CISH

Summary

CISH (cytokine inducible SH2 containing protein, HGNC:1984) is a protein-coding gene on chromosome 3p21.2, encoding Cytokine-inducible SH2-containing protein (Q9NSE2). SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction.

The protein encoded by this gene contains a SH2 domain and a SOCS box domain. The protein thus belongs to the cytokine-induced STAT inhibitor (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), protein family. CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by IL2, IL3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1154 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 42 total
• MANE Select transcript: NM_145071

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1984
Approved symbol	CISH
Name	cytokine inducible SH2 containing protein
Location	3p21.2
Locus type	gene with protein product
Status	Approved
Aliases	CIS, G18, CIS-1, SOCS
Ensembl gene	ENSG00000114737
Ensembl biotype	protein_coding
OMIM	602441
Entrez	1154

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000348721, ENST00000443053, ENST00000491847, ENST00000864813

RefSeq mRNA: 2 — MANE Select: NM_145071 NM_013324, NM_145071

CCDS: CCDS2831, CCDS46834

Canonical transcript exons

ENST00000348721 — 3 exons

Exon	Start	End
ENSE00001347133	50608373	50608593
ENSE00001834647	50606489	50608142
ENSE00001875804	50611631	50611774

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 93.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.9216 / max 1071.6535, expressed in 1351 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42353	17.0225	1264
42355	0.4114	231
42351	0.2753	108
42354	0.0904	26
42352	0.0885	33
42350	0.0334	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	93.33	gold quality
left lobe of thyroid gland	UBERON:0001120	91.54	gold quality
right lobe of thyroid gland	UBERON:0001119	91.08	gold quality
adult mammalian kidney	UBERON:0000082	91.03	gold quality
thyroid gland	UBERON:0002046	90.14	gold quality
tibialis anterior	UBERON:0001385	89.93	silver quality
right lobe of liver	UBERON:0001114	89.92	gold quality
upper lobe of left lung	UBERON:0008952	89.35	gold quality
blood	UBERON:0000178	89.28	gold quality
placenta	UBERON:0001987	88.94	gold quality
upper lobe of lung	UBERON:0008948	88.77	gold quality
diaphragm	UBERON:0001103	88.42	gold quality
apex of heart	UBERON:0002098	87.31	gold quality
kidney	UBERON:0002113	86.91	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.90	gold quality
gastrocnemius	UBERON:0001388	86.74	gold quality
metanephros cortex	UBERON:0010533	86.43	gold quality
muscle of leg	UBERON:0001383	86.08	gold quality
ileal mucosa	UBERON:0000331	86.03	silver quality
adenohypophysis	UBERON:0002196	85.87	gold quality
oocyte	CL:0000023	85.86	gold quality
decidua	UBERON:0002450	85.73	gold quality
liver	UBERON:0002107	85.58	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.48	gold quality
heart left ventricle	UBERON:0002084	85.42	gold quality
cardiac ventricle	UBERON:0002082	85.30	gold quality
deltoid	UBERON:0001476	85.10	silver quality
body of pancreas	UBERON:0001150	84.81	gold quality
muscle organ	UBERON:0001630	84.76	gold quality
type B pancreatic cell	CL:0000169	84.75	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-8	yes	62.15
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPB, CREM, CTCF, DBP, DNMT1, EGR1, EGR2, ESR1, FLT3, GATA4, GTF2I, GTF2IRD1, HIF1A, HOXA10, HOXA13, HR, IRF3, MAZ, MYB, NFAT5, NFE2L2, NFKB, NR1H4, NRL, PAX3, SATB1, SP1, STAT1, STAT3, STAT5A, STAT5B, STAT6, TCF3, ZFPM2, ZNF148

miRNA regulators (miRDB)

55 targeting CISH, 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-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-361-5P	98.95	70.16	1340
HSA-MIR-760	98.81	66.65	1392

Literature-anchored findings (GeneRIF, showing 37)

• Up-regulation of cytokine inducible SH2-containing protein is associated with adult T-cell leukemia (PMID:14630083)
• CIS (cytokine-inducible SH2 protein)is binding with the conserved Y985 and Y1077 motifs in the cytosolic domain of the leptin receptor. (PMID:16684815)
• analysis of STAT5, CIS, and SOCS2 interactions with the growth hormone receptor (PMID:17666591)
• RACK1 has a role in protecting cancer cells from apoptosis by regulating the degradation of BimEL, which together with CIS could play an important role of drug resistance in chemotherapy (PMID:18420585)
• Elongin B/C recruitment regulates substrate binding by CIS (PMID:18508766)
• CISH expression in allergen-stimulated CD4(+) T cells from HE-allergic patients was significantly increased in both mRNA and protein levels compared with that from non-HE-allergic children. (PMID:18647318)
• CIS can serve as an SLE disease marker and may be involved in the pathogenesis of SLE, and that TNF-alpha may play an important role in the regulation of CIS (PMID:18820827)
• miR-98 and let-7 confer cholangiocyte expression of CIS in response to microbial challenge, a process that may be relevant to the regulation of TLR-mediated epithelial innate immune response. (PMID:19592657)
• These results suggest that RSV infection escapes the innate antiviral response by inducing SOCS1, SOCS3 or CIS expression in epithelial cells. (PMID:19595407)
• Low level of CISH expression in various tissues suggests that it is a novel prospective marker for diagnosis of colon cancer. (PMID:19807022)
• Variants of CISH are associated with susceptibility to diseases caused by diverse infectious pathogens. (PMID:20484391)
• The authors conclude that Mycobacterium tuberculosis infection induces development of Tregs from CCR4(+) cells through a process that depends on PD-1and CISH. (PMID:21383382)
• Study indicates the vital role of CISH single nucleotide polymorphism (SNP)-292A>T variant to hepatitis B virus infection in a Vietnamese population. (PMID:22033525)
• Suppressors of both cytokine signaling SOCS7 and cytokine-inducible SH2 protein (CIS) are expressed constitutively at higher levels in LNCaP-S17 (prostate cancer) cells than in LNCaP-C3 cells. (PMID:22213096)
• data suggest FXR-mediated upregulation of cytokine inducible SH2-containing protein (CISH) may play an important role in the homeostasis of cytokine signal networks and be beneficial to control cytokine-associated inflammatory diseases (PMID:22817871)
• In GH transduction defect, abnormal GH signalling may be caused by over-expression of CIS, which may increase degradation of GHR (PMID:23426819)
• two genetic variants in CISH gene appear to increase susceptibility to TB in Chinese Han population (PMID:23949851)
• methylation of SOCS1, SOCS2, SOCS3 and CISH is infrequent in Ph-ve MPN. (PMID:24131863)
• CISH promoter rs414171 and rs809451 polymorphisms may play a vital role in mediating individual susceptibility to tuberculosis (PMID:24632804)
• CISH gene polymorphisms at -292 (rs414171) are associated with HBV clearance in HBeAg-positive CHB patients in the immune active phase, and AA is a favorable genotype for this effect. (PMID:24791876)
• Two SNPs (rs414171 and rs2239751) in the CISH gene were associated with persistent HBV infection in Han Chinese population (PMID:24964072)
• SOCS single nucleotide polymorphism is associated with breast cancer. (PMID:25104439)
• This study showed that there was significantly increased levels of CIS mRNA in elderly and Alzheimer’s disease brains. (PMID:25286386)
• Data indicate that CIS protein stability is regulated through multiple mechanisms, including ubiquitination and interaction with Elongin B/C proteins, whereas CIS functional inhibition of PRLR signaling is dependent on the Elongin B/C interaction. (PMID:25448846)
• Study in Chinese Han population confirms that previously identified variants of CISH are associated with susceptibility to pulmonary tuberculosis. (PMID:25460819)
• CISH rs414171 and rs6768300 variants might be associated with protection from pulmonary tuberculosis in Zahedan, Southeast Iran. (PMID:27266592)
• CIS interacted with phosphorylated EpoR at Y401, which was critical for the activation of STAT5 and ERK. (PMID:28038963)
• Studies indicate that suppressors of cytokine signaling (SOCS) proteins CIS, SOCS1, and SOCS3 can be considered the third immunocheckpoint molecules since they regulate cytokine signals that control the polarization of CD4(+) T cells and the maturation of CD8(+) T cells. (PMID:28188673)
• identified P2RX2, KCNQ5, ERBB3 and SOCS3 to be associated with the progression of age-related hearing impairment (PMID:29325454)
• We conclude that the Cish-SH2 domain is essential for PLC-gamma1 regulation in TCR-stimulated CD8(+) T cells. (PMID:29593227)
• The CISH rs414171 polymorphism is associated significantly with susceptibility to sepsis and multiple organ dysfunction syndrome in traumatic patients, which might prove to be a novel biomarker for indicating risk of infectious outcomes in critically injured patients. (PMID:29920655)
• These findings suggest that CISH plays a key role in the eosinophilic inflammation associated with bronchial asthma by regulating IL-13-induced CCL26 production. (PMID:30197185)
• NK cell-derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS. (PMID:32097462)
• MiR-944/CISH mediated inflammation via STAT3 is involved in oral cancer malignance by cigarette smoking. (PMID:32961483)
• Genetic Predisposition to the Mortality in Septic Shock Patients: From GWAS to the Identification of a Regulatory Variant Modulating the Activity of a CISH Enhancer. (PMID:34072601)
• CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging. (PMID:37118554)
• CIS deletion by CRISPR/Cas9 enhances human primary natural killer cell functions against allogeneic glioblastoma. (PMID:37563692)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cishb	ENSDARG00000016773
danio_rerio	cisha	ENSDARG00000060316
mus_musculus	Cish	ENSMUSG00000032578
rattus_norvegicus	Cish	ENSRNOG00000029543
drosophila_melanogaster	Socs44A	FBGN0033266
drosophila_melanogaster	Socs36E	FBGN0041184

Paralogs (7): SOCS2 (ENSG00000120833), SOCS6 (ENSG00000170677), SOCS5 (ENSG00000171150), SOCS4 (ENSG00000180008), SOCS3 (ENSG00000184557), SOCS1 (ENSG00000185338), SOCS7 (ENSG00000274211)

Protein

Protein identifiers

Cytokine-inducible SH2-containing protein — Q9NSE2 (reviewed: Q9NSE2)

Alternative names: CIS-1, Protein G18, Suppressor of cytokine signaling

All UniProt accessions (1): Q9NSE2

UniProt curated annotations — full annotation on UniProt →

Function. SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. CIS is involved in the negative regulation of cytokines that signal through the JAK-STAT5 pathway such as erythropoietin, prolactin and interleukin 3 (IL3) receptor. Inhibits STAT5 trans-activation by suppressing its tyrosine phosphorylation. May be a substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

Subunit / interactions. Stably associated with the tyrosine-phosphorylated IL3 receptor beta chain and tyrosine-phosphorylated EPO receptor (EPOR).

Tissue specificity. Expressed in various epithelial tissues. Abundantly expressed in liver and kidney, and to a lesser extent in lung. The tissue distribution of isoforms 1 and 1B is distinct.

Post-translational modifications. Association with EPOR may target the protein for proteolysis by the ubiquitin-dependent proteasome pathway. CIS is mainly monubiquitinated (37 kDa form) but may also exist in a polyubiquitinated form (45 kDa).

Induction. By a subset of cytokines including EPO/erythropoietin.

Pathway. Protein modification; protein ubiquitination.

Polymorphism. CISH polymorphisms are involved in susceptibility to malaria [MIM:611162]. Genetic variations in CISH are involved in susceptibility to tuberculosis [MIM:607948]. Genetic variations in CISH are associated with susceptibility to bacterial invasion of the blood and define the bacteremia susceptibility locus 2 (BACTS2) [MIM:614383].

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NSE2-1	1	yes
Q9NSE2-2	1B
Q9NSE2-3	1C

RefSeq proteins (2): NP_037456, NP_659508* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001496	SOCS_box	Domain
IPR035887	CIS_SH2	Domain
IPR036036	SOCS_box-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily

Pfam: PF00017, PF07525

UniProt features (6 total): domain 2, splice variant 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NSE2-F1	73.91	0.48

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1266695	Interleukin-7 signaling
R-HSA-8951664	Neddylation
R-HSA-982772	Growth hormone receptor signaling

MSigDB gene sets: 0 (showing top):

GO Biological Process (7): regulation of cell growth (GO:0001558), negative regulation of cytokine-mediated signaling pathway (GO:0001960), protein ubiquitination (GO:0016567), cytokine-mediated signaling pathway (GO:0019221), intracellular signal transduction (GO:0035556), negative regulation of receptor signaling pathway via JAK-STAT (GO:0046426), negative regulation of signal transduction (GO:0009968)

GO Molecular Function (2): cytokine receptor binding (GO:0005126), protein binding (GO:0005515)

GO Cellular Component (2): cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by Interleukins	1
Post-translational protein modification	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
regulation of cytokine-mediated signaling pathway	1
negative regulation of signal transduction	1
cytokine-mediated signaling pathway	1
negative regulation of response to cytokine stimulus	1
protein modification by small protein conjugation	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
intracellular anatomical structure	1
cell surface receptor signaling pathway via JAK-STAT	1
regulation of receptor signaling pathway via JAK-STAT	1
negative regulation of receptor signaling pathway via STAT	1
regulation of signal transduction	1
negative regulation of cell communication	1
negative regulation of signaling	1
negative regulation of response to stimulus	1
signaling receptor binding	1
binding	1
cytoplasm	1
cellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

2358 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CISH	CUL5	Q93034	994
CISH	ELOB	Q15370	984
CISH	ELOC	Q15369	976
CISH	CUL2	Q13617	960
CISH	RNF7	Q9UBF6	952
CISH	JAK2	O60674	949
CISH	SPSB1	Q96BD6	864
CISH	TYK2	P29597	860
CISH	JAK1	P23458	855
CISH	SPSB2	Q99619	831
CISH	STAT3	P40763	818
CISH	STAT5B	P51692	816
CISH	ASB2	Q96Q27	811
CISH	ANK1	P16157	807
CISH	SPSB4	Q96A44	807
CISH	ANK2	Q01484	807

IntAct

35 interactions, top by confidence:

A	B	Type	Score
EGFR	CISH	psi-mi:“MI:0915”(physical association)	0.740
CISH	EGFR	psi-mi:“MI:0407”(direct interaction)	0.740
CISH	TPP1	psi-mi:“MI:0915”(physical association)	0.560
CISH	DNM2	psi-mi:“MI:0915”(physical association)	0.560
CISH	CARF	psi-mi:“MI:0915”(physical association)	0.560
ATXN1	CISH	psi-mi:“MI:0915”(physical association)	0.560
DYNLL1	BCL2L11	psi-mi:“MI:0914”(association)	0.500
CISH	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.440
ETV5	CISH	psi-mi:“MI:0915”(physical association)	0.370
CISH	HSPA6	psi-mi:“MI:0915”(physical association)	0.370
MAP3K7CL	CISH	psi-mi:“MI:0915”(physical association)	0.370
EPOR	CISH	psi-mi:“MI:0915”(physical association)	0.370
SMAD2	CISH	psi-mi:“MI:0915”(physical association)	0.370
CISH	CUL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (60): CISH (Two-hybrid), TBC1D10B (Affinity Capture-MS), CUL5 (Affinity Capture-MS), AMBRA1 (Affinity Capture-MS), CISH (Affinity Capture-Western), UBC (Affinity Capture-Western), CISH (PCA), CISH (Affinity Capture-Luminescence), GHR (Protein-peptide), CUL5 (Affinity Capture-MS), AMBRA1 (Affinity Capture-MS), CISH (Affinity Capture-Western), tat (Reconstituted Complex), IL7R (Affinity Capture-Western), CISH (Affinity Capture-Western)

ESM2 similar proteins: A4Q9F4, A6QLH5, D3Z7P3, D3ZVU9, E9PV86, M0R7T9, O35652, O43414, O54804, O60242, O60347, O70512, O94925, P08887, P0C7M8, P13264, P35790, P85298, Q01134, Q08DW9, Q13202, Q13505, Q2HJ53, Q2TBM7, Q3UGX3, Q4R766, Q4R7M4, Q58DH2, Q5XI70, Q62225, Q6AYT7, Q6DN14, Q80T74, Q80UW0, Q80ZF8, Q86W50, Q8C460, Q8N2K0, Q8NBA8, Q8NHH1

Diamond homologs: O00459, O08908, O14508, O14512, O14543, O14544, O15524, O35716, O35717, O35718, O46404, O54928, O55033, O70512, O75159, O88582, O88583, P23726, P23727, P26450, P27986, Q0VC91, Q29RN6, Q2HJ53, Q54RB7, Q5R685, Q5RCM6, Q5RDX2, Q62225, Q63787, Q63788, Q63789, Q64143, Q68AM8, Q7YRV6, Q861R0, Q8UUU2, Q8VHQ2, Q8WXH5, Q90X67

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FLT3	“up-regulates quantity by expression”	CISH	“transcriptional regulation”
STAT5A	“up-regulates quantity by expression”	CISH	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 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
Neddylation	5	16.9×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein ubiquitination	5	12.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

451 predictions. Top by Δscore:

Variant	Effect	Δscore
3:50608368:CTCA:C	donor_loss	1.0000
3:50608369:TCA:T	donor_loss	1.0000
3:50608370:CA:C	donor_loss	1.0000
3:50608371:A:AT	donor_loss	1.0000
3:50608589:GAGGT:G	acceptor_gain	1.0000
3:50608590:AGGT:A	acceptor_gain	1.0000
3:50608591:GGT:G	acceptor_gain	1.0000
3:50608592:GT:G	acceptor_gain	1.0000
3:50608593:TCT:T	acceptor_loss	1.0000
3:50608594:C:CC	acceptor_gain	1.0000
3:50608594:CTAGA:C	acceptor_loss	1.0000
3:50611626:CTTA:C	donor_loss	1.0000
3:50611627:TTA:T	donor_loss	1.0000
3:50611628:TA:T	donor_loss	1.0000
3:50611629:A:AC	donor_gain	1.0000
3:50611629:A:AG	donor_loss	1.0000
3:50611629:AC:A	donor_gain	1.0000
3:50611629:ACC:A	donor_gain	1.0000
3:50611630:C:CC	donor_gain	1.0000
3:50611630:CC:C	donor_gain	1.0000
3:50611630:CCC:C	donor_gain	1.0000
3:50608138:CCAGC:C	acceptor_gain	0.9900
3:50608139:CAGCC:C	acceptor_gain	0.9900
3:50608141:GCC:G	acceptor_loss	0.9900
3:50608143:C:CA	acceptor_loss	0.9900
3:50608144:T:G	acceptor_loss	0.9900
3:50608148:CAAG:C	acceptor_gain	0.9900
3:50608151:G:C	acceptor_gain	0.9900
3:50608151:G:GC	acceptor_gain	0.9900
3:50608154:C:CT	acceptor_gain	0.9900

AlphaMissense

1650 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:50607970:G:C	F138L	1.000
3:50607970:G:T	F138L	1.000
3:50607972:A:G	F138L	1.000
3:50607992:A:T	I131N	1.000
3:50608064:C:G	R107P	1.000
3:50608065:G:T	R107S	1.000
3:50608072:G:C	F104L	1.000
3:50608072:G:T	F104L	1.000
3:50608073:A:G	F104S	1.000
3:50608074:A:G	F104L	1.000
3:50607908:A:G	L159P	0.999
3:50607925:A:C	F153L	0.999
3:50607925:A:T	F153L	0.999
3:50607927:A:G	F153L	0.999
3:50607971:A:C	F138C	0.999
3:50607971:A:G	F138S	0.999
3:50607992:A:C	I131S	0.999
3:50607996:G:T	R130S	0.999
3:50608029:A:G	S119P	0.999
3:50608031:A:G	L118P	0.999
3:50608037:A:G	F116S	0.999
3:50608057:G:C	S109R	0.999
3:50608057:G:T	S109R	0.999
3:50608058:C:A	S109I	0.999
3:50608059:T:G	S109R	0.999
3:50608070:A:G	L105S	0.999
3:50608079:C:A	G102V	0.999
3:50608080:C:G	G102R	0.999
3:50608140:A:G	W82R	0.999
3:50608140:A:T	W82R	0.999

dbSNP variants (sampled 300 via entrez): RS1000420183 (3:50611502 T>C), RS1000516669 (3:50606810 G>A), RS1001025462 (3:50609518 C>T), RS1001523882 (3:50606117 C>G), RS1001644100 (3:50612637 G>A), RS1001989852 (3:50612891 C>A,T), RS1003251703 (3:50607356 C>T), RS1003402691 (3:50610473 T>C), RS1003860190 (3:50609443 T>C), RS1003932284 (3:50609688 C>T), RS1004269324 (3:50610933 T>G), RS1004872510 (3:50609034 C>A,T), RS1005268032 (3:50611327 G>C), RS1005535865 (3:50612325 T>A), RS1006002676 (3:50612107 G>A,C)

Disease associations

OMIM: gene MIM:602441 | disease phenotypes: MIM:614383, MIM:611162

GenCC curated gene-disease

Mondo (2): bacteremia, susceptibility to, 2 (MONDO:0013724), malaria, susceptibility to (MONDO:0021024)

Orphanet (1): Malaria (Orphanet:673)

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002796_1	Bronchodilator response in asthma	2.000000e-10
GCST005860_2	Cholangiocarcinoma in primary sclerosing cholangitis (time to event)	4.000000e-06
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13
GCST90002382_567	Eosinophil percentage of white cells	8.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	3
Estradiol	increases expression	3
Doxorubicin	affects response to substance, decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
OTX015	decreases expression	1
aminomethylphosphonic acid (AMPA)	decreases expression	1
afimoxifene	decreases reaction, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases reaction, increases expression	1
di-n-butylphosphoric acid	affects expression	1
beta-hydroxy simvastatin acid	decreases expression	1
abrine	decreases expression	1
stattic	increases expression, decreases reaction	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Vehicle Emissions	decreases methylation	1
Benzene	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Benzoates	increases expression	1
Diuron	decreases expression	1
Estrogens	decreases reaction, increases expression	1
Ethinyl Estradiol	increases expression	1
Hydrogen Peroxide	affects expression	1
Methotrexate	decreases expression	1
Nickel	increases expression	1
Niclosamide	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Triclosan	increases expression	1

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8DT	Abcam HCT 116 CISH KO	Cancer cell line	Male
CVCL_B9G1	Abcam A-549 CISH KO	Cancer cell line	Male
CVCL_D2EG	Abcam MCF-7 CISH KO	Cancer cell line	Female
CVCL_D8J2	Ubigene HCT 116 CISH KO	Cancer cell line	Male
CVCL_D9C2	Ubigene HEK293 CISH KO	Transformed cell line	Female
CVCL_E0A8	Ubigene HeLa CISH KO	Cancer cell line	Female

Clinical trials (associated diseases)

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