CASKIN2

Summary

CASKIN2 (CASK interacting protein 2, HGNC:18200) is a protein-coding gene on chromosome 17q25.1, encoding Caskin-2 (Q8WXE0).

This gene encodes a large protein that contains six ankyrin repeats, as well as a Src homology 3 (SH3) domain and two sterile alpha motif (SAM) domains, which may be involved in protein-protein interactions. The C-terminal portion of this protein is proline-rich and contains a conserved region. A related protein interacts with calcium/calmodulin-dependent serine protein kinase (CASK). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 57513 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 279 total
• MANE Select transcript: NM_020753

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18200
Approved symbol	CASKIN2
Name	CASK interacting protein 2
Location	17q25.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1139, FLJ21609, ANKS5B
Ensembl gene	ENSG00000177303
Ensembl biotype	protein_coding
OMIM	612185
Entrez	57513

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 18 protein_coding, 3 retained_intron

ENST00000321617, ENST00000433559, ENST00000580021, ENST00000580075, ENST00000581870, ENST00000583246, ENST00000583258, ENST00000861906, ENST00000861907, ENST00000861908, ENST00000861909, ENST00000861910, ENST00000861911, ENST00000861912, ENST00000861913, ENST00000861914, ENST00000861915, ENST00000913138, ENST00000913139, ENST00000913140, ENST00000913141

RefSeq mRNA: 2 — MANE Select: NM_020753 NM_001142643, NM_020753

CCDS: CCDS11723, CCDS45775

Canonical transcript exons

ENST00000321617 — 20 exons

Exon	Start	End
ENSE00001223244	75501779	75503254
ENSE00001223253	75503389	75503527
ENSE00001223259	75503659	75503760
ENSE00001223268	75503852	75503962
ENSE00001223274	75504215	75504306
ENSE00001223276	75504420	75504480
ENSE00001223281	75504572	75504693
ENSE00001223287	75504812	75505073
ENSE00001223294	75505557	75505651
ENSE00001223298	75505821	75505929
ENSE00001223303	75506305	75506413
ENSE00001223311	75506583	75506713
ENSE00001223345	75501468	75501690
ENSE00001223379	75513711	75514208
ENSE00001333556	75500261	75501170
ENSE00001410688	75515401	75515537
ENSE00003480847	75506984	75507129
ENSE00003515785	75507584	75507681
ENSE00003539695	75508234	75508285
ENSE00003653360	75506799	75506894

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 96.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.5490 / max 41.9549, expressed in 1357 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168079	2.2315	763
168080	2.1251	1186
168078	0.1233	55
168077	0.0691	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	96.94	gold quality
sural nerve	UBERON:0015488	96.16	gold quality
tibial nerve	UBERON:0001323	94.22	gold quality
right lung	UBERON:0002167	93.74	gold quality
left uterine tube	UBERON:0001303	92.25	gold quality
type B pancreatic cell	CL:0000169	92.18	gold quality
upper lobe of left lung	UBERON:0008952	92.17	gold quality
upper lobe of lung	UBERON:0008948	91.67	gold quality
apex of heart	UBERON:0002098	90.97	gold quality
left ventricle myocardium	UBERON:0006566	90.70	silver quality
mucosa of stomach	UBERON:0001199	90.64	gold quality
omental fat pad	UBERON:0010414	90.63	gold quality
peritoneum	UBERON:0002358	90.57	gold quality
metanephros cortex	UBERON:0010533	90.28	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.22	gold quality
lower lobe of lung	UBERON:0008949	89.82	gold quality
cardiac muscle of right atrium	UBERON:0003379	89.70	silver quality
right lobe of thyroid gland	UBERON:0001119	89.67	gold quality
trigeminal ganglion	UBERON:0001675	88.80	gold quality
spleen	UBERON:0002106	88.31	gold quality
heart left ventricle	UBERON:0002084	88.26	gold quality
lung	UBERON:0002048	88.15	gold quality
cardiac ventricle	UBERON:0002082	88.05	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.82	gold quality
lower esophagus	UBERON:0013473	87.78	gold quality
left lobe of thyroid gland	UBERON:0001120	87.74	gold quality
dorsal root ganglion	UBERON:0000044	87.72	gold quality
left adrenal gland cortex	UBERON:0035825	87.46	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.36	gold quality
left coronary artery	UBERON:0001626	87.28	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

53 targeting CASKIN2, 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-4692	100.00	67.32	2066
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-4742-5P	98.89	68.41	1542

Literature-anchored findings (GeneRIF, showing 2)

• While the NMR structure demonstrates that the CASKIN2 SH3 domain is folded, its cleft has suffered two substitutions that prevent it from binding typical polyproline ligands. (PMID:27619958)
• Caskin2 is a novel talin- and Abi1-binding protein that promotes cell motility. (PMID:38587458)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	caskin2	ENSDARG00000043818
		ENSDARG00000114473
mus_musculus	Caskin2	ENSMUSG00000034471
rattus_norvegicus	Caskin2	ENSRNOG00000004310

Paralogs (1): CASKIN1 (ENSG00000167971)

Protein

Protein identifiers

Caskin-2 — Q8WXE0 (reviewed: Q8WXE0)

Alternative names: CASK-interacting protein 2

All UniProt accessions (3): Q8WXE0, J3QKS3, J3QRN1

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. May not bind CASK.

Subcellular location. Cytoplasm.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WXE0-1	1	yes
Q8WXE0-2	2

RefSeq proteins (2): NP_001136115, NP_065804* (*=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
IPR035497	Caskin1/2_SAM_1	Domain
IPR035498	Caskin1/2_SAM_2	Domain
IPR035499	Caskin2_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

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

UniProt features (64 total): helix 15, modified residue 13, compositionally biased region 12, repeat 6, strand 5, region of interest 3, domain 3, sequence conflict 2, turn 2, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7ZW4	X-RAY DIFFRACTION	2.72
4IS7	X-RAY DIFFRACTION	2.75
5L1M	X-RAY DIFFRACTION	2.75
2KE9	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WXE0-F1	58.59	0.16

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 (13): 253, 358, 393, 396, 403, 406, 409, 471, 725, 858, 877, 878, 892

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 127 (showing top): RNGTGGGC_UNKNOWN, CREL_01, GCANCTGNY_MYOD_Q6, SP3_Q3, KENNY_CTNNB1_TARGETS_UP, CAGCTG_AP4_Q5, MYOD_01, BLALOCK_ALZHEIMERS_DISEASE_UP, ZIC1_01, MYOD_Q6, AACTTT_UNKNOWN, RYTTCCTG_ETS2_B, VDR_Q3, LEF1_Q6, YAMAZAKI_TCEB3_TARGETS_UP

GO Biological Process (0):

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (1): cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1212 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASKIN2	APBA1	Q02410	673
CASKIN2	CASK	O14936	644
CASKIN2	NRXN1	Q9ULB1	602
CASKIN2	TMEM94	Q12767	590
CASKIN2	PTPRS	Q13332	533
CASKIN2	TMEM161A	Q9NX61	483
CASKIN2	SLCO6A1	Q86UG4	440
CASKIN2	FBXO24	O75426	407
CASKIN2	C1orf198	Q9H425	392
CASKIN2	WHRN	Q9P202	381
CASKIN2	SH2D5	Q6ZV89	376
CASKIN2	LRRC58	Q96CX6	369
CASKIN2	BEND6	Q5SZJ8	361
CASKIN2	GSG1	Q2KHT4	348
CASKIN2	MROH9	Q5TGP6	348

IntAct

23 interactions, top by confidence:

A	B	Type	Score
BRK1	HSBP1	psi-mi:“MI:0914”(association)	0.740
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
P4HA3	FAM171A2	psi-mi:“MI:0914”(association)	0.640
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
NCK1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
NEC1	CASKIN2	psi-mi:“MI:0915”(physical association)	0.370
HIF1AN	CNOT1	psi-mi:“MI:0914”(association)	0.350
BMI1	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350
B3GAT1	RTL8C	psi-mi:“MI:0914”(association)	0.350
ABI2	OBSL1	psi-mi:“MI:0914”(association)	0.350
NPAS1	CIBAR1	psi-mi:“MI:0914”(association)	0.350
P4HA3	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
SLC2A1	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
CDH1	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
PTPRG	HSPA12A	psi-mi:“MI:2364”(proximity)	0.270
PTPRS	TRIO	psi-mi:“MI:2364”(proximity)	0.270
EPHB2	ARHGAP32	psi-mi:“MI:2364”(proximity)	0.270
CFTR	UBA6	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (58): CASKIN2 (Affinity Capture-MS), CASKIN2 (Proximity Label-MS), CASKIN2 (Proximity Label-MS), CASKIN2 (Proximity Label-MS), CASKIN2 (Affinity Capture-MS), CASKIN2 (Affinity Capture-MS), CASKIN2 (Affinity Capture-MS), CASKIN2 (Affinity Capture-MS), CASKIN2 (Affinity Capture-MS), CASKIN2 (Proximity Label-MS), CASKIN2 (Affinity Capture-RNA), CASKIN2 (Affinity Capture-RNA), CASKIN2 (Proximity Label-MS), CASKIN2 (Proximity Label-MS), CASKIN2 (Proximity Label-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, A5PMU4, D3ZAR1, O09127, O15357, O70143, P0C6S7, P29321, P29353, P54753, P54754, P54755, P54756, P54758, P59672, P98083, Q03145, Q07498, Q09YL6, Q0IIE2, Q2I6J1, Q32PV0, Q3V1H9, Q5M824, Q5PQS4, Q5R7W7, Q5SW96, Q5TGI4, Q60629, Q61120, Q62413, Q6DD51, Q6P549, Q6P9K8, Q6S5L9, Q7Z6G8, Q801G1, Q8BIZ1, Q8C142, Q8K2A1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 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
RAC2 GTPase cycle	5	25.4×	7e-05
RAC3 GTPase cycle	5	23.8×	8e-05
RHO GTPase Effectors	6	16.3×	7e-05
RAC1 GTPase cycle	5	12.2×	1e-03
RHO GTPase cycle	5	12.0×	1e-03
Signaling by Rho GTPases	8	10.9×	4e-05
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	8	10.7×	4e-05
Infectious disease	6	6.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	253
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2741 predictions. Top by Δscore:

Variant	Effect	Δscore
17:75501171:C:CC	acceptor_gain	1.0000
17:75501466:ACC:A	donor_gain	1.0000
17:75501467:CCC:C	donor_gain	1.0000
17:75501467:CCCCT:C	donor_gain	1.0000
17:75501477:T:TA	donor_gain	1.0000
17:75503028:C:CA	donor_gain	1.0000
17:75503101:G:C	donor_gain	1.0000
17:75503251:TGCC:T	acceptor_gain	1.0000
17:75503252:GCC:G	acceptor_gain	1.0000
17:75503253:CC:C	acceptor_gain	1.0000
17:75503253:CCC:C	acceptor_gain	1.0000
17:75503254:CC:C	acceptor_gain	1.0000
17:75503255:C:CC	acceptor_gain	1.0000
17:75503255:C:CG	acceptor_loss	1.0000
17:75503260:A:AC	acceptor_gain	1.0000
17:75503260:A:C	acceptor_gain	1.0000
17:75503383:CCTTA:C	donor_loss	1.0000
17:75503384:CTTAC:C	donor_loss	1.0000
17:75503385:TTACC:T	donor_loss	1.0000
17:75503386:TAC:T	donor_loss	1.0000
17:75503387:A:AC	donor_gain	1.0000
17:75503387:ACC:A	donor_loss	1.0000
17:75503388:C:CT	donor_gain	1.0000
17:75503388:CCGAG:C	donor_gain	1.0000
17:75503523:TCCGT:T	acceptor_gain	1.0000
17:75503524:CCGT:C	acceptor_gain	1.0000
17:75503524:CCGTC:C	acceptor_gain	1.0000
17:75503525:CGT:C	acceptor_gain	1.0000
17:75503525:CGTC:C	acceptor_gain	1.0000
17:75503526:GTC:G	acceptor_loss	1.0000

AlphaMissense

7659 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:75503756:A:G	L528P	1.000
17:75503901:A:G	F510S	1.000
17:75503937:A:G	L498P	1.000
17:75504994:A:G	F337S	1.000
17:75505040:C:G	G322R	1.000
17:75505046:A:G	W320R	1.000
17:75505046:A:T	W320R	1.000
17:75505826:A:G	L277P	1.000
17:75505834:C:A	K274N	1.000
17:75505834:C:G	K274N	1.000
17:75505864:G:C	F264L	1.000
17:75505864:G:T	F264L	1.000
17:75505865:A:G	F264S	1.000
17:75505866:A:G	F264L	1.000
17:75505892:T:G	Q255P	1.000
17:75505903:A:C	N251K	1.000
17:75505903:A:T	N251K	1.000
17:75505904:T:A	N251I	1.000
17:75506312:A:G	L240P	1.000
17:75506336:C:A	G232V	1.000
17:75506336:C:T	G232D	1.000
17:75506342:A:G	L230P	1.000
17:75506346:C:G	A229P	1.000
17:75506349:C:G	A228P	1.000
17:75506357:A:G	L225P	1.000
17:75506357:A:T	L225H	1.000
17:75506366:C:T	G222D	1.000
17:75506408:A:G	L208P	1.000
17:75506610:G:T	A197D	1.000
17:75506613:G:T	A196D	1.000

dbSNP variants (sampled 300 via entrez): RS1000240380 (17:75500727 G>A), RS1000983325 (17:75515599 G>A,C), RS1001140190 (17:75509927 G>A,C), RS1001171968 (17:75509157 C>A,G,T), RS1001299942 (17:75500181 G>C), RS1001317005 (17:75515835 C>T), RS1001420054 (17:75504544 G>A), RS1001453499 (17:75509548 G>A), RS1001648170 (17:75499887 GC>G), RS1001677464 (17:75503602 G>T), RS1001873980 (17:75514746 GC>G,GCC), RS1001985670 (17:75508466 G>A), RS1002494620 (17:75515416 G>T), RS1002770187 (17:75515132 G>C), RS1002778112 (17:75508575 C>T)

Disease associations

OMIM: gene MIM:612185 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003042_1	Sight-threatening diabetic retinopathy in type 2 diabetes	7.000000e-07
GCST010320_51	PR interval	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004462	PR interval

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
titanium dioxide	decreases methylation	1
sodium arsenite	increases abundance, decreases expression	1
butyraldehyde	decreases expression	1
coumarin	affects phosphorylation	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Amiodarone	increases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Cisplatin	decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Phthalic Acids	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Quercetin	decreases phosphorylation	1
Smoke	decreases expression	1
Tamoxifen	affects cotreatment, decreases expression	1
Testosterone	decreases expression	1
Dronabinol	increases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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