TNF Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human TNF — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene TNF, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene TNF, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene TNF protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene TNF protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene TNF, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene TNF, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene TNF, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene TNF protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene TNF, summarize transcription factor regulatory data. If TNF is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate TNF — names with evidence type (ChIP-seq / predicted / experimentally validated) If TNF is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene TNF protein as a drug target, summarize pharmacology data. If TNF is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If TNF is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene TNF, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene TNF, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in TNF: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
TNF (tumor necrosis factor, HGNC:11892) is a master pro-inflammatory cytokine encoded on chromosome 6 and one of the most clinically actionable genes in immunology. Its protein (UniProt P01375) forms a compact 4-exon gene and signals through two cognate receptors, TNFR1 and TNFR2, driving NF-κB activation, apoptosis, and a broad cytokine cascade involving IL-1β, IL-6, and IFN-γ. Expression is highest in myeloid cells — granulocytes, monocytes, and bone marrow — and is transcriptionally controlled by 248 upstream regulators including NF-κB, STAT1/3, and AP-1. TNF is an exceptionally well-validated drug target with 1,875 molecules in ChEMBL and 7 approved agents, led by adalimumab (439 trials) and infliximab (340 trials), used across rheumatoid arthritis, IBD, and psoriasis. It is a VIP pharmacogene in PharmGKB, with 128 variant annotations — notably the promoter polymorphisms −308G/A and −238G/A — linked to variable therapeutic response. GWAS evidence connects the TNF locus to ulcerative colitis (p = 5.0e-65), inflammatory bowel disease, Crohn’s disease, and asthma, cementing its centrality in complex immune-mediated disease.
Gene identifiers
| Identifier | Value |
|---|---|
| HGNC ID | HGNC:11892 |
| Approved Symbol | TNF |
| Ensembl Gene ID | ENSG00000232810 |
| Entrez Gene ID | 7124 |
| OMIM ID | 191160 |
| Chromosome | 6 |
| Start Position (GRCh38) | 31,575,565 |
| End Position (GRCh38) | 31,578,336 |
| Strand | + |
Transcript identifiers
Ensembl Transcripts (2 total)
| Transcript ID | Biotype |
|---|---|
| ENST00000449264 | protein_coding |
| ENST00000699334 | protein_coding |
RefSeq Transcripts
| RefSeq ID | Type | MANE Select |
|---|---|---|
| NM_000594 | mRNA | ✓ |
CCDS
| CCDS ID |
|---|
| CCDS4702 |
Canonical Transcript: ENST00000449264 (Exons)
| Exon ID | Start | End | Length |
|---|---|---|---|
| ENSE00001939157 | 31,575,565 | 31,575,927 | 363 bp |
| ENSE00001610044 | 31,576,534 | 31,576,579 | 46 bp |
| ENSE00001691672 | 31,576,767 | 31,576,814 | 48 bp |
| ENSE00001933375 | 31,577,116 | 31,578,336 | 1,221 bp |
Total exon count: 4
Protein identifiers
UniProt accessions
- P01375 ✓ CANONICAL (reviewed SwissProt entry)
- A0A8V8TNL2 (unreviewed TrEMBL)
- Q5STB3 (unreviewed/secondary)
RefSeq protein (NP_)
- NP_000585 (MANE select, reviewed)
Protein domains and families
| ID | Name | Type | Database |
|---|---|---|---|
| IPR002959 | Tumour necrosis factor alpha | Family | InterPro |
| IPR006052 | Tumour necrosis factor domain | Domain | InterPro |
| IPR006053 | Tumour necrosis factor | Family | InterPro |
| IPR008983 | Tumour necrosis factor-like domain superfamily | Homologous superfamily | InterPro |
| IPR021184 | Tumour necrosis factor, conserved site | Conserved site | InterPro |
| PF00229 | TNF domain | Domain | Pfam |
| SM00207 | TNF domain | Domain | SMART |
| CD00184 | TNF domain | Domain | CDD |
| SSF49842 | TNF-like superfamily | Superfamily | SUPERFAMILY |
Antibody resources
9 therapeutic antibodies targeting TNF:
- Adalimumab (Whole mAb, G1, Active)
- Brivekimig1 (Trispecific, Active)
- Certolizumab (Fab, G1, Active)
- Golimumab (Whole mAb, G1, Active)
- Infliximab (Whole mAb, G1, NFD)
- Licaminlimab (scFv, Active)
- Ozoralizumab (Bispecific, NFD)
- Placulumab (VL+Fc, G1, Discontinued)
- Remtolumab (Bispecific Dual VD IG, Discontinued)
Structure
Experimental Structures
Total PDB entries: 50
X-ray Diffraction (44 structures):
- 1A8M (2.3 Å), 1TNF (2.6 Å), 2A25 (2.1 Å), 2E7A (1.8 Å), 2TUN (3.1 Å), 2ZJC (2.5 Å), 2ZPX (2.83 Å)
- 3ALQ (3.0 Å), 3IT8 (2.8 Å), 3L9J (2.1 Å), 3WD5 (3.101 Å)
- 4G3Y (2.6 Å), 4TSV (1.8 Å), 4TWT (2.85 Å), 4Y6O (1.6 Å)
- 5M2I (2.15 Å), 5M2J (1.9 Å), 5M2M (2.3 Å), 5MU8 (3.0 Å), 5TSW (2.5 Å), 5UUI (1.4 Å), 5WUX (2.9 Å), 5YOY (2.727 Å)
- 6OOY (2.5 Å), 6OOZ (2.8 Å), 6OP0 (2.55 Å), 6RMJ (2.65 Å)
- 6X81 (2.81 Å), 6X82 (2.75 Å), 6X83 (2.83 Å), 6X85 (2.85 Å), 6X86 (2.93 Å)
- 7JRA (2.1 Å), 7KP9 (2.15 Å), 7KPA (2.3 Å), 7KPB (3.0 Å), 7TA3 (2.5 Å), 7TA6 (2.67 Å)
- 8Z8M (2.59 Å), 9BN7 (1.92 Å), 9DJW (3.43 Å), 9OJO (1.358 Å), 9OJS (1.849 Å), 9OJY (2.158 Å), 9OK6 (2.776 Å)
Solution NMR (4 structures):
- 7ASY, 7AT7, 7ATB, 7QLF (transmembrane helix conformations)
Electron Microscopy (1 structure):
- 8ZUI (2.56 Å)
Predicted Structures
AlphaFold Model:
- Model ID: P01375 (human TNF)
- Global pLDDT Score: 84.72 (high confidence)
- Fraction with pLDDT > 70: 0.63 (63% very high confidence regions)
Cross-species orthologs
| Organism | Gene ID | Gene Symbol |
|---|---|---|
| Mouse (Mus musculus) | MGI:104798 | Tnf |
| Rat (Rattus norvegicus) | RGD:3876 | Tnf |
| Zebrafish (Danio rerio) | none | none |
| Fruit fly (Drosophila melanogaster) | none | none |
| Worm (C. elegans) | none | none |
| Yeast (S. cerevisiae) | none | none |
Clinical variants & AI predictions
Clinical Variants (ClinVar)
Total variants: 26
| Classification | Count |
|---|---|
| Pathogenic | 3 |
| Likely Pathogenic | 0 |
| VUS / Uncertain Significance | 13 |
| Likely Benign | 4 |
| Benign / Likely Benign | 1 |
| Benign | 1 |
| Risk Factor | 2 |
| Protective | 1 |
| Drug Response | 1 |
Top Pathogenic/Likely Pathogenic Variants:
| Variant ID | HGVS | Condition |
|---|---|---|
| 12386 | NM_000594.4:c.322C>T (p.Arg108Trp) | TNF receptor binding, altered |
| 12385 | L29S | TNF receptor binding, altered |
| 3362893 | TNF, 20-BP INS, NT190 | Immunodeficiency 127 (autosomal recessive) |
AI-Based Variant Effect Predictions
SpliceAI Predictions
- Total variants: 205 splice predictions
- Effect types: donor_gain, donor_loss, acceptor_gain, acceptor_loss
- Score range: 0.20–1.00
Top 30 scored predictions:
| Position | Effect | Score |
|---|---|---|
| 6:31575924:AGAG:A | donor_gain | 1.00 |
| 6:31575925:GAG:G | donor_gain | 1.00 |
| 6:31575925:GAGG:G | donor_gain | 1.00 |
| 6:31575926:AG:A | donor_gain | 1.00 |
| 6:31575927:GG:G | donor_gain | 1.00 |
| 6:31575928:G:GG | donor_gain | 1.00 |
| 6:31576580:G:GG | donor_gain | 1.00 |
| 6:31576532:A:AG | acceptor_gain | 1.00 |
| 6:31576533:G:GG | acceptor_gain | 1.00 |
| 6:31575922:G:T | donor_gain | 0.99 |
| 6:31575923:AAGAG:A | donor_gain | 0.99 |
| 6:31575924:AGAGG:A | donor_loss | 1.00 |
| 6:31575925:GAGGT:G | donor_loss | 1.00 |
| 6:31575927:GGTG:G | donor_loss | 1.00 |
| 6:31575929:T:G | donor_loss | 0.94 |
| 6:31576528:CAACA:C | acceptor_gain | 0.94 |
| 6:31576529:A:AG | acceptor_gain | 0.95 |
| 6:31576578:CAG:C | acceptor_loss | 0.98 |
| 6:31576579:AGT:A | acceptor_loss | 0.98 |
| 6:31576580:GTA:G | acceptor_loss | 0.98 |
| 6:31576533:G:T | acceptor_gain | 0.88 |
| 6:31576572:GGCA:G | donor_gain | 0.98 |
| 6:31576573:GCAG:G | donor_gain | 0.98 |
| 6:31575679:C:T | donor_gain | 0.84 |
| 6:31576578:C:A | donor_gain | 0.83 |
| 6:31575784:G:GT | donor_gain | 0.83 |
| 6:31575602:C:G | donor_gain | 0.74 |
| 6:31575922:G:GT | donor_gain | 0.74 |
| 6:31576445:GGC:G | donor_gain | 0.61 |
| 6:31576573:GCA:G | donor_gain | 0.60 |
AlphaMissense Pathogenicity Predictions
- Total variants: 176 total (100+ likely_pathogenic)
- Filter: likely_pathogenic variants
Top 30 likely-pathogenic variants (by AM pathogenicity score):
| Position | Variant | AM Pathogenicity Score |
|---|---|---|
| 6:31575869:G:A | G43D | 0.978 |
| 6:31576803:C:A | A90D | 0.991 |
| 6:31576805:C:G | H91D | 0.988 |
| 6:31576805:C:T | H91Y | 0.955 |
| 6:31576806:A:C | H91P | 0.956 |
| 6:31576806:A:G | H91R | 0.971 |
| 6:31576807:T:A | H91Q | 0.983 |
| 6:31576807:T:G | H91Q | 0.983 |
| 6:31576809:T:A | V92D | 0.988 |
| 6:31576802:G:C | A90P | 0.984 |
| 6:31576805:C:A | H91N | 0.969 |
| 6:31576865:G:C | A42P | 0.788 |
| 6:31576866:C:A | A42E | 0.914 |
| 6:31575761:T:C | I7T | 0.906 |
| 6:31575841:A:C | S34R | 0.906 |
| 6:31575843:C:A | S34R | 0.906 |
| 6:31575843:C:G | S34R | 0.906 |
| 6:31577140:T:A | L102H | 0.934 |
| 6:31577116:C:A | A94E | 0.947 |
| 6:31575872:C:A | A44D | 0.949 |
| 6:31576805:C:A | H91N | 0.969 |
| 6:31575871:G:C | A44P | 0.865 |
| 6:31575761:T:G | I7S | 0.844 |
| 6:31575759:G:A | M6I | 0.836 |
| 6:31575759:G:C | M6I | 0.836 |
| 6:31575759:G:T | M6I | 0.836 |
| 6:31576808:G:T | V92F | 0.842 |
| 6:31576802:G:A | A90T | 0.821 |
| 6:31576800:T:A | V89E | 0.821 |
| 6:31576803:C:T | A90V | 0.821 |
Pathways & Gene Ontology
Reactome Pathways (10)
| ID | Pathway Name |
|---|---|
| R-HSA-75893 | TNF signaling |
| R-HSA-5357786 | TNFR1-induced proapoptotic signaling |
| R-HSA-5357905 | Regulation of TNFR1 signaling |
| R-HSA-5357956 | TNFR1-induced NF-kappa-B signaling pathway |
| R-HSA-5626978 | TNFR1-mediated ceramide production |
| R-HSA-5668541 | TNFR2 non-canonical NF-kB pathway |
| R-HSA-381340 | Transcriptional regulation of white adipocyte differentiation |
| R-HSA-6783783 | Interleukin-10 signaling |
| R-HSA-6785807 | Interleukin-4 and Interleukin-13 signaling |
| R-HSA-9942503 | Differentiation of naive CD+ T cells to T helper 1 cells (Th1 cells) |
MSigDB Gene Sets (100)
TNF participates in 100 gene sets including inflammatory response (GO:0006954), immune response (GO:0006955), and NF-kappaB signaling pathway annotations.
Gene Ontology Annotations
Biological Process: 99 terms
TOP 20:
| GO ID | Term |
|---|---|
| GO:0006954 | inflammatory response |
| GO:0006955 | immune response |
| GO:0043123 | positive regulation of canonical NF-kappaB signal transduction |
| GO:0007249 | canonical NF-kappaB signal transduction |
| GO:0033209 | tumor necrosis factor-mediated signaling pathway |
| GO:0043065 | positive regulation of apoptotic process |
| GO:0008625 | extrinsic apoptotic signaling pathway via death domain receptors |
| GO:0032755 | positive regulation of interleukin-6 production |
| GO:0032731 | positive regulation of interleukin-1 beta production |
| GO:0032757 | positive regulation of interleukin-8 production |
| GO:0050729 | positive regulation of inflammatory response |
| GO:0010744 | positive regulation of macrophage derived foam cell differentiation |
| GO:0045672 | positive regulation of osteoclast differentiation |
| GO:0030316 | osteoclast differentiation |
| GO:0002281 | macrophage activation involved in immune response |
| GO:0043410 | positive regulation of MAPK cascade |
| GO:0001819 | positive regulation of cytokine production |
| GO:0032722 | positive regulation of chemokine production |
| GO:0007254 | JNK cascade |
| GO:0046330 | positive regulation of JNK cascade |
Molecular Function: 8 terms
| GO ID | Term |
|---|---|
| GO:0005125 | cytokine activity |
| GO:0005164 | tumor necrosis factor receptor binding |
| GO:0048018 | receptor ligand activity |
| GO:0038177 | death receptor agonist activity |
| GO:0000976 | transcription cis-regulatory region binding |
| GO:0042802 | identical protein binding |
| GO:0002020 | protease binding |
| GO:0140072 | histone H3K9ac reader activity |
Cellular Component: 9 terms
| GO ID | Term |
|---|---|
| GO:0005576 | extracellular region |
| GO:0005615 | extracellular space |
| GO:0009986 | cell surface |
| GO:0005886 | plasma membrane |
| GO:0009897 | external side of plasma membrane |
| GO:0045121 | membrane raft |
| GO:0001891 | phagocytic cup |
| GO:0055037 | recycling endosome |
| GO:0043025 | neuronal cell body |
Protein interactions & networks
Protein-Protein Interactions (STRING, IntAct, BioGRID)
Total Interaction Count:
- STRING: ~10,273 interaction pairs
- BioGRID: 631 physical/genetic interactions
- IntAct: 212 curated binary interactions
TOP 30 Highest-Confidence Interacting Proteins:
| Rank | UniProt ID | Protein Name | STRING Score (evidence) | Interaction Type |
|---|---|---|---|---|
| 1 | P19438 | TNF Receptor Superfamily Member 1A (TNFRSF1A/TNFR1) | 9484 refs | Direct receptor |
| 2 | Q9Y4K3 | TNF Receptor-Associated Factor 6 (TRAF6) | 4234 refs | Signal transduction |
| 3 | P01584 | Interleukin-1 beta (IL-1β) | 8488 refs | Cytokine crosstalk |
| 4 | P05231 | Interleukin-6 (IL-6) | 9188 refs | Cytokine crosstalk |
| 5 | P01579 | Interferon gamma (IFN-γ) | 7348 refs | Cytokine crosstalk |
| 6 | P19838 | Nuclear Factor NF-kappa-B p105 (NFKB1) | 9484 refs | Transcription factor |
| 7 | P02751 | Fibronectin | 7594 refs | Extracellular matrix |
| 8 | P01730 | T-cell surface glycoprotein CD4 | 8138 refs | Immune cell interaction |
| 9 | P20333 | TNF Receptor Superfamily Member 1B (TNFRSF1B/TNFR2) | 2574 refs | Direct receptor |
| 10 | P22301 | Interleukin-10 (IL-10) | 6126 refs | Anti-inflammatory cytokine |
| 11 | O00220 | TNF Receptor Superfamily Member 10A (TNFRSF10A/DR4) | 1943 refs | Death receptor |
| 12 | P13500 | C-C Motif Chemokine 2 (CCL2) | 5672 refs | Chemokine crosstalk |
| 13 | P01732 | T-cell surface glycoprotein CD8 alpha (CD8A) | 6570 refs | Immune cell interaction |
| 14 | O14763 | TNF Receptor Superfamily Member 10B (TNFRSF10B/DR5) | 2176 refs | Death receptor |
| 15 | Q04206 | Transcription Factor p65 (NFKB3) | 5896 refs | Transcription factor |
| 16 | P48023 | TNF Ligand Superfamily Member 6 (FASL) | 4069 refs | Apoptosis ligand |
| 17 | P01583 | Interleukin-1 alpha (IL-1α) | 5063 refs | Cytokine crosstalk |
| 18 | O00206 | Toll-like Receptor 4 (TLR4) | 6826 refs | Pattern recognition receptor |
| 19 | P10145 | Interleukin-8 (IL-8) | 5340 refs | Chemokine crosstalk |
| 20 | P25445 | TNF Receptor Superfamily Member 6 (FAS/TNFRSF6) | 2638 refs | Death receptor |
| 21 | Q15628 | TNF Receptor Type 1-Associated DEATH Domain Protein (TRADD) | 1806 refs | Signal transduction |
| 22 | P08887 | Interleukin-6 Receptor Subunit Alpha (IL-6R) | 2716 refs | Receptor for IL-6 |
| 23 | P14778 | Interleukin-1 Receptor Type 1 (IL1R1) | 2743 refs | Cytokine receptor |
| 24 | P05112 | Interleukin-4 (IL-4) | 4899 refs | Th2 cytokine |
| 25 | P25942 | TNF Receptor Superfamily Member 5 (CD40) | 3416 refs | Co-stimulatory receptor |
| 26 | Q13158 | FAS-Associated Death Domain Protein (FADD) | 3372 refs | Signal transduction |
| 27 | P50591 | TNF Ligand Superfamily Member 10 (TRAIL) | 2598 refs | Apoptosis ligand |
| 28 | P01585 | Interleukin-2 (IL-2) | 6356 refs | T-cell growth factor |
| 29 | Q16552 | Interleukin-17A (IL-17A) | 4092 refs | Pro-inflammatory cytokine |
| 30 | P78507 | Unknown | 1700 refs | Unknown |
Protein Similarity
Structural/Embedding Similarity (ESM2, ~77 similar proteins):
Top 20 structurally/embedding-similar proteins:
- O35734, O77510, O77764 (TNF orthologs - different species)
- P01374 (Lymphotoxin-alpha)
- P04924 (Lymphotoxin-beta)
- P06804 (TNF Ligand Superfamily Member 11/RANKL)
- P13296 (TNF Ligand Superfamily Member 4/OX40L)
- P16599 (TNF Ligand Superfamily Member 5/CD40L)
- P19101 (TNF Ligand Superfamily Member 7/CD27L)
- P23383 (TNF Ligand Superfamily Member 8/GITRL)
- P23563 (TNF Ligand Superfamily Member 9/4-1BBL)
- P29553, P29965, P33620 (Additional TNF superfamily members)
- P36939, P36940 (TNF superfamily ligands)
- P48094, P48023 (TNF ligand superfamily members)
- P51435, P51742, P51743 (TNF superfamily ligands)
- P59684-P59695 (TNF superfamily ligands)
- P79337, P79374 (TNF-like ligands)
- Q06599, Q06600 (TNF-related cytokines)
- Q9BDM3, Q9BDM7, Q9BDN1, Q9BDN3 (TNF superfamily ligands)
Sequence Homology (Diamond/BLAST, 78 total):
Top 20 sequence homologous proteins (TNF superfamily members):
- P01374 (Lymphotoxin-alpha)
- P04924 (Lymphotoxin-beta)
- P06804 (RANKL/TNFSF11)
- P09225, P10154 (TNF superfamily members)
- P13296, P16599 (TNFSF4, CD40L/TNFSF5)
- P19101 (TNF Ligand Superfamily Member 7)
- P23383, P23563 (TNFSF8, TNFSF9/4-1BBL)
- P26445 (TNF superfamily member)
- P29553, P33620 (TNF superfamily ligands)
- P36939, P36940 (TNF superfamily members)
- P41047 (TNF superfamily ligand)
- P48023 (FAS ligand/TNFSF6)
- P48094 (TNF superfamily member)
- P51435, P51742, P51743 (TNF superfamily ligands)
- P59684, P59693-P59695 (TNF superfamily members)
- P61125 (TNF-related weak inducer of apoptosis/TWEAK)
- P63304-P63308 (TNF superfamily members)
- Q9BDM3 (TNF superfamily ligand)
Key Observations:
- TNF interactors primarily involve its two cognate receptors (TNFR1, TNFR2) and major signaling adaptors (TRAF proteins, TRADD, FADD)
- Strong interactions with inflammation-related cytokines (IL-1, IL-6, IFN-γ, IL-8) indicating cooperative immune activation
- Integration with NF-κB and MAPK signaling cascades via p105/p65
- Death receptor superfamily cross-talk through FAS, TRAIL, and DR4/DR5
- Structural homologs are exclusively TNF superfamily ligands sharing the ~17 kDa TNF homology domain
- Immune regulation via IL-10 and other anti-inflammatory mediators
Transcription factor regulatory data
TNF is not a transcription factor. TNF (tumor necrosis factor, P01375) is a pro-inflammatory cytokine, not a DNA-binding transcription factor. No JASPAR DNA-binding motifs are associated with TNF, confirming it lacks sequence-specific DNA-binding capacity.
While the CollectRI database shows TNF as a gene regulating other genes (e.g., TNF→ICAM1, TNF→IL6), these represent indirect transcriptional effects through TNF receptor signaling and downstream TF activation, not direct transcriptional regulation.
Upstream regulators of TNF
Total count: 248 transcription factors regulate TNF gene expression.
Selected upstream regulators with evidence type:
| TF | Regulation | Confidence |
|---|---|---|
| NF-κB (NFKB1) | Activation | High (ChIP-seq) |
| STAT1 | Activation | High |
| STAT3 | Activation | High |
| AP-1 (FOS/JUN/ATF) | Activation | High |
| IRF1 | Activation | High |
| IRF3 | Activation | High |
| IRF8 | Activation | High |
| RELA (p65) | Activation | High |
| EGR1 | Activation | High |
| HIF1A | Activation | High |
| NFATC1 | Activation | High |
| NFATC2 | Activation | High |
| NFATC3 | Activation | High |
| ETS1 | Activation | High |
| ELK1 | Activation | High |
| SP1 | Activation | High |
| LITAF | Activation | High |
| NRF1 | Activation | High |
| HMGB2 | Activation | High |
| ESR1 | Activation | High |
| CREBP/CREB1 | Activation | High |
| CREM | Activation | High |
| ATF2 | Activation | High |
| ATF3 | Activation | High |
| PPARA | Repression | High |
| PPARG | Repression | High |
| NR4A1 | Repression | High |
Drug & pharmacology data
TNF is a well-characterized and highly clinically relevant drug target. Total molecules targeting TNF in ChEMBL: 1,875
Top 30 Targeting Molecules by Development Phase
Phase 4 (Approved):
| ID | Name | Type | Mechanism |
|---|---|---|---|
| CHEMBL1201580 | Adalimumab | Antibody | TNF-α inhibitor |
| CHEMBL1201581 | Infliximab | Antibody | TNF-α inhibitor |
| CHEMBL1201572 | Etanercept | Protein | TNF receptor fusion protein |
| CHEMBL1201833 | Golimumab | Antibody | TNF-α inhibitor |
| CHEMBL514800 | Apremilast | Small molecule | PDE4 inhibitor (indirect TNF suppression) |
| CHEMBL3707247 | Ozanimod | Small molecule | S1P receptor modulator (indirect TNF modulation) |
| CHEMBL131 | Prednisolone | Small molecule | Corticosteroid (TNF suppression) |
Phase 3:
| ID | Name | Type |
|---|---|---|
| CHEMBL4297565 | Certolizumab pegol | Antibody |
| CHEMBL2107911 | Onercept | Protein |
Phase 2:
| ID | Name | Type |
|---|---|---|
| CHEMBL1743057 | Pegsunercept | Protein |
| CHEMBL103667 | Doramapimod | Small molecule |
Top 20 Clinical Trials (by drug)
Adalimumab (CHEMBL1201580): 439 trials
- NCT00216177: Comparison with Infliximab for Rheumatoid Arthritis (Phase 4, Unknown)
- NCT01500278: Certolizumab vs Adalimumab for moderate-severe RA (Phase 4, Completed)
- NCT04183608: Treat-to-target with telemonitoring in Ulcerative Colitis (Phase 4, Recruiting)
Infliximab (CHEMBL1201581): 340 trials
- NCT00133315: TNF-α Blocking for Spondylarthropathies (Phase 4, Completed)
- NCT00246064: Infliximab RA Methotrexate Tapering Study (Phase 4, Completed)
- NCT00554710: Top-Down vs Step-Up for Crohn’s Disease (Phase 4, Completed)
- NCT00463580: Infliximab for Treatment-Resistant Depression (Phase 4, Completed)
Etanercept (CHEMBL1201572): 339 trials
- NCT00127842: REPArE Rating in Psoriatic Arthritis (Phase 4, Completed)
- NCT00259610: Treatment of Early Aggressive RA (Phase 4, Completed)
- NCT00654368: CAMEO—Methotrexate and Etanercept (Phase 4, Completed)
Golimumab (CHEMBL1201833): 89 trials
- NCT00264550: Efficacy in Rheumatoid Arthritis (Phase 3, Completed)
- NCT00265083: Safety and Efficacy in Ankylosing Spondylitis (Phase 3, Completed)
- NCT02425865: In-TARGET—Intensive Treatment in Ulcerative Colitis (Phase 4, Completed)
Certolizumab pegol (CHEMBL4297565): 13 trials
- NCT01500278: vs Adalimumab for moderate-severe RA (Phase 4, Completed)
Pharmacogenomics
TNF is a VIP (Very Important Pharmacogene) in PharmGKB with 128 variant annotations associated with drug response.
Known Drug-Gene Interactions:
| Drug | PharmGKB ID | Clinical Annotations | Variant Annotations | Key Finding |
|---|---|---|---|---|
| Infliximab | PA452639 | 21 | 128 | Strong pharmacogenomic evidence; response variability associated with TNF promoter polymorphisms (-308G/A, -238G/A) |
| Certolizumab pegol | PA165107055 | 4 | 15 | Clinical efficacy associations with TNF genetic variants |
| Golimumab | PA166316702 | 0 | 2 | Limited pharmacogenomic data available |
Key Pharmacogenomic Findings:
- TNF promoter region variants (-308G/A and -238G/A) are associated with baseline TNF production levels and therapeutic response to TNF inhibitors
- High TNF-producing genotypes (A/A) are associated with better response to TNF inhibitors in rheumatoid arthritis
- Genetic variants affecting TNF expression may predict clinical efficacy and dosing requirements
- Cross-reactivity to TNF inhibitors exists; variants may inform switch therapy decisions
Clinical Applications:
- TNF inhibitors are first-line agents for TNF-driven inflammatory conditions (RA, IBD, psoriasis, ankylosing spondylitis)
- Therapeutic drug monitoring (TDM) is increasingly used to optimize dosing and predict response
- No formal FDA-approved TNF genotyping guidelines exist, but genetic testing is emerging in research settings
Expression profiles
Tissue expression
TNF shows ubiquitous expression across tissues with distinct enrichment patterns. Expression breadth: ubiquitous (119 present calls out of 133 conditions). Based on Bgee data:
| Rank | Tissue/Cell Type | Expression Score | Quality |
|---|---|---|---|
| 1 | Granulocyte | 96.17 | Gold |
| 2 | Male germ line stem cell in testis | 87.11 | Gold |
| 3 | Bone marrow | 86.37 | Gold |
| 4 | Leukocyte | 85.79 | Gold |
| 5 | Monocyte | 85.61 | Gold |
| 6 | Bone marrow cell | 84.38 | Gold |
| 7 | Blood | 77.44 | Gold |
| 8 | Lymph node | 77.13 | Gold |
| 9 | Spleen | 72.08 | Gold |
| 10 | Vermiform appendix | 71.58 | Gold |
| 11 | Duodenum | 68.35 | Gold |
| 12 | Gall bladder | 65.81 | Gold |
| 13 | Apex of heart | 63.92 | Gold |
| 14 | Smooth muscle tissue | 62.41 | Gold |
| 15 | Primordial germ cell in gonad | 61.57 | Gold |
| 16 | Tonsil | 61.23 | Gold |
| 17 | Placenta | 60.86 | Gold |
| 18 | Rectum | 60.33 | Gold |
| 19 | Upper lobe of left lung | 59.23 | Gold |
| 20 | Metanephros cortex | 59.03 | Gold |
| 21 | Small intestine | 58.30 | Gold |
| 22 | Islet of Langerhans | 58.08 | Gold |
| 23 | Small intestine Peyer’s patch | 57.98 | Gold |
| 24 | Skin of abdomen | 57.84 | Gold |
| 25 | Lung | 57.39 | Gold |
| 26 | Heart left ventricle | 57.27 | Gold |
| 27 | Omental fat pad | 57.27 | Gold |
| 28 | Right coronary artery | 56.43 | Gold |
| 29 | Mucosa of transverse colon | 56.20 | Gold |
| 30 | Olfactory segment of nasal mucosa | 56.13 | Gold |
Tissue-specific patterns: TNF shows highest expression in myeloid lineage cells (granulocytes, monocytes) and immune tissues (bone marrow, lymph nodes, spleen), consistent with its canonical role in immune/inflammatory response. Secondary enrichment in barrier tissues (intestine, appendix, tonsil) and reproductive tissues (testis, placenta).
Cell type expression
Single Cell Expression Atlas (SCXA) analysis across 6 experiments:
| Metric | Value |
|---|---|
| Total experiments | 6 |
| Marker experiment count | 6 |
| Total cell clusters | 1,407 |
| Max mean expression | 5,009.09 |
| Average mean expression | 633.95 |
Notable single-cell datasets: TNF is marked as a signature gene in all 6 SCXA experiments, indicating robust and consistent cell-type-specific expression. Key dataset includes:
- E-GEOD-106540: Single-cell transcriptome analysis of CD4+ cytotoxic T lymphocyte precursors (2,244 cells) — demonstrates TNF expression in effector T cell populations
Cell-type-specific patterns: Expression marked across diverse cell populations, reflecting TNF’s roles in CD4+ T cell activation, myeloid cell inflammatory response, and immune regulation. The high marker frequency (6/6 experiments) indicates TNF serves as a reliable cell-type differentiator across multiple immune and stromal compartments.
Disease associations
Mendelian / Monogenic Disease
TNF is not annotated as a primary gene for Mendelian diseases in GenCC (curated gene-disease database), but the following immunodeficiency condition is linked:
| Disease | ID | Inheritance | Evidence |
|---|---|---|---|
| Immunodeficiency 127 | MONDO:0975832 | Unknown | ClinVar |
Note: TNF (MIM:191160) is primarily associated with disease susceptibility rather than monogenic disease causation. Most TNF-related conditions are complex traits with genetic predisposition.
Phenotype Associations (HPO)
17 clinical phenotypes associated with TNF:
| HPO ID | Phenotype |
|---|---|
| HP:0000006 | Autosomal dominant inheritance |
| HP:0000007 | Autosomal recessive inheritance |
| HP:0000613 | Photophobia |
| HP:0001426 | Non-Mendelian inheritance |
| HP:0002013 | Vomiting |
| HP:0002018 | Nausea |
| HP:0002077 | Migraine with aura |
| HP:0002083 | Migraine without aura |
| HP:0002099 | Asthma |
| HP:0002183 | Phonophobia |
| HP:0002202 | Pleural effusion |
| HP:0010516 | Thymus hyperplasia |
| HP:0011462 | Young adult onset |
| HP:0031273 | Shock |
| HP:0032262 | Pulmonary tuberculosis |
| HP:0032933 | Airway hyperresponsiveness |
| HP:4000007 | Bronchoconstriction |
Complex-Disease / GWAS Associations
28 GWAS loci associated with TNF (top associations by p-value):
| Trait | GWAS ID | P-value | Mapped Gene(s) |
|---|---|---|---|
| Ulcerative colitis | GCST004133_30 | 5.0e-65 | HLA-DQA1 |
| Inflammatory bowel disease | GCST004131_25 | 2.0e-31 | HLA-DQA1 |
| AIDS progression | GCST000308_1 | 3.0e-19 | HCP5 |
| Asthma | GCST008916_32 | 2.0e-14 | HLA-B |
| Asthma and major depressive disorder | GCST008921_1 | 2.0e-16 | MICB |
| Autism spectrum disorder or schizophrenia | GCST004521_229 | 8.0e-20 | SFTA2 |
| Pulse pressure | GCST007269_18 | 8.0e-19 | LTA - TNF |
| Neonatal lupus | GCST000738_5 | 5.0e-10 | HCP5, MICB-DT |
| Crohn’s disease | GCST000879_48 | 4.0e-11 | LTA - TNF |
| Type 1 diabetes (age at diagnosis) | GCST011773_10 | 3.0e-07 | TNF |
| Cervical cancer | GCST004833_9 | 6.0e-09 | LTA |
| Waist-to-hip ratio adjusted for BMI | GCST012230_545 | 3.0e-12 | LTA - TNF |
| Autism spectrum disorder or schizophrenia | GCST004521_53 | 2.0e-15 | LINC00243 |
| Autism spectrum disorder or schizophrenia | GCST004521_209 | 5.0e-16 | LINC02571 - HLA-B |
| Autism spectrum disorder or schizophrenia | GCST004521_211 | 5.0e-15 | HCP5, MICB-DT |
| Asthma | GCST008916_35 | 1.0e-09 | NFKBIL1 - LTA |
| Malaria | GCST010725_96 | 3.0e-06 | MICB-DT, HCP5 |
| Autism spectrum disorder or schizophrenia | GCST004521_265 | 7.0e-14 | PSORS1C1 |
| Asthma | GCST008916_130 | 1.0e-09 | NFKBIL1 - LTA |
| Asthma (childhood onset) | GCST008917_2 | 4.0e-07 | MICB |
| Psychosis (atypical) | GCST002211_10 | 4.0e-06 | PRRC2A, SNORA38 |
| Autism spectrum disorder or schizophrenia | GCST004521_76 | 2.0e-10 | TNXB |
| Autism spectrum disorder or schizophrenia | GCST004521_188 | 1.0e-09 | RNU6-1133P - C6orf15 |
| Autism spectrum disorder or schizophrenia | GCST004521_17 | 3.0e-15 | FGFR3P1 - ZDHHC20P2 |
| Autism spectrum disorder or schizophrenia | GCST004521_156 | 1.0e-14 | TSBP1-AS1 |
| Autism spectrum disorder or schizophrenia | GCST004521_213 | 5.0e-13 | PPT2 |
| Malaria | GCST010725_71 | 5.0e-07 | MICB-DT, HCP5 |
| Mondo disease susceptibilities | - | - | Migraine (MONDO:0008000), Endometriosis (MONDO:0005133), Asthma (MONDO:0010940), Psoriatic arthritis (MONDO:0100232) |