
postsynaptic density assembly	1
regulation of postsynaptic specialization assembly	1
regulation of excitatory synapse assembly	1
regulation of postsynaptic density organization	1
protein binding	1
binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1986 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASKIN1	NRXN1	Q9ULB1	914
CASKIN1	CASK	O14936	871
CASKIN1	APBA1	Q02410	827
CASKIN1	LIN7A	O14910	601
CASKIN1	ABI2	Q9NYB9	537
CASKIN1	TBR1	Q16650	533
CASKIN1	KIF17	Q9P2E2	532
CASKIN1	NCK1	P16333	503
CASKIN1	CAMK2A	Q9UQM7	484
CASKIN1	SLCO6A1	Q86UG4	463
CASKIN1	PPFIA3	O75145	448
CASKIN1	PPFIA2	O75334	440
CASKIN1	BRICD5	Q6PL45	438
CASKIN1	SDC2	P34741	425
CASKIN1	CALML6	Q8TD86	410
CASKIN1	CALML3	P27482	410

IntAct

21 interactions, top by confidence:

A	B	Type	Score
CASKIN1	CASKIN1	psi-mi:“MI:0407”(direct interaction)	0.740
HIF1AN	GMDS	psi-mi:“MI:0914”(association)	0.640
CASKIN1	CASK	psi-mi:“MI:0407”(direct interaction)	0.640
CASK	CASKIN1	psi-mi:“MI:0915”(physical association)	0.640
CASKIN1	CASK	psi-mi:“MI:0914”(association)	0.640
CASKIN1	CASK	psi-mi:“MI:0407”(direct interaction)	0.520
APP	ESYT2	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
	CDC14B	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): CASKIN1 (Affinity Capture-MS), CASKIN1 (Affinity Capture-MS), CASKIN1 (Affinity Capture-MS), CASKIN1 (Affinity Capture-MS), CASKIN1 (Affinity Capture-RNA), CASKIN1 (Affinity Capture-MS), CASKIN1 (Affinity Capture-MS), CASKIN1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8P0N4K0, A2AB59, B4F7F3, D3YZU1, D3ZD05, O35681, O75427, O95382, P22455, P22607, P40748, P55144, P70218, Q06418, Q14160, Q1LZH7, Q2PS20, Q32P44, Q495M9, Q4ACU6, Q4H4B6, Q505F5, Q5F488, Q61851, Q63ZY3, Q6P9K8, Q6TLK4, Q6ZUM4, Q7KRY7, Q80T11, Q80U72, Q8BH60, Q8BX02, Q8N1G4, Q8TE68, Q8VC03, Q8VHK1, Q8VHK2, Q8WXD9, Q8WXE0

Diamond homologs: A0A8I3NFE2, A0FI79, A0JNB0, A1Y2K1, A6QLK6, B2RZ59, B5KFD7, D3ZGS3, D7PF45, F1RDG9, G5ECJ6, O14306, O14796, O15357, O35324, O60880, O88890, O88900, P00519, P00520, P00521, P00522, P03949, P06239, P06241, P09851, P0CE43, P10447, P17713, P20936, P29350, P29351, P32019, P34370, P39688, P42684, P42685, P42686, P50904, P53356

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
EPHB1	“up-regulates activity”	CASKIN1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	288
Likely benign	14
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1696837	NC_000016.10:g.2047157_2220112del	Pathogenic
3243458	NC_000016.9:g.(?2104449)(2286921_?)del	Pathogenic
1809088	GRCh37/hg19 16p13.3(chr16:2106895-2227470)x1	Likely pathogenic

SpliceAI

2841 predictions. Top by Δscore:

Variant	Effect	Δscore
16:2181598:CCCT:C	acceptor_loss	1.0000
16:2181790:CCCAG:C	donor_gain	1.0000
16:2181794:G:C	donor_gain	1.0000
16:2181903:C:CT	acceptor_gain	1.0000
16:2181925:TTAGC:T	acceptor_gain	1.0000
16:2181926:TAGC:T	acceptor_gain	1.0000
16:2181927:AGC:A	acceptor_gain	1.0000
16:2181928:GCCT:G	acceptor_loss	1.0000
16:2181929:CCTA:C	acceptor_loss	1.0000
16:2181930:C:CC	acceptor_gain	1.0000
16:2181930:CT:C	acceptor_loss	1.0000
16:2183644:A:AC	donor_gain	1.0000
16:2183645:C:CC	donor_gain	1.0000
16:2183645:CGGG:C	donor_gain	1.0000
16:2183645:CGGGT:C	donor_gain	1.0000
16:2183680:AGG:A	donor_gain	1.0000
16:2183825:GCTCA:G	donor_loss	1.0000
16:2183826:CTCAC:C	donor_loss	1.0000
16:2183827:TCA:T	donor_loss	1.0000
16:2183828:CA:C	donor_loss	1.0000
16:2183829:A:AT	donor_loss	1.0000
16:2183830:C:A	donor_loss	1.0000
16:2183830:CCT:C	donor_gain	1.0000
16:2184772:TGTAC:T	donor_loss	1.0000
16:2184774:TACCT:T	donor_loss	1.0000
16:2184775:ACCTT:A	donor_loss	1.0000
16:2184780:G:A	donor_gain	1.0000
16:2184864:CACAC:C	acceptor_gain	1.0000
16:2184866:CAC:C	acceptor_gain	1.0000
16:2184867:ACCTG:A	acceptor_loss	1.0000

AlphaMissense

9141 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:2178564:C:G	A1428P	1.000
16:2178569:A:G	L1426P	1.000
16:2178581:A:G	L1422P	1.000
16:2178581:A:T	L1422Q	1.000
16:2178589:G:C	F1419L	1.000
16:2178589:G:T	F1419L	1.000
16:2178591:A:G	F1419L	1.000
16:2181817:A:G	L581P	1.000
16:2181910:A:G	L550P	1.000
16:2181914:A:G	W549R	1.000
16:2181914:A:T	W549R	1.000
16:2183710:C:G	R522P	1.000
16:2183743:A:G	L511P	1.000
16:2186745:A:G	F337S	1.000
16:2186790:C:T	G322D	1.000
16:2186791:C:G	G322R	1.000
16:2186823:A:T	V311D	1.000
16:2187360:A:G	L240P	1.000
16:2187456:A:G	L208P	1.000
16:2189054:G:T	A197D	1.000
16:2189144:A:G	L167P	1.000
16:2189147:A:G	L166P	1.000
16:2189250:G:C	F158L	1.000
16:2189250:G:T	F158L	1.000
16:2189252:A:G	F158L	1.000
16:2189256:G:C	C156W	1.000
16:2189257:C:T	C156Y	1.000
16:2189269:A:G	L152P	1.000
16:2189272:G:C	P151R	1.000
16:2189272:G:T	P151H	1.000

dbSNP variants (sampled 300 via entrez): RS1000086408 (16:2198111 G>C), RS1000183439 (16:2193621 C>G,T), RS1000202869 (16:2197380 C>T), RS1000280463 (16:2187802 G>A), RS1000423787 (16:2184112 C>A,T), RS1000615724 (16:2179898 C>A,G), RS1000729981 (16:2180157 T>A,G), RS1000755858 (16:2193199 T>C), RS1000916201 (16:2183729 C>T), RS1001025387 (16:2176955 G>C,T), RS1001087704 (16:2196204 T>A), RS1001277690 (16:2181040 G>A,T), RS1001643762 (16:2184438 A>C), RS1001968696 (16:2184151 C>A,G,T), RS1002031798 (16:2194091 C>T)

Disease associations

OMIM: gene MIM:612184 | disease phenotypes: MIM:613254

GenCC curated gene-disease

Mondo (1): tuberous sclerosis 2 (MONDO:0013199)

Orphanet (1): Tuberous sclerosis complex (Orphanet:805)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000817_186	Height	9.000000e-17
GCST012227_361	Hip circumference adjusted for BMI	1.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566021	Tuberous Sclerosis 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	increases expression, decreases methylation	2
FR900359	affects phosphorylation	1
bisphenol A	affects cotreatment, decreases methylation	1
mono-(2-ethylhexyl)phthalate	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
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	decreases expression	1
Arsenic	affects methylation	1
Cadmium	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02201212	PHASE2	COMPLETED	Everolimus for Cancer With TSC1 or TSC2 Mutation
NCT05103358	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03817515	Not specified	APPROVED_FOR_MARKETING	Expanded Access for ABI-009 in Patients With Advanced PEComa and Patients With a Malignancy With Relevant Genetic Mutations or mTOR Pathway Activation