TNIP2

Summary

TNIP2 (TNFAIP3 interacting protein 2, HGNC:19118) is a protein-coding gene on chromosome 4p16.3, encoding TNFAIP3-interacting protein 2 (Q8NFZ5). Inhibits NF-kappa-B activation by blocking the interaction of RIPK1 with its downstream effector NEMO/IKBKG.

This gene encodes a protein which acts as an inhibitor of NFkappaB activation. The encoded protein is also involved in MAP/ERK signaling pathway in specific cell types. It may be involved in apoptosis of endothelial cells. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on the X chromosome.

Source: NCBI Gene 79155 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 65 total
• MANE Select transcript: NM_024309

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19118
Approved symbol	TNIP2
Name	TNFAIP3 interacting protein 2
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	ABIN-2, MGC4289, KLIP, FLIP1, ABIN2
Ensembl gene	ENSG00000168884
Ensembl biotype	protein_coding
OMIM	610669
Entrez	79155

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000315423, ENST00000502256, ENST00000503235, ENST00000505186, ENST00000507686, ENST00000510267, ENST00000511352, ENST00000892917, ENST00000892918, ENST00000892919

RefSeq mRNA: 3 — MANE Select: NM_024309 NM_001161527, NM_001292016, NM_024309

CCDS: CCDS3362, CCDS54714, CCDS75093

Canonical transcript exons

ENST00000315423 — 6 exons

Exon	Start	End
ENSE00001340093	2756014	2756336
ENSE00002062117	2741648	2742520
ENSE00003596655	2744387	2744506
ENSE00003634160	2745446	2745535
ENSE00003649859	2747655	2747945
ENSE00003694688	2744697	2744945

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 95.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.1549 / max 215.6569, expressed in 1805 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51138	13.2520	1802
51137	0.2892	154
51132	0.2634	109
51134	0.1519	65
51136	0.1517	69
51133	0.0333	9
51135	0.0135	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	95.37	gold quality
pancreatic ductal cell	CL:0002079	94.59	silver quality
small intestine Peyer’s patch	UBERON:0003454	94.26	gold quality
granulocyte	CL:0000094	93.47	gold quality
mucosa of transverse colon	UBERON:0004991	93.45	gold quality
transverse colon	UBERON:0001157	93.01	gold quality
apex of heart	UBERON:0002098	92.97	gold quality
small intestine	UBERON:0002108	92.97	gold quality
mucosa of stomach	UBERON:0001199	92.89	gold quality
metanephros cortex	UBERON:0010533	92.59	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.51	gold quality
body of stomach	UBERON:0001161	92.09	gold quality
upper lobe of left lung	UBERON:0008952	92.00	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.97	gold quality
lower esophagus	UBERON:0013473	91.96	gold quality
monocyte	CL:0000576	91.87	gold quality
mononuclear cell	CL:0000842	91.82	gold quality
omental fat pad	UBERON:0010414	91.73	gold quality
mucosa of urinary bladder	UBERON:0001259	91.71	gold quality
peritoneum	UBERON:0002358	91.70	gold quality
upper lobe of lung	UBERON:0008948	91.67	gold quality
spleen	UBERON:0002106	91.66	gold quality
lymph node	UBERON:0000029	91.63	gold quality
leukocyte	CL:0000738	91.62	gold quality
gastrocnemius	UBERON:0001388	91.59	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.54	gold quality
gluteal muscle	UBERON:0002000	91.25	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.17	gold quality
triceps brachii	UBERON:0001509	91.11	gold quality
ascending aorta	UBERON:0001496	91.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.12

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB, NR1I2

miRNA regulators (miRDB)

39 targeting TNIP2, 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-340-5P	100.00	72.50	4437
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-6744-5P	99.93	66.82	748

Literature-anchored findings (GeneRIF, showing 24)

• transcription repressed by promyelocytic leukemia protein expression (PMID:12080044)
• FLIP1 has a role in the regulation of NF-kappaB activity related to the role of LKB1 in tumor suppression (PMID:12595760)
• Endothelial tyrosine kinase Tie2 interacts with ABIN-2. (PMID:12609966)
• ABIN-2 exerts unexpected function in mediating transcriptional coactivation. (PMID:12753905)
• ABIN-2 was found to inhibit endothelial apoptosis and rescue cells from death following growth factor deprivation. Deletion of the carboxy-terminus of ABIN-2 removed its ability to inhibit apoptosis. (PMID:12933576)
• optimal TPL-2 stability in vivo requires interaction with ABIN-2 as well as p105 (PMID:15169888)
• ABIN-2 may function as a negative regulator that downregulates NF-kappaB activation during liver regeneration (PMID:16480954)
• Thus, CIH-mediated NF-kappaB activation may be a molecular mechanism linking OSA and cardiovascular pathologies seen in OSA patients. (PMID:16554025)
• Thus the present results showed a correlation between NF-kappaB activation and the repair of sublethal damage in split-dose irradiation. (PMID:17038805)
• role for an ABIN-sensitive non-classical NF-kappaB signalling pathway in the proliferation of EGFR-overexpressing tumour cells. (PMID:18622428)
• This review defines ABIN-2 based on three different parameters: ability to bind A20; ability to inhibit NF-kappaB activation upon overexpression; the presence of specific short amino acid regions of strong homology, designated ABIN homology domains. (PMID:19464428)
• A20, ABIN-1/2, and CARD11 mutations have prognostic value in gastrointestinal diffuse large B-cell lymphoma (PMID:21266526)
• ABIN-2 acts as a positive regulator of NF-kappaB-dependent transcription by activating IKKalpha. (PMID:21784860)
• miR let-7a-regulated USP35 can inhibit NF-kappaB activation by deubiquitination and stabilization of ABIN-2 protein (PMID:26348204)
• miR-1180 might act as a tumor promoter by targeting TNIP2 during development of hepatocellular carcinoma. (PMID:27044843)
• Findings suggest an expanded role for the NF-kappaB network hub protein TNIP2 and reveals an association between TNIP2 and YLPM1, TNIP2 and ESCRT-I, together with many RNA processing proteins and a distinct set of mRNAs. (PMID:27609421)
• Study reports the crystal structure of hABIN2 in complex with linear triubiquitin, which shows the ubiquitins with M1-linkage could form a right-handed helical trimer when bridging two hABIN2 dimers, and thus allow the assembly of a higher-order signaling complex with A20. (PMID:27916521)
• RelAp43 interacts with the p105-ABIN2-TPL2 complex and we observe a strong perturbation of this complex in presence of M protein. (PMID:29084252)
• the data indicated that TNIP2 is significantly decreased in MODS following severe trauma, and it plays a protective role in MODS development by inhibiting the inflammation response and oxidative stress by preventing NFkappaB activation. (PMID:30720079)
• The increased inflammation of Map3k8(-/-) mice in allergic airway inflammation and colitis results from reduced ABIN-2 signaling, rather than blocked TPL-2 signaling. (PMID:31401161)
• TNIP2 mediates GRbeta-promoted inflammation and is associated with severity of major depressive disorder. (PMID:33932528)
• Long noncoding RNA NAV2-AS5 relieves chondrocyte inflammation by targeting miR-8082/TNIP2 in osteoarthritis. (PMID:36503346)
• TNIP2 inhibits amyloidogenesis by regulating the 3’UTR of BACE1: An in vitro study. (PMID:37085111)
• TNFAIP3 interacting protein 2 relieves lipopolysaccharide (LPS)-induced inflammatory injury in endometritis by inhibiting NF-kappaB activation. (PMID:37904691)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnip2	ENSDARG00000074501
mus_musculus	Tnip2	ENSMUSG00000059866
rattus_norvegicus	Tnip2	ENSRNOG00000013805

Paralogs (2): TNIP3 (ENSG00000050730), TNIP1 (ENSG00000145901)

Protein

Protein identifiers

TNFAIP3-interacting protein 2 — Q8NFZ5 (reviewed: Q8NFZ5)

Alternative names: A20-binding inhibitor of NF-kappa-B activation 2, Fetal liver LKB1-interacting protein

All UniProt accessions (2): D6RGJ2, Q8NFZ5

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits NF-kappa-B activation by blocking the interaction of RIPK1 with its downstream effector NEMO/IKBKG. Forms a ternary complex with NFKB1 and MAP3K8 but appears to function upstream of MAP3K8 in the TLR4 signaling pathway that regulates MAP3K8 activation. Involved in activation of the MEK/ERK signaling pathway during innate immune response; this function seems to be stimulus- and cell type specific. Required for stability of MAP3K8. Involved in regulation of apoptosis in endothelial cells; promotes TEK agonist-stimulated endothelial survival. May act as transcriptional coactivator when translocated to the nucleus. Enhances CHUK-mediated NF-kappa-B activation involving NF-kappa-B p50-p65 and p50-c-Rel complexes.

Subunit / interactions. Interacts with STK11/LKB1, TNFAIP3, IKBKG, NFKB1, MAP3K8, TEK, RIPK1, CHUK, IKBKB and SMARCD1. Interacts with polyubiquitin. (Microbial infection) Interacts with severe fever with thrombocytopenia syndrome virus (SFTSV) NSs; this interaction promotes TPL2 complex formation and signaling activity leading to IL-10 production.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Ubiquitously expressed in all tissues examined.

Post-translational modifications. In vitro phosphorylated by CHUK. Ubiquitinated; undergoes ‘Lys-48’-linked polyubiquitination probably leading to constitutive proteasomal degradation which can be impaired by IKK-A/CHUK or IKBKB probably involving deubiquitination. Deubiquitinated by USP35; leading to stabilization and inhibition of TNFalpha-induced NF-kappa-B activation.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NFZ5-1	1	yes
Q8NFZ5-2	2

RefSeq proteins (3): NP_001154999, NP_001278945, NP_077285* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022008	EABR	Domain
IPR034735	NEMO_ZF	Domain

Pfam: PF12180

UniProt features (26 total): binding site 4, mutagenesis site 4, sequence variant 3, region of interest 3, coiled-coil region 3, helix 2, compositionally biased region 2, chain 1, zinc finger region 1, modified residue 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5H07	X-RAY DIFFRACTION	2.59

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFZ5-F1	82.09	0.59

Functional residue map

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

Ligand- & substrate-binding residues (4): 405; 408; 423; 427

Post-translational modifications (1): 7

Mutagenesis-validated functional residues (4):

Position	Phenotype
62	reduces phosphorylation.
146	reduces phosphorylation; reduces chuk-mediated nf-kappa-b activation.
309–310	abolishes ubiquitin binding.
313–314	abolishes ubiquitin binding; loss of inhibitory activity on nf-kappa-b activation.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5684264	MAP3K8 (TPL2)-dependent MAPK1/3 activation
R-HSA-5689896	Ovarian tumor domain proteases

MSigDB gene sets: 230 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_B_CELL_ACTIVATION, GOBP_TOLL_LIKE_RECEPTOR_9_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_MACROPHAGE_ACTIVATION, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (17): regulation of transcription by RNA polymerase II (GO:0006357), apoptotic process (GO:0006915), inflammatory response (GO:0006954), CD40 signaling pathway (GO:0023035), toll-like receptor 2 signaling pathway (GO:0034134), toll-like receptor 3 signaling pathway (GO:0034138), toll-like receptor 9 signaling pathway (GO:0034162), positive regulation of macrophage activation (GO:0043032), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), positive regulation of transcription by RNA polymerase II (GO:0045944), protein stabilization (GO:0050821), positive regulation of B cell activation (GO:0050871), interleukin-1-mediated signaling pathway (GO:0070498), cellular response to lipopolysaccharide (GO:0071222), negative regulation of endothelial cell apoptotic process (GO:2000352), regulation of canonical NF-kappaB signal transduction (GO:0043122)

GO Molecular Function (6): zinc ion binding (GO:0008270), protein kinase binding (GO:0019901), polyubiquitin modification-dependent protein binding (GO:0031593), K63-linked polyubiquitin modification-dependent protein binding (GO:0070530), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytosol (GO:0005829), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
MAP kinase activation	1
Interleukin-1 signaling	1
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
canonical NF-kappaB signal transduction	3
cellular anatomical structure	3
transcription by RNA polymerase II	2
endolysosomal toll-like receptor signaling pathway	2
regulation of canonical NF-kappaB signal transduction	2
regulation of DNA-templated transcription	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
defense response	1
cell surface receptor signaling pathway	1
cell surface toll-like receptor signaling pathway	1
positive regulation of leukocyte activation	1
macrophage activation	1
regulation of macrophage activation	1
positive regulation of intracellular signal transduction	1
negative regulation of intracellular signal transduction	1
regulation of transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
regulation of protein stability	1
B cell activation	1
regulation of B cell activation	1
positive regulation of lymphocyte activation	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-1	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
negative regulation of apoptotic process	1
endothelial cell apoptotic process	1
regulation of endothelial cell apoptotic process	1
regulation of intracellular signal transduction	1
transition metal ion binding	1
kinase binding	1
modification-dependent protein binding	1
polyubiquitin modification-dependent protein binding	1
binding	1
cation binding	1
nuclear lumen	1

Protein interactions and networks

STRING

2477 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNIP2	TNFAIP3	P21580	985
TNIP2	MAP3K8	P41279	915
TNIP2	TEK	Q02763	821
TNIP2	TNIP3	Q96KP6	763
TNIP2	NFKB1	P19838	758
TNIP2	TNIP1	Q15025	718
TNIP2	NFKB2	Q00653	607
TNIP2	NFKBIB	Q15653	546
TNIP2	IKBKB	O14920	511
TNIP2	BIRC2	Q13490	496
TNIP2	RELA	Q04206	489
TNIP2	CYLD	Q9NQC7	485
TNIP2	NFKBIA	P25963	465
TNIP2	REL	Q04864	459
TNIP2	TRADD	Q15628	459

IntAct

106 interactions, top by confidence:

A	B	Type	Score
MAP3K8	NFKB1	psi-mi:“MI:0914”(association)	0.930
IKBKG	RIPK1	psi-mi:“MI:0914”(association)	0.890
TNIP2	MAP3K8	psi-mi:“MI:0915”(physical association)	0.770
MAP3K8	TNIP2	psi-mi:“MI:0915”(physical association)	0.770
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.760
TNIP2	IKBKG	psi-mi:“MI:0915”(physical association)	0.760
IKBKG	TNIP2	psi-mi:“MI:0915”(physical association)	0.760
IKBKG	TNIP2	psi-mi:“MI:0403”(colocalization)	0.760
TNIP2	TNFAIP3	psi-mi:“MI:0915”(physical association)	0.690
NFKB1	TNIP2	psi-mi:“MI:0915”(physical association)	0.690
STK11	TNIP2	psi-mi:“MI:0915”(physical association)	0.680
TNIP2	STK11	psi-mi:“MI:0915”(physical association)	0.680
RELB	NFKBIE	psi-mi:“MI:0914”(association)	0.670
REL	NFKBIE	psi-mi:“MI:0914”(association)	0.670
TNIP2	NFKB1	psi-mi:“MI:0914”(association)	0.650
NFKB1	TNIP2	psi-mi:“MI:0915”(physical association)	0.650

BioGRID (1073): UBC (Reconstituted Complex), TNIP2 (Affinity Capture-MS), TNIP2 (Affinity Capture-MS), TNIP2 (Affinity Capture-MS), TNIP2 (Biochemical Activity), TNIP2 (Affinity Capture-MS), TNIP2 (Affinity Capture-MS), TNIP2 (Biochemical Activity), TNIP2 (Affinity Capture-MS), TNIP2 (Affinity Capture-MS), TNIP2 (Affinity Capture-MS), TNIP2 (Affinity Capture-MS), TNIP2 (Affinity Capture-MS), TNIP2 (Affinity Capture-MS), TNIP2 (Affinity Capture-MS)

ESM2 similar proteins: A0JMK8, A0JNH6, A0JNT9, A1A5D9, A6NC98, A6NGB0, A7YWC8, A9QT41, B1MTG4, B3EX63, B7ZNG0, F6XLV1, H7BZ55, O15049, O75154, P0CF95, P58660, Q0V9T6, Q2KJ21, Q2M1P5, Q2TAC2, Q3LUD3, Q3TMW1, Q3UMT1, Q4QRL3, Q5ND29, Q5TZA2, Q60952, Q6NSJ2, Q6NZW0, Q6PGZ0, Q6PHN1, Q6QZQ4, Q6ZP65, Q7TMK6, Q8BP01, Q8C7U1, Q8CB62, Q8CHW5, Q8CJ40

Diamond homologs: Q8NFZ5, Q99JG7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ITCH	down-regulates	TNIP2	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 76 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
RIP-mediated NFkB activation via ZBP1	6	82.3×	7e-09
TNFR1-induced NF-kappa-B signaling pathway	11	75.4×	4e-16
MAP3K8 (TPL2)-dependent MAPK1/3 activation	5	72.8×	2e-07
TNFR1-induced proapoptotic signaling	7	62.8×	2e-09
TICAM1, RIP1-mediated IKK complex recruitment	5	61.3×	5e-07
TRAF6 mediated NF-kB activation	6	55.9×	4e-08
TNF signaling	6	51.8×	6e-08
IKK complex recruitment mediated by RIP1	5	50.7×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
non-canonical NF-kappaB signal transduction	8	99.1×	2e-12
canonical NF-kappaB signal transduction	15	80.8×	9e-23
tumor necrosis factor-mediated signaling pathway	7	34.0×	2e-07
negative regulation of canonical NF-kappaB signal transduction	10	25.3×	1e-09
obsolete positive regulation of NF-kappaB transcription factor activity	7	21.2×	5e-06
cellular response to tumor necrosis factor	7	16.8×	2e-05
positive regulation of canonical NF-kappaB signal transduction	13	13.9×	1e-09
T cell receptor signaling pathway	5	11.2×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

945 predictions. Top by Δscore:

Variant	Effect	Δscore
4:2744385:ACC:A	donor_loss	1.0000
4:2744386:CC:C	donor_loss	1.0000
4:2744744:T:TA	donor_gain	1.0000
4:2745444:A:AC	donor_gain	1.0000
4:2745445:C:CC	donor_gain	1.0000
4:2745531:TCCGA:T	acceptor_gain	1.0000
4:2745532:CCGA:C	acceptor_gain	1.0000
4:2745532:CCGAC:C	acceptor_gain	1.0000
4:2745533:CGA:C	acceptor_gain	1.0000
4:2745533:CGAC:C	acceptor_gain	1.0000
4:2745536:C:CC	acceptor_gain	1.0000
4:2745536:CT:C	acceptor_loss	1.0000
4:2745539:CA:C	acceptor_gain	1.0000
4:2745540:A:C	acceptor_gain	1.0000
4:2747650:CCTA:C	donor_loss	1.0000
4:2747651:CTAC:C	donor_loss	1.0000
4:2747652:TA:T	donor_loss	1.0000
4:2747654:C:T	donor_loss	1.0000
4:2747681:T:A	donor_gain	1.0000
4:2747941:ATTTC:A	acceptor_gain	1.0000
4:2747942:TTTC:T	acceptor_gain	1.0000
4:2747943:TTC:T	acceptor_gain	1.0000
4:2747944:TC:T	acceptor_gain	1.0000
4:2747945:CC:C	acceptor_gain	1.0000
4:2747945:CCT:C	acceptor_loss	1.0000
4:2747946:C:CC	acceptor_gain	1.0000
4:2747947:T:C	acceptor_loss	1.0000
4:2747950:G:C	acceptor_gain	1.0000
4:2747950:G:GC	acceptor_gain	1.0000
4:2756011:TACCT:T	donor_loss	1.0000

AlphaMissense

2788 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:2742334:A:G	C405R	0.985
4:2744463:C:G	R317P	0.984
4:2744924:A:G	W227R	0.983
4:2744924:A:T	W227R	0.983
4:2744483:G:C	F310L	0.981
4:2744483:G:T	F310L	0.981
4:2744485:A:G	F310L	0.981
4:2744922:C:A	W227C	0.979
4:2744922:C:G	W227C	0.979
4:2744486:G:C	D309E	0.977
4:2744486:G:T	D309E	0.977
4:2744484:A:G	F310S	0.975
4:2742333:C:G	C405S	0.972
4:2742334:A:T	C405S	0.972
4:2744455:C:G	A320P	0.972
4:2742311:G:C	F412L	0.968
4:2742311:G:T	F412L	0.968
4:2742313:A:G	F412L	0.968
4:2744471:C:A	R314S	0.968
4:2744471:C:G	R314S	0.968
4:2744488:C:G	D309H	0.965
4:2744487:T:A	D309V	0.958
4:2744474:T:A	E313D	0.957
4:2744474:T:G	E313D	0.957
4:2744707:A:G	L299P	0.956
4:2744487:T:G	D309A	0.955
4:2744698:T:G	Q302P	0.952
4:2742332:G:C	C405W	0.948
4:2744492:C:A	K307N	0.948
4:2744492:C:G	K307N	0.948

dbSNP variants (sampled 300 via entrez): RS1000189091 (4:2746858 C>A), RS1000205122 (4:2752867 G>A), RS1000257257 (4:2752531 C>T), RS1000335260 (4:2742047 C>T), RS1000373527 (4:2741721 C>T), RS1000501734 (4:2751356 A>G), RS1000558113 (4:2747582 T>C,G), RS1000575574 (4:2752776 G>C), RS1000630076 (4:2750288 T>C,G), RS1000633896 (4:2757054 C>G,T), RS1000644370 (4:2746663 C>T), RS1000680989 (4:2742934 G>A), RS1000733115 (4:2742743 C>T), RS1000959491 (4:2751638 T>A,C), RS10011484 (4:2754707 G>A)

Disease associations

OMIM: gene MIM:610669 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005288_1	Extrinsic epigenetic age acceleration	2.000000e-11
GCST009597_185	Multiple sclerosis	2.000000e-06
GCST011096_22	Systemic lupus erythematosus	5.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0000473	epigenetic status
EFO:0022597	aging

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol S	decreases expression, affects cotreatment	2
Nickel	increases expression	2
Valproic Acid	affects expression, increases methylation	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
coumarin	increases phosphorylation	1
motexafin gadolinium	decreases expression	1
abrine	increases expression	1
jinfukang	increases expression	1
1-(2-chlorobenzyl)-5’-phenyl-3’H-spiro(indoline-3,2’-(1,3,4)thiadiazol)-2-one	increases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, affects expression	1
Arsenic	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Copper	affects binding, increases expression	1
Dexamethasone	decreases expression, affects cotreatment	1
Disulfiram	affects binding, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ozone	affects expression, increases abundance	1
Smoke	decreases expression	1
Thiram	increases expression	1
Vincristine	increases expression	1
1-Methyl-3-isobutylxanthine	decreases expression, affects cotreatment	1
Aflatoxin B1	increases expression	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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