TNFRSF9

Summary

TNFRSF9 (TNF receptor superfamily member 9, HGNC:11924) is a protein-coding gene on chromosome 1p36.23, encoding Tumor necrosis factor receptor superfamily member 9 (Q07011). Receptor for TNFSF9/4-1BBL.

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. The expression of this receptor is induced by lymphocyte activation. TRAF adaptor proteins have been shown to bind to this receptor and transduce the signals leading to activation of NF-kappaB.

Source: NCBI Gene 3604 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 109 with lymphoproliferation (Definitive, ClinGen)
• GWAS associations: 12
• Clinical variants (ClinVar): 208 total — 10 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 18
• Druggable target: yes
• MANE Select transcript: NM_001561

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11924
Approved symbol	TNFRSF9
Name	TNF receptor superfamily member 9
Location	1p36.23
Locus type	gene with protein product
Status	Approved
Aliases	CD137, 4-1BB
Ensembl gene	ENSG00000049249
Ensembl biotype	protein_coding
OMIM	602250
Entrez	3604

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 nonsense_mediated_decay

ENST00000377507, ENST00000474475, ENST00000492571, ENST00000674210, ENST00000875592

RefSeq mRNA: 1 — MANE Select: NM_001561 NM_001561

CCDS: CCDS92

Canonical transcript exons

ENST00000377507 — 8 exons

Exon	Start	End
ENSE00000737094	7938721	7938828
ENSE00000737133	7938193	7938330
ENSE00001474151	7915871	7920923
ENSE00001474161	7939895	7940078
ENSE00001474163	7940784	7940839
ENSE00002813071	7937690	7937756
ENSE00002917042	7933162	7933296
ENSE00003563949	7935013	7935143

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 93.78.

FANTOM5 (CAGE): breadth broad, TPM avg 6.8426 / max 512.2046, expressed in 553 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10081	6.8426	553

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	93.78	gold quality
lymph node	UBERON:0000029	74.17	gold quality
cartilage tissue	UBERON:0002418	72.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.28	silver quality
blood	UBERON:0000178	70.92	gold quality
vermiform appendix	UBERON:0001154	69.68	gold quality
leukocyte	CL:0000738	67.05	gold quality
monocyte	CL:0000576	66.96	gold quality
mononuclear cell	CL:0000842	66.77	gold quality
caecum	UBERON:0001153	66.44	gold quality
granulocyte	CL:0000094	65.36	gold quality
heart right ventricle	UBERON:0002080	63.57	gold quality
vena cava	UBERON:0004087	63.56	gold quality
gall bladder	UBERON:0002110	63.44	gold quality
tonsil	UBERON:0002372	63.23	gold quality
thymus	UBERON:0002370	62.82	silver quality
pancreatic ductal cell	CL:0002079	61.57	silver quality
quadriceps femoris	UBERON:0001377	60.70	gold quality
left ventricle myocardium	UBERON:0006566	60.50	gold quality
vastus lateralis	UBERON:0001379	60.35	gold quality
cerebellar vermis	UBERON:0004720	60.02	gold quality
spleen	UBERON:0002106	59.87	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	59.59	gold quality
rectum	UBERON:0001052	59.54	gold quality
cardiac muscle of right atrium	UBERON:0003379	59.49	gold quality
bone marrow	UBERON:0002371	59.34	gold quality
endometrium epithelium	UBERON:0004811	59.34	gold quality
nasal cavity epithelium	UBERON:0005384	59.16	gold quality
decidua	UBERON:0002450	58.90	gold quality
jejunal mucosa	UBERON:0000399	58.59	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-29	yes	1449.56
E-CURD-89	yes	848.09
E-GEOD-100618	yes	12.22
E-ANND-3	yes	6.14
E-MTAB-6678	no	3.58

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, JUN, NFKB1, NFKB, RELA

miRNA regulators (miRDB)

162 targeting TNFRSF9, 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-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-9983-3P	99.94	71.48	3631

Literature-anchored findings (GeneRIF, showing 40)

• intragraft gene expression is not a risk factor for acute cardiac allograft rejection (PMID:12009595)
• 4-1BB enhanced expansion, survival and effector functions of newly primed CD8(+) T cells. (PMID:12356681)
• 4-1BB plays a role in the differentiation of CD28(-)CD8(+) effector memory CTLs in cord blood. (PMID:12384425)
• relative importance of CD134 (OX40) and CD137 (4-1BB) in the costimulation of CD4+ and CD8+ T cells under comparable conditions of antigenic stimulation (PMID:12516549)
• 4-1 BB ligand can costimulate human CD28- T cells, resulting in cell division, inflammatory cytokine production, increased perforin levels, enhancement of cytolytic effector function, as well as the up-regulation of the anti-apoptotic protein Bcl-X(L). (PMID:12645943)
• First evidence of expression and synthesis of CD137 and its ligand by human brain cells. (PMID:13130507)
• 4-1BB mRNA, which was not detectable in normal liver, was found in 19 liver tissues adjacent to tumor edge (<1.0 cm). Low expression of 4-1BB mRNA was shown in hepatocellular carcinoma tissues and liver tissues within 1 to 5 cm away from tumor edge (PMID:14716821)
• Data suggest that levels of soluble 4-1BB and 4-1BB ligand in sera at the time of diagnosis may be indicative of the severity and outcome of rheumatoid arthritis. (PMID:15031666)
• 4-1BB/4-1BBL interactions contribute to the persistence of gut inflammation in Crohn’s disease (PMID:15308117)
• critical roles for interleukin-4 and IL-12 in regulating 4-1BB effects on Transforming growth factor-beta1-mediated suppression (PMID:15353478)
• The CD137 is a member of the tumor necrosis factor receptor family and a potent regulator of T cell activities. (PMID:15618293)
• The expression of CD134 was markedly higher, compared to CD137, both on the day of the surgery and ten days after colorectal cancer sursgery (PMID:15638367)
• stimulation of OX40/4-1BB rendered cells sensitive to apoptosis induced by TNF-alpha and reduced activation of NF-kappaB. OX40/4-1BB stimulation repressed the mitogen response in activated CD25+CD4+ T cells and preactivated CD8+ T cells (PMID:15941918)
• CD3+ T lymphocytes co-expressing CD134 and CD137 antigens on peripheral blood revealed an increased percentages of OX-40/CD137 positive cells in patients with Graves’ disease (p<0.025) compared to the controls. (PMID:16232366)
• Significantly higher soluble CD137 protein is associated with colorectal cancer patients (PMID:16596186)
• Transduction of HMCLs with 4-1BBL retroviruses induced a high expression of 4-1BBL molecules and a strong T-cell activation ability. (PMID:17309825)
• 4-1BB costimulation is essential for expanding memory CD8+ T cells ex vivo and is superior to CD28 costimulation for generating Ag-specific products for adoptive cell therapy (PMID:17878391)
• showed CD137L to be a key costimulatory ligand for proliferation of CD28(-) CD45RA(hi) CD8(+) T cells and not CD80, CD86, or CD275 (ICOSL) (PMID:17878400)
• Co-expression of NKG2D and 4-1BB may represent an important biomarker for defining competency of tumor infiltrating CD8(+) T cells (PMID:18024793)
• Tax was sufficient to induce the expression of the endogenous 4-1BB gene in uninfected T cells, and it strongly activated (45-fold) the 4-1BB promoter via a single NF-kappaB site. (PMID:18276843)
• CD137 can be enhanced on NK cells in an Fc-dependent fashion and expression correlates with phenotypic and functional parameters of activation. (PMID:18519814)
• These data offer a novel approach for UCB Treg expansion using aAPCs, including those coexpressing OX40L or 4-1BBL. (PMID:18645038)
• CCL23, M-CSF, TNFRSF9, TNF-alpha, and CXCL13 are predictive of rheumatoid arthritis disease activity and may be useful in the definition of disease subphenotypes and in the measurement of response to therapy in clinical studies. (PMID:18668547)
• The majority of beryllium-responsive IFN-gamma-producing CD4+ T cells in blood coexpress CD28 and 4-1BB; a transition occurs within the memory CD4+ T cell population from CD28 dependence in blood to a requirement for 4-1BB costimulation in lung. (PMID:18768897)
• Clinical association of serum CD137 (4-1BB) levels in patients with systemic sclerosis. (PMID:18838252)
• Incorporation of the CD137 signaling domain specifically reprogrammed cells for multifunctional cytokine secretion and enhanced persistence of T cells (PMID:19211796)
• Findings indicate that the loss of 4-1BB on HIV-specific CD4+ T cells is associated with viral replication and that it may contribute to reduced IL-2 production observed during chronic infection. (PMID:19406689)
• 4-1BBL and 4-1BB may have immunomodulatory functions, as shown by the anti-leukemia activity of MS-275 histone deacetylase inhibitor (PMID:19759901)
• CD137 costimulation may play a role in defining the fate of Ag-stimulated human B cells (PMID:20008291)
• Patients with acute coronary syndromes showed increased soluble and membrane-bound CD137 expression. sCD137 level showed a significantly positive correlation with CRP level in patients with acute coronary syndromes . (PMID:20026323)
• Data support a role for CD137 in the recruitment of monocytes to inflammatory tissues. (PMID:20347151)
• Results suggest with a two-step model of M cell differentiation, with initial CD137-independent commitment to the M cell lineage followed by CD137-CD137L interaction of M cells with CD137-activated B cells or dendritic cells for functional maturation. (PMID:20616340)
• CD137 ligand can also be expressed as a transmembrane protein on the cell surface and transmit signals into the cells on which it is expressed (reverse signaling). (PMID:20643812)
• significantly positive correlation between CD137 expression and complex coronary stenosis morphology (PMID:21396356)
• This work is the first to demonstrate the contribution of CD137 signaling to DENV-mediated apoptosis. (PMID:21669186)
• The measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with diffuse large B-cell lymphoma. (PMID:21670469)
• Data indicate that ex4-1BBL augments 4-1BB expression not only on the primed T cell, but also on DC. (PMID:21745658)
• CD137:CD137L interactions regulate the innate and adaptive immune response of the host against M. tuberculosis (PMID:21747409)
• The sCD137 levels correlate with the probability of complications and lethality. The association of sCD137, a product of activated T cells, with the severity of acute pancreatitis suggests that T cells contribute to the pathogenesis of acute pancreatitis. (PMID:21963611)
• Data indicate that 4-1BBL mediates NK-cell immunosubversion in CLL, and thus might contribute to the reportedly compromised efficacy of Rituximab to induce NK-cell reactivity in the disease. (PMID:22144129)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tnfrsf9	ENSMUSG00000028965
rattus_norvegicus	Tnfrsf9	ENSRNOG00000036942

Paralogs (21): FAS (ENSG00000026103), TNFRSF1B (ENSG00000028137), RELT (ENSG00000054967), NGFR (ENSG00000064300), TNFRSF1A (ENSG00000067182), CD40 (ENSG00000101017), TNFRSF10A (ENSG00000104689), LTBR (ENSG00000111321), TNFRSF10B (ENSG00000120889), TNFRSF8 (ENSG00000120949), CD27 (ENSG00000139193), TNFRSF11A (ENSG00000141655), TNFRSF21 (ENSG00000146072), TNFRSF14 (ENSG00000157873), TNFRSF11B (ENSG00000164761), TNFRSF10D (ENSG00000173530), TNFRSF10C (ENSG00000173535), TNFRSF4 (ENSG00000186827), TNFRSF18 (ENSG00000186891), TNFRSF25 (ENSG00000215788), TNFRSF6B (ENSG00000243509)

Protein

Protein identifiers

Tumor necrosis factor receptor superfamily member 9 — Q07011 (reviewed: Q07011)

Alternative names: 4-1BB ligand receptor, CDw137, T-cell antigen 4-1BB homolog, T-cell antigen ILA

All UniProt accessions (4): A0A6I8PRR4, Q07011, K7EJ11, K7EJQ2

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for TNFSF9/4-1BBL. Conveys a signal that enhances CD8(+) T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors.

Subunit / interactions. Predominantly homodimeric, but may also exist as a monomer. Interacts with TRAF1, TRAF2 and TRAF3. Interacts with LRR-repeat protein 1/LRR-1.

Subcellular location. Cell membrane.

Tissue specificity. Expressed on the surface of activated T-cells.

Disease relevance. Immunodeficiency 109 with lymphoproliferation (IMD109) [MIM:620282] An autosomal recessive primary immune disorder characterized by recurrent sinopulmonary infections, susceptibility to infection with Epstein-Barr virus (EBV), persistent EBV viremia, and EBV-induced lymphoproliferation or B-cell lymphoma. The disease may be caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_001552* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001368	TNFR/NGFR_Cys_rich_reg	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR020413	TNFR_9	Family
IPR034020	TNFRSF9_N	Domain

Pfam: PF00020

UniProt features (47 total): strand 15, disulfide bond 10, sequence variant 5, repeat 4, helix 3, region of interest 2, glycosylation site 2, topological domain 2, signal peptide 1, chain 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
6A3W	X-RAY DIFFRACTION	2
6Y8K	X-RAY DIFFRACTION	2.01
6MGP	X-RAY DIFFRACTION	2.13
8GYE	X-RAY DIFFRACTION	2.3
7YXU	X-RAY DIFFRACTION	2.31
6BWV	X-RAY DIFFRACTION	2.4
6CPR	X-RAY DIFFRACTION	2.7
6MI2	X-RAY DIFFRACTION	2.72
6MHR	X-RAY DIFFRACTION	2.8
9F7Z	X-RAY DIFFRACTION	2.81
8OZ3	X-RAY DIFFRACTION	3.1
7D4B	X-RAY DIFFRACTION	3.14
6CU0	X-RAY DIFFRACTION	3.2
6A3V	X-RAY DIFFRACTION	3.39

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q07011-F1	81.78	0.53

Antibody-complex structures (SAbDab): 7 — 6A3W, 6MHR, 6MI2, 7D4B, 7YXU, 8GYE, 8OZ3

Functional residue map

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

Disulfide bonds (10): 28–37, 31–45, 48–62, 65–78, 68–86, 88–94, 99–106, 102–117, 121–133, 139–158

Glycosylation sites (2): 138, 149

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5669034	TNFs bind their physiological receptors

MSigDB gene sets: 0 (showing top):

GO Biological Process (4): apoptotic process (GO:0006915), negative regulation of cell population proliferation (GO:0008285), regulation of immature T cell proliferation in thymus (GO:0033084), regulation of cell population proliferation (GO:0042127)

GO Molecular Function (2): signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TNFR2 non-canonical NF-kB pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell population proliferation	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
immature T cell proliferation in thymus	1
regulation of immature T cell proliferation	1
regulation of cellular process	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2178 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFRSF9	TNFSF9	P41273	999
TNFRSF9	TNFSF4	P23510	993
TNFRSF9	CD247	P20963	988
TNFRSF9	CD70	P32970	985
TNFRSF9	CD80	P33681	958
TNFRSF9	TRAF1	Q13077	950
TNFRSF9	LGALS9	O00182	930
TNFRSF9	ICOSLG	O75144	926
TNFRSF9	A0A087X1L8	A0A087X1L8	925
TNFRSF9	CD276	Q5ZPR3	924
TNFRSF9	CD28	P10747	924
TNFRSF9	CD86	P42081	920
TNFRSF9	CD27	P26842	915
TNFRSF9	CD40	P25942	908
TNFRSF9	TNFRSF18	Q9Y5U5	907

IntAct

11 interactions, top by confidence:

A	B	Type	Score
TNFRSF9	TNFSF9	psi-mi:“MI:0914”(association)	0.820
TNFSF9	TNFRSF9	psi-mi:“MI:0915”(physical association)	0.820
TNFSF9	TNFRSF9	psi-mi:“MI:0407”(direct interaction)	0.820
TNFRSF9	SERP1	psi-mi:“MI:0915”(physical association)	0.560
TNFRSF9	WFS1	psi-mi:“MI:0914”(association)	0.350
TNFRSF9	SCO1	psi-mi:“MI:0914”(association)	0.350
MFSD14A	FAM171A2	psi-mi:“MI:0914”(association)	0.350
SERP1	TNFRSF9	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (56): ATP12A (Affinity Capture-MS), SLC39A6 (Affinity Capture-MS), CERK (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TRAF1 (Affinity Capture-Western), TRAF2 (Affinity Capture-Western), TRAF1 (Reconstituted Complex), TRAF2 (Reconstituted Complex), CERK (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), SNX11 (Affinity Capture-MS), ATP12A (Affinity Capture-MS), CYLD (Affinity Capture-Western), TRAF2 (Affinity Capture-Western), SERP1 (Two-hybrid)

ESM2 similar proteins: A5D7R1, D3ZF92, F1LW30, O00300, O08712, O08727, O14763, O62802, O70458, O70535, O75509, O77736, O95256, P01590, P20334, P20352, P22934, P25118, P25445, P25446, P26897, P30836, P41690, P42703, P51867, P83626, Q07011, Q13478, Q5M9I1, Q61098, Q63199, Q65Z14, Q6UXZ4, Q6X782, Q6X784, Q6X786, Q764M8, Q8K1S2, Q8K5B1, Q90VY2

Diamond homologs: A5D7R1, O00300, O08712, O08727, O35305, O73559, O95407, P07174, P08138, P0DTN0, P15725, P20333, P20334, P25119, P25942, P27512, P36941, P43489, P47741, P50284, P68636, P68637, Q07011, Q28203, Q3LRP1, Q3ZTK5, Q7YRL5, Q8SQ34, Q9Y6Q6, Q9Z0W1, P26842, O35714, Q9Y5U5, Q80WY6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	3
Uncertain significance	85
Likely benign	82
Benign	12

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1098717	Single allele	Pathogenic
1497827	NM_001561.6(TNFRSF9):c.100+1G>A	Pathogenic
2017053	NM_001561.6(TNFRSF9):c.310C>T (p.Gln104Ter)	Pathogenic
2020530	NM_001561.6(TNFRSF9):c.163del (p.Ser55fs)	Pathogenic
2033256	NM_001561.6(TNFRSF9):c.302del (p.Met101fs)	Pathogenic
2988687	NM_001561.6(TNFRSF9):c.345dup (p.Gly116fs)	Pathogenic
3727116	NM_001561.6(TNFRSF9):c.328_332del (p.Gln110fs)	Pathogenic
4712165	NM_001561.6(TNFRSF9):c.408G>A (p.Trp136Ter)	Pathogenic
4734619	NM_001561.6(TNFRSF9):c.151_157delinsCCCAGTCCCTGTCCACC (p.Asn51fs)	Pathogenic
4766537	NM_001561.6(TNFRSF9):c.58del (p.Arg20fs)	Pathogenic
1465455	NM_001561.6(TNFRSF9):c.545-1G>A	Likely pathogenic
3012278	NM_001561.6(TNFRSF9):c.413+2T>C	Likely pathogenic
3247912	NC_000001.10:g.(?7993202)(7993376_?)del	Likely pathogenic

SpliceAI

1536 predictions. Top by Δscore:

Variant	Effect	Δscore
1:7920787:T:TA	donor_gain	1.0000
1:7920829:T:TA	donor_gain	1.0000
1:7920830:C:A	donor_gain	1.0000
1:7937688:A:AC	donor_gain	1.0000
1:7937689:C:CC	donor_gain	1.0000
1:7937758:T:C	acceptor_gain	1.0000
1:7937763:T:TC	acceptor_gain	1.0000
1:7937769:A:C	acceptor_gain	1.0000
1:7940077:CT:C	acceptor_gain	1.0000
1:7920784:ATTT:A	donor_gain	0.9900
1:7920847:T:TA	donor_gain	0.9900
1:7921923:A:AC	donor_gain	0.9900
1:7933160:A:AC	donor_gain	0.9900
1:7933161:C:CC	donor_gain	0.9900
1:7935141:CAGCT:C	acceptor_gain	0.9900
1:7935145:T:C	acceptor_gain	0.9900
1:7935145:T:TC	acceptor_gain	0.9900
1:7935151:A:T	acceptor_gain	0.9900
1:7935155:C:CT	acceptor_gain	0.9900
1:7935156:A:T	acceptor_gain	0.9900
1:7935157:A:AC	acceptor_gain	0.9900
1:7935157:A:C	acceptor_gain	0.9900
1:7937689:CT:C	donor_gain	0.9900
1:7937756:CCT:C	acceptor_gain	0.9900
1:7937758:T:TC	acceptor_gain	0.9900
1:7937763:T:C	acceptor_gain	0.9900
1:7937769:A:AC	acceptor_gain	0.9900
1:7938188:CGTA:C	donor_loss	0.9900
1:7938189:GTAC:G	donor_loss	0.9900
1:7938190:TA:T	donor_loss	0.9900

AlphaMissense

1681 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:7937728:A:C	F125L	0.995
1:7937728:A:T	F125L	0.995
1:7937730:A:G	F125L	0.995
1:7938770:G:C	F53L	0.993
1:7938770:G:T	F53L	0.993
1:7938772:A:G	F53L	0.993
1:7937695:C:A	W136C	0.991
1:7937695:C:G	W136C	0.991
1:7938282:C:G	C86S	0.987
1:7938283:A:T	C86S	0.987
1:7938306:C:G	C78S	0.982
1:7938307:A:T	C78S	0.982
1:7938726:C:G	C68S	0.982
1:7938727:A:T	C68S	0.982
1:7938275:G:C	C88W	0.981
1:7938276:C:G	C88S	0.981
1:7938277:A:T	C88S	0.981
1:7938324:A:C	F72C	0.981
1:7938214:C:A	G109C	0.980
1:7938276:C:T	C88Y	0.980
1:7938786:C:G	C48S	0.979
1:7938787:A:T	C48S	0.979
1:7939895:C:A	G34C	0.979
1:7937729:A:C	F125C	0.977
1:7938234:C:G	C102S	0.976
1:7938235:A:T	C102S	0.976
1:7938744:C:T	C62Y	0.976
1:7935084:C:G	C158S	0.975
1:7935085:A:T	C158S	0.975
1:7937705:C:G	C133S	0.975

dbSNP variants (sampled 300 via entrez): RS1000050617 (1:7922746 A>T), RS1000115443 (1:7937726 T>C), RS1000116961 (1:7920665 T>G), RS1000145310 (1:7922987 C>T), RS1000164731 (1:7925827 G>A), RS1000285862 (1:7919301 A>G), RS1000358804 (1:7925421 T>C), RS1000631448 (1:7929932 G>A,T), RS1000692394 (1:7923834 C>G,T), RS1000725609 (1:7925609 C>T), RS1000750606 (1:7924188 G>A), RS1000944273 (1:7942268 T>G), RS1000953670 (1:7942236 A>C,T), RS1000964213 (1:7930349 G>A), RS1001091651 (1:7935740 G>A)

Disease associations

OMIM: gene MIM:602250 | disease phenotypes: MIM:620282

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 109 with lymphoproliferation	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency 109 with lymphoproliferation	Definitive	AR

Mondo (2): juvenile-onset Parkinson disease (MONDO:0000828), immunodeficiency 109 with lymphoproliferation (MONDO:0859526)

Orphanet (1): EBV-induced lymphoproliferative disease due to CD137 deficiency (Orphanet:664726)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001744	Splenomegaly
HP:0001876	Pancytopenia
HP:0002110	Bronchiectasis
HP:0002155	Hypertriglyceridemia
HP:0002783	Recurrent lower respiratory tract infections
HP:0003621	Juvenile onset
HP:0004315	Decreased circulating IgG concentration
HP:0008940	Generalized lymphadenopathy
HP:0011108	Recurrent sinusitis
HP:0011463	Childhood onset
HP:0011900	Hypofibrinogenemia
HP:0012189	Hodgkin lymphoma
HP:0012476	Decreased specific pneumococcal antibody level
HP:0020072	Persistent EBV viremia
HP:0030252	Absent circulating B cells
HP:0031382	Decreased anti-CD3/28-induced T-cell proliferation
HP:0410295	Complete or near-complete absence of specific antibody response to tetanus vaccine

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000612_39	Celiac disease	9.000000e-08
GCST000964_5	Ulcerative colitis	5.000000e-09
GCST001725_31	Inflammatory bowel disease	1.000000e-15
GCST002318_157	Rheumatoid arthritis	3.000000e-09
GCST002874_20	Psoriasis	8.000000e-07
GCST004131_79	Inflammatory bowel disease	1.000000e-12
GCST004132_92	Crohn’s disease	3.000000e-06
GCST004133_62	Ulcerative colitis	4.000000e-09
GCST005527_22	Psoriasis	2.000000e-08
GCST006959_96	Rheumatoid arthritis	5.000000e-06
GCST006988_210	Blond vs. brown/black hair color	2.000000e-23
GCST008155_65	Waist-hip ratio	8.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0003924	hair color
EFO:0004343	waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712857 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Tumour necrosis factor (TNF) receptor family

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
BT7480	Agonist	8.43	pKd
utomilumab	Agonist	8.06	pKd
urelumab	Agonist	7.78	pKd

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.46	EC50	3.5	nM	CHEMBL5204681
7.14	EC50	73	nM	CHEMBL5209847
6.97	Kd	108	nM	CHEMBL5202442
5.62	Kd	2370	nM	CHEMBL5176354

PubChem BioAssay actives

4 with measured affinity, of 13 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[(9R,12S,18S,21S,24R,30S,33S,36R,39S,42S,45S,51S,54S,57S,60R)-9-acetamido-60-[[(2S)-1-amino-3-[3-[1-[2-[[(9R,12S,15S,17R,21S,27S,30S,33S,36S,39S,42S,45R,48R,51S,54S,60R)-39-(4-carbamimidamidobutyl)-9-carbamoyl-36,48-bis(carboxymethyl)-17-hydroxy-27-[(1R)-1-hydroxyethyl]-30-(hydroxymethyl)-12,33-bis(1H-indol-3-ylmethyl)-42-(2-methylsulfanylethyl)-51-(naphthalen-1-ylmethyl)-4,11,14,20,26,29,32,35,38,41,44,47,50,53,59,65,68-heptadecaoxo-7,62,71-trithia-1,3,10,13,19,25,28,31,34,37,40,43,46,49,52,58,66-heptadecazahexacyclo[43.22.5.13,66.015,19.021,25.054,58]triheptacontan-60-yl]amino]-2-oxoethyl]triazol-4-yl]propanoylamino]-1-oxopropan-2-yl]carbamoyl]-39-benzyl-57-butyl-45-(carboxymethyl)-12-(2,2-dimethylpropyl)-33,54-bis[(4-hydroxyphenyl)methyl]-24,42-dimethyl-4,10,13,19,22,25,31,34,37,40,43,46,52,55,58,65,68-heptadecaoxo-7,62,71-trithia-1,3,11,14,20,23,26,32,35,38,41,44,47,53,56,59,66-heptadecazahexacyclo[34.31.5.13,66.014,18.026,30.047,51]triheptacontan-21-yl]propanoic acid	1893340: Agonist activity at human CD137 expressed in Jurkat T cells co-expressing response element driven luciferase reporter gene assessed as luminescence measured after 6 hrs by HT1376/CD137 reporter co-culture assay	ec50	0.0035	uM
3-[(9R,12S,15S,18S,24S,27S,30S,33R,36S,39S,45S,48S,54R)-54-[[(2S)-2-acetamidopropanoyl]amino]-9-[[(2S)-1-amino-3-[3-[1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[(9R,12S,15S,17R,21S,27S,30S,33S,36S,39S,42S,45R,48R,51S,54S,60R)-39-(4-carbamimidamidobutyl)-9-carbamoyl-36,48-bis(carboxymethyl)-17-hydroxy-27-[(1R)-1-hydroxyethyl]-30-(hydroxymethyl)-12,33-bis(1H-indol-3-ylmethyl)-42-(2-methylsulfanylethyl)-51-(naphthalen-1-ylmethyl)-4,11,14,20,26,29,32,35,38,41,44,47,50,53,59,65,68-heptadecaoxo-7,62,71-trithia-1,3,10,13,19,25,28,31,34,37,40,43,46,49,52,58,66-heptadecazahexacyclo[43.22.5.13,66.015,19.021,25.054,58]triheptacontan-60-yl]carbamoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]propanoylamino]-1-oxopropan-2-yl]carbamoyl]-39-(3-amino-3-oxopropyl)-30-benzyl-51-[(2S)-butan-2-yl]-12-butyl-48-(2-carboxyethyl)-24-(carboxymethyl)-15,36-bis[(4-hydroxyphenyl)methyl]-27-methyl-4,11,14,17,23,26,29,32,35,38,41,44,47,50,53,59,62-heptadecaoxo-7,56,65-trithia-1,3,10,13,16,22,25,28,31,34,37,40,43,46,49,52,60-heptadecazatetracyclo[31.28.5.13,60.018,22]heptahexacontan-45-yl]propanoic acid	1893340: Agonist activity at human CD137 expressed in Jurkat T cells co-expressing response element driven luciferase reporter gene assessed as luminescence measured after 6 hrs by HT1376/CD137 reporter co-culture assay	ec50	0.0730	uM
3-[(9R,12S,15S,18S,24S,27S,30S,33R,36S,39S,45S,48S,54R)-54-[[(2S)-2-acetamidopropanoyl]amino]-9-[[(2S)-1-amino-3-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[4-[3-[[3-[[2-[[2-[[2-[[2-[[2-[[2-[[2-[[2-[[2-[[2-[[(9R,12S,15S,17R,21S,27S,30S,33S,36S,39S,42S,45R,48R,51S,54S,60R)-39-(4-carbamimidamidobutyl)-9-carbamoyl-36,48-bis(carboxymethyl)-17-hydroxy-27-[(1R)-1-hydroxyethyl]-30-(hydroxymethyl)-12,33-bis(1H-indol-3-ylmethyl)-42-(2-methylsulfanylethyl)-51-(naphthalen-1-ylmethyl)-4,11,14,20,26,29,32,35,38,41,44,47,50,53,59,65,68-heptadecaoxo-7,62,71-trithia-1,3,10,13,19,25,28,31,34,37,40,43,46,49,52,58,66-heptadecazahexacyclo[43.22.5.13,66.015,19.021,25.054,58]triheptacontan-60-yl]amino]-2-oxoethyl]-methylamino]-2-oxoethyl]-methylamino]-2-oxoethyl]-methylamino]-2-oxoethyl]-methylamino]-2-oxoethyl]-methylamino]-2-oxoethyl]-methylamino]-2-oxoethyl]-methylamino]-2-oxoethyl]-methylamino]-2-oxoethyl]-methylamino]-2-oxoethyl]-methylamino]-3-oxopropyl]amino]-3-oxopropyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-1-oxopropan-2-yl]carbamoyl]-39-(3-amino-3-oxopropyl)-30-benzyl-51-[(2S)-butan-2-yl]-12-butyl-48-(2-carboxyethyl)-24-(carboxymethyl)-15,36-bis[(4-hydroxyphenyl)methyl]-27-methyl-4,11,14,17,23,26,29,32,35,38,41,44,47,50,53,59,62-heptadecaoxo-7,56,65-trithia-1,3,10,13,16,22,25,28,31,34,37,40,43,46,49,52,60-heptadecazatetracyclo[31.28.5.13,60.018,22]heptahexacontan-45-yl]propanoic acid	1893339: Binding affinity to human recombinant CD137 by surface plasmon resonance analysis	kd	0.1080	uM
3-[(9R,12S,18S,21S,24R,30S,33S,36R,39S,42S,45S,51S,54S,57S,60R)-9-acetamido-39-benzyl-57-butyl-24-[4-[3-[1-[2-[2-[2-[2-[2-[3-[[(9R,12S,15S,17R,21S,27S,30S,33S,36S,39S,42S,45R,48R,51S,54S,60R)-39-(4-carbamimidamidobutyl)-9-carbamoyl-36,48-bis(carboxymethyl)-17-hydroxy-27-[(1R)-1-hydroxyethyl]-30-(hydroxymethyl)-12,33-bis(1H-indol-3-ylmethyl)-42-(2-methylsulfanylethyl)-51-(naphthalen-1-ylmethyl)-4,11,14,20,26,29,32,35,38,41,44,47,50,53,59,65,68-heptadecaoxo-7,62,71-trithia-1,3,10,13,19,25,28,31,34,37,40,43,46,49,52,58,66-heptadecazahexacyclo[43.22.5.13,66.015,19.021,25.054,58]triheptacontan-60-yl]amino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]propanoylamino]butyl]-60-carbamoyl-45-(2-carboxyethyl)-12-(2,2-dimethylpropyl)-33,54-bis[(4-hydroxyphenyl)methyl]-42-methyl-4,10,13,19,22,25,31,34,37,40,43,46,52,55,58,65,68-heptadecaoxo-7,62,71-trithia-1,3,11,14,20,23,26,32,35,38,41,44,47,53,56,59,66-heptadecazahexacyclo[34.31.5.13,66.014,18.026,30.047,51]triheptacontan-21-yl]propanoic acid	1893327: Binding affinity to human CD137 assessed as dissociation constant by surface plasmon resonance analysis	kd	2.3700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	affects expression, increases expression	3
Benzo(a)pyrene	increases expression, affects methylation	3
Methotrexate	affects cotreatment, increases expression, decreases expression	3
Silicon Dioxide	increases expression	3
Cyclosporine	increases expression	3
bisphenol A	affects cotreatment, increases methylation, increases expression	2
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
(+)-JQ1 compound	decreases expression	2
Zoledronic Acid	increases expression, decreases expression	2
Acetaminophen	affects cotreatment, increases expression	2
Cisplatin	affects cotreatment, increases expression, decreases expression	2
Folic Acid	affects expression, affects response to substance, affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	affects expression, increases expression, increases reaction	2
Triclosan	increases expression, affects cotreatment	2
Zinc	affects cotreatment, increases expression, affects expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
bisphenol F	decreases expression, increases expression	1
apocarotenal	increases expression	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
propionaldehyde	increases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, increases expression	1
styrene oxide	increases expression	1
arsenite	affects expression	1
sulforaphane	increases expression	1
cobaltous chloride	decreases expression, increases expression	1
butyraldehyde	increases expression	1
2-tert-butylhydroquinone	increases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5149455	Binding	Agonist activity at recombinant human CD137 expressed in Jurkat T cells co-expressing response element driven luciferase reporter gene co-cultured with Nectin-4 expressing mouse MC38 cells assessed as luminescence measured after 6 hrs by lu	Discovery and Optimization of a Synthetic Class of Nectin-4-Targeted CD137 Agonists for Immuno-oncology. — J Med Chem

Cellosaurus cell lines

11 cell lines: 7 cancer cell line, 2 spontaneously immortalized cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7ZV	Raji-h4-1BB	Cancer cell line	Male
CVCL_B8R7	Abcam HCT 116 TNFRSF9 KO	Cancer cell line	Male
CVCL_B9TL	Abcam A-549 TNFRSF9 KO	Cancer cell line	Male
CVCL_D2HJ	Abcam MCF-7 TNFRSF9 KO	Cancer cell line	Female
CVCL_E6S7	Genomeditech CHO-K1 H_TNFRSF9(4-1BB)	Spontaneously immortalized cell line	Female
CVCL_E6V8	Genomeditech HEK-293 H_TNFRSF9(4-1BB) Reporter	Transformed cell line	Female
CVCL_E6W2	Genomeditech Jurkat H_TNFRSF9(4-1BB) Reporter	Cancer cell line	Male
CVCL_E8F0	Jurkat-Lucia h4-1BB	Cancer cell line	Male
CVCL_KA46	CHO-K1/4-1BB	Spontaneously immortalized cell line	Female
CVCL_UE20	293T human CD137	Transformed cell line	Female

Clinical trials (associated diseases)

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