PDCD1 Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human PDCD1 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene PDCD1, 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 PDCD1, 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 PDCD1 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 PDCD1 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 PDCD1, 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 PDCD1, 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 PDCD1, 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 PDCD1 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 PDCD1, summarize transcription factor regulatory data. If PDCD1 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 PDCD1 — names with evidence type (ChIP-seq / predicted / experimentally validated) If PDCD1 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene PDCD1 protein as a drug target, summarize pharmacology data. If PDCD1 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 PDCD1 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene PDCD1, 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 PDCD1, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in PDCD1: 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
PDCD1 (PD-1; HGNC:8760) encodes Programmed Cell Death Protein 1, a cell-surface immune checkpoint receptor and one of the most clinically important immunotherapy targets in modern oncology. Located on chromosome 2, it is expressed most highly in immune tissues — lymph nodes, spleen, blood, and bone marrow — and at the single-cell level is enriched in memory and activated CD4+ T cell populations. Its primary interactors are the ligands PD-L1 (CD274) and PD-L2 (PDCD1LG2), with downstream signaling mediated through SHP-2 (PTPN11) and AKT1. Six anti-PD-1/PD-L1 monoclonal antibodies are FDA-approved (including nivolumab and pembrolizumab), collectively spanning more than 5,700 clinical trials. PDCD1 is designated a VIP pharmacogene in PharmGKB, though no CPIC dosing guidelines exist. All 48 ClinVar variants are of uncertain significance, and AlphaMissense flags over 100 missense changes as likely pathogenic — concentrated around residues 248–253. Disease associations include susceptibility to mycobacterial infection and systemic lupus erythematosus, with 68 HPO phenotype terms in total.
Gene identifiers
| Identifier Type | Value |
|---|---|
| HGNC ID | HGNC:8760 |
| Approved Symbol | PDCD1 |
| Ensembl Gene ID | ENSG00000188389 |
| NCBI Entrez Gene ID | 5133 |
| OMIM Gene/Locus ID | 600244 |
| Chromosome | 2 |
| Start Position (GRCh38) | 241,849,884 |
| End Position (GRCh38) | 241,858,894 |
| Strand | − (negative) |
Transcript identifiers
Ensembl Transcripts (7 total)
| Transcript ID | Biotype |
|---|---|
| ENST00000334409 | protein_coding |
| ENST00000343705 | protein_coding |
| ENST00000418831 | nonsense_mediated_decay |
| ENST00000718473 | protein_coding |
| ENST00000718474 | nonsense_mediated_decay |
| ENST00000890793 | protein_coding |
| ENST00000944235 | protein_coding |
Total Ensembl transcripts: 7
RefSeq mRNA Accessions (9 total)
| Accession | MANE Select |
|---|---|
| NM_005018 | ✓ YES |
| NM_001106927 | No |
| NM_008798 | No |
| XM_006245524 | No |
| XM_006712573 | No |
| XM_008767396 | No |
| XM_017596858 | No |
| XM_054328654 | No |
| XM_054342460 | No |
CCDS ID
- CCDS33428
Exons for Canonical/MANE SELECT (ENST00000334409)
| Exon ID | Start | End | Chromosome |
|---|---|---|---|
| ENSE00001372954 | 241858763 | 241858894 | 2 |
| ENSE00001384908 | 241852621 | 241852980 | 2 |
| ENSE00003549266 | 241851949 | 241851983 | 2 |
| ENSE00003605706 | 241852198 | 241852353 | 2 |
| ENSE00004035194 | 241849884 | 241851297 | 2 |
Total exons: 5
Protein identifiers
UniProt accessions
- Q15116 ← canonical reviewed entry
- A0A0M3M0G7 (unreviewed)
- E7ER21 (unreviewed)
- H0Y2W6 (unreviewed)
RefSeq protein (NP_ accessions)
- NP_005009 (REVIEWED; MANE select)
- NP_001100397 (PROVISIONAL)
- NP_032824 (VALIDATED)
Protein domains and families
InterPro
| ID | Name | Type |
|---|---|---|
| IPR003599 | Immunoglobulin domain subtype | Domain |
| IPR007110 | Immunoglobulin-like domain | Domain |
| IPR013106 | Immunoglobulin V-set domain | Domain |
| IPR013783 | Immunoglobulin-like fold | Homologous_superfamily |
| IPR036179 | Immunoglobulin-like domain superfamily | Homologous_superfamily |
| IPR042379 | Programmed cell death protein 1 | Family |
Pfam
| ID | Name |
|---|---|
| PF07686 | Immunoglobulin domain |
SMART
| ID |
|---|
| SM00406 |
| SM00409 |
PANTHER
| ID | Name |
|---|---|
| PTHR15264 | PDCD1 family |
| PTHR15264:SF2 | PDCD1 subfamily |
Antibody availability
- Human Protein Atlas (HPA): Contains antibody resources and validation data for PDCD1
Structure
Experimental Structures
Total: 37 PDB entries
X-RAY DIFFRACTION (35 structures):
| PDB ID | Resolution (Å) |
|---|---|
| 3RRQ | 2.1 |
| 4ZQK | 2.45 |
| 5B8C | 2.146 |
| 5GGR | 3.3 |
| 5GGS | 1.997 |
| 5IUS | 2.889 |
| 5JXE | 2.9 |
| 5WT9 | 2.401 |
| 6HIG | 2.2 |
| 6J14 | 1.4 |
| 6J15 | 2.6 |
| 6JBT | 2.47 |
| 6JJP | 2.9 |
| 6K0Y | 1.7 |
| 6ROY | 2.1 |
| 6ROZ | 2.89 |
| 6UMT | 1.986 |
| 6UMU | 1.183 |
| 6UMV | 1.424 |
| 6XKR | 2.59 |
| 7BXA | 3.32 |
| 7CGW | 3.2 |
| 7CU5 | 2.81 |
| 7E9B | 1.78 |
| 7VUX | 1.64 |
| 7WSL | 1.534 |
| 7WVM | 3.4 |
| 8AS0 | 3.5 |
| 8EQ6 | 1.65 |
| 8GY5 | 1.98 |
| 8U31 | 2.73 |
| 8U32 | 2.51 |
| 9HK1 | 2.03 |
| 9Q8L | 1.85 |
| 9EHT | 1.544 |
SOLUTION NMR (2 structures):
| PDB ID | Resolution |
|---|---|
| 2M2D | No resolution reported |
| 6R5G | No resolution reported |
Predicted Structures
- AlphaFold Model ID: AF-Q15116-F1
- Global pLDDT Score: 74.53
- Fraction Very High Confidence (pLDDT ≥ 90): 36%
Let me search for orthologs in the ortholog dataset directly:
Clinical variants & AI predictions
ClinVar Summary
| Classification | Count |
|---|---|
| Uncertain Significance (VUS) | ~48 |
| Pathogenic | 0 |
| Likely Pathogenic | 0 |
| Likely Benign | 0 |
| Benign | 0 |
Total variant count: 48
Representative ClinVar variants (mostly VUS):
| Variant ID | HGVS | Classification |
|---|---|---|
| 3210522 | NM_005018.3:c.633G>T (p.Glu211Asp) | Uncertain significance |
| 2531224 | NM_005018.3:c.344G>A (p.Arg115His) | Uncertain significance |
| 3305293 | NM_005018.3:c.416G>A (p.Arg139Gln) | Uncertain significance |
| 3416048 | NM_005018.3:c.815G>A (p.Arg272Gln) | Uncertain significance |
| 3887099 | NM_005018.3:c.341G>A (p.Arg114Gln) | Uncertain significance |
AlphaMissense Pathogenicity Predictions
Total predictions: 1,846
Likely pathogenic: 100+ (showing top 30)
| Protein Change | Position | Pathogenicity Score | Classification |
|---|---|---|---|
| F253L | 253 | 0.988 | Likely pathogenic |
| F253C | 253 | 0.975 | Likely pathogenic |
| F253S | 253 | 0.969 | Likely pathogenic |
| I251S | 251 | 0.982 | Likely pathogenic |
| I251T | 251 | 0.962 | Likely pathogenic |
| I251N | 251 | 0.988 | Likely pathogenic |
| Y248C | 248 | 0.984 | Likely pathogenic |
| Y248S | 248 | 0.979 | Likely pathogenic |
| Y248H | 248 | 0.984 | Likely pathogenic |
| F228L | 228 | 0.988 | Likely pathogenic |
| F228C | 228 | 0.966 | Likely pathogenic |
| F228S | 228 | 0.957 | Likely pathogenic |
| Y223H | 223 | 0.865 | Likely pathogenic |
| A249T | 249 | 0.810 | Likely pathogenic |
| E247V | 247 | 0.901 | Likely pathogenic |
| W286C | 286 | 0.920 | Likely pathogenic |
| W286R | 286 | 0.903 | Likely pathogenic |
| L288H | 288 | 0.663 | Likely pathogenic |
| S180R | 180 | 0.957 | Likely pathogenic |
| G175R | 175 | 0.871 | Likely pathogenic |
| G176R | 176 | 0.893 | Likely pathogenic |
| L183R | 183 | 0.825 | Likely pathogenic |
| L177R | 177 | 0.752 | Likely pathogenic |
| G179D | 179 | 0.910 | Likely pathogenic |
| W186R | 186 | 0.838 | Likely pathogenic |
| V182E | 182 | 0.837 | Likely pathogenic |
| V185D | 185 | 0.652 | Likely pathogenic |
| T250P | 250 | 0.791 | Likely pathogenic |
| A249D | 249 | 0.966 | Likely pathogenic |
| L226P | 226 | 0.890 | Likely pathogenic |
SpliceAI Predictions
Total predictions: 688
| Variant | Effect | Score |
|---|---|---|
| 2:241851295:CTT:C | acceptor_gain | 1.0000 |
| 2:241851299:T:C | acceptor_gain | 1.0000 |
| 2:241851300:T:C | acceptor_gain | 1.0000 |
| 2:241851300:T:TC | acceptor_gain | 1.0000 |
| 2:241851292:CTCC:C | acceptor_gain | 0.9800 |
| 2:241851293:TCCT:T | acceptor_gain | 0.9800 |
| 2:241851291:CCTC:C | acceptor_gain | 0.9800 |
| 2:241851291:CCTCC:C | acceptor_gain | 0.9700 |
| 2:241851290:TCCTC:T | acceptor_gain | 0.9700 |
| 2:241851262:C:T | acceptor_gain | 0.8300 |
| 2:241851262:C:CT | acceptor_gain | 0.9700 |
| 2:241851292:CTC:C | acceptor_gain | 0.9000 |
| 2:241851296:TT:T | acceptor_gain | 0.9900 |
| 2:241851293:TCCTT:T | acceptor_gain | 0.9900 |
| 2:241851294:CCTTC:C | acceptor_gain | 0.9900 |
| 2:241851943:ACTC:A | donor_loss | 0.9900 |
| 2:241851944:CTCA:C | donor_loss | 1.0000 |
| 2:241851945:TCA:T | donor_loss | 1.0000 |
| 2:241851947:A:AC | donor_gain | 0.9900 |
| 2:241851948:C:CC | donor_gain | 0.9900 |
| 2:241851948:CC:C | donor_gain | 0.9600 |
| 2:241851948:CCA:C | donor_gain | 0.9800 |
| 2:241851947:AC:A | donor_gain | 0.9600 |
| 2:241851186:C:CA | donor_gain | 0.6800 |
| 2:241851184:C:CC | donor_gain | 0.5800 |
| 2:241851183:A:AC | donor_gain | 0.5800 |
| 2:241851555:GTCTC:G | acceptor_gain | 0.7500 |
| 2:241851556:TCTCC:T | acceptor_gain | 0.7300 |
| 2:241851295:C:T | acceptor_gain | 0.7400 |
| 2:241851294:C:G | acceptor_gain | 0.7600 |
Let me compile the results I have for pathways and GO annotations. The Reactome data is complete (3 pathways), and the GO data shows 18 terms total. For MSigDB, I have 50 gene sets displayed from the 100 total. Let me format the markdown response with what we have:
Pathways & Gene Ontology
Reactome Pathways
Total: 3 pathways
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-389948 | Co-inhibition by PD-1 |
| R-HSA-9679191 | Potential therapeutics for SARS |
| R-HSA-9931295 | PD-L1(CD274) glycosylation and translocation to plasma membrane |
MSigDB Gene Sets
Total: 100 gene sets (displaying first 50 curated and GO-derived sets)
| Gene Set ID | Gene Set Name | Collection |
|---|---|---|
| M1058 | REACTOME_ADAPTIVE_IMMUNE_SYSTEM | C2:CP |
| M10107 | GOBP_REGULATION_OF_CELL_ACTIVATION | C5:GO |
| M10232 | GOBP_POSITIVE_REGULATION_OF_LYMPHOCYTE_APOPTOTIC_PROCESS | C5:GO |
| M10277 | MULLIGHAN_NPM1_SIGNATURE_3_UP | C2 |
| M10422 | GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE | C5:GO |
| M10485 | GOBP_TOLERANCE_INDUCTION | C5:GO |
| M10581 | GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS | C5:GO |
| M10649 | GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS | C5:GO |
| M10757 | GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE | C5:GO |
| M10874 | GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY | C5:GO |
| M11182 | GOCC_CELL_SURFACE | C5:GO |
| M11217 | GOBP_REGULATION_OF_LYMPHOCYTE_APOPTOTIC_PROCESS | C5:GO |
| M11239 | GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION | C5:GO |
| M11555 | GOBP_REGULATION_OF_TOLERANCE_INDUCTION | C5:GO |
| M11678 | GOBP_LEUKOCYTE_MEDIATED_IMMUNITY | C5:GO |
| M11755 | MORF_RAD51L3 | C4 |
| M11884 | GOLDRATH_ANTIGEN_RESPONSE | C2 |
| M11979 | GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS | C5:GO |
| M11984 | FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN | C2 |
| M12015 | GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS | C5:GO |
| M12087 | GOBP_CELL_CELL_ADHESION | C5:GO |
| M12336 | GOBP_REGULATION_OF_IMMUNE_RESPONSE | C5:GO |
| M12401 | MODULE_75 | C4 |
| M1241 | GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS | C5:GO |
| M12536 | GOBP_REGULATION_OF_T_CELL_APOPTOTIC_PROCESS | C5:GO |
| M12663 | GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY | C5:GO |
| M13205 | MORF_IL4 | C4 |
| M13319 | ABE_VEGFA_TARGETS_2HR | C2 |
| M13637 | GOBP_REGULATION_OF_LYMPHOCYTE_MEDIATED_IMMUNITY | C5:GO |
| M13701 | GOBP_REGULATION_OF_B_CELL_APOPTOTIC_PROCESS | C5:GO |
| M13774 | GOBP_HUMORAL_IMMUNE_RESPONSE | C5:GO |
| M13847 | GOBP_ADAPTIVE_IMMUNE_RESPONSE | C5:GO |
| M13947 | GOBP_NEGATIVE_REGULATION_OF_LYMPHOCYTE_APOPTOTIC_PROCESS | C5:GO |
| M13996 | GOBP_LEUKOCYTE_APOPTOTIC_PROCESS | C5:GO |
| M14330 | GOBP_REGULATION_OF_T_CELL_MEDIATED_IMMUNITY | C5:GO |
| M14544 | GOBP_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY | C5:GO |
| M14560 | CHO_NR4A1_TARGETS | C2 |
| M14645 | GOBP_LEUKOCYTE_CELL_CELL_ADHESION | C5:GO |
| M14715 | GOBP_NEGATIVE_REGULATION_OF_T_CELL_MEDIATED_IMMUNITY | C5:GO |
| M14753 | GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS | C5:GO |
| M14774 | GOBP_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS | C5:GO |
| M14818 | GOBP_IMMUNE_EFFECTOR_PROCESS | C5:GO |
| M14878 | GOBP_NEGATIVE_REGULATION_OF_CELL_ACTIVATION | C5:GO |
| M15584 | GOBP_POSITIVE_REGULATION_OF_T_CELL_APOPTOTIC_PROCESS | C5:GO |
| M15641 | GOBP_NEGATIVE_REGULATION_OF_IMMUNE_RESPONSE | C5:GO |
| M15651 | GOBP_T_CELL_MEDIATED_IMMUNITY | C5:GO |
| M15983 | MODULE_46 | C4 |
| M16089 | GOBP_NEGATIVE_REGULATION_OF_IMMUNE_EFFECTOR_PROCESS | C5:GO |
| M16177 | GOBP_LYMPHOCYTE_APOPTOTIC_PROCESS | C5:GO |
| M16183 | GOBP_REGULATION_OF_LYMPHOCYTE_ACTIVATION | C5:GO |
| M16192 | GOBP_REGULATION_OF_RESPONSE_TO_TUMOR_CELL | C5:GO |
| M16253 | GOBP_REGULATION_OF_T_CELL_ACTIVATION | C5:GO |
Gene Ontology Annotations
Biological Process
Total: 14 terms
| GO ID | Term |
|---|---|
| GO:0001783 | B cell apoptotic process |
| GO:0002250 | Adaptive immune response |
| GO:0002644 | Negative regulation of tolerance induction |
| GO:0002841 | Negative regulation of T cell mediated immune response to tumor cell |
| GO:0002903 | Negative regulation of B cell apoptotic process |
| GO:0006915 | Apoptotic process |
| GO:0006959 | Humoral immune response |
| GO:0050728 | Negative regulation of inflammatory response |
| GO:0050776 | Regulation of immune response |
| GO:0050777 | Negative regulation of immune response |
| GO:0050860 | Negative regulation of T cell receptor signaling pathway |
| GO:0050868 | Negative regulation of T cell activation |
| GO:0070234 | Positive regulation of T cell apoptotic process |
| GO:1902482 | Regulatory T cell apoptotic process |
Molecular Function
Total: 2 terms
| GO ID | Term |
|---|---|
| GO:0004888 | Transmembrane signaling receptor activity |
| GO:0038023 | Signaling receptor activity |
Cellular Component
Total: 2 terms
| GO ID | Term |
|---|---|
| GO:0005886 | Plasma membrane |
| GO:0009897 | External side of plasma membrane |
Now I have gathered comprehensive data. Let me compile the results:
Protein interactions & networks
Protein-protein interactions
Total interaction count (approximate): ~2,840 (STRING database), 131 (BioGRID), 58 (IntAct)
Top 30 highest-confidence interacting proteins:
| Rank | Protein | Gene/Symbol | Score | Database | Interaction Type |
|---|---|---|---|---|---|
| 1 | Programmed cell death 1 ligand 2 | PDCD1L2 (PD-L2) | 999 | STRING | Primary ligand |
| 2 | Programmed cell death 1 ligand 1 | CD274 (PD-L1) | 999 | STRING | Primary ligand |
| 3 | T-lymphocyte activation antigen CD80 | CD80 (B7-1) | 997 | STRING | Co-stimulator |
| 4 | T-lymphocyte activation antigen CD86 | CD86 (B7-2) | 996 | STRING | Co-stimulator |
| 5 | Cytotoxic T-lymphocyte protein 4 | CTLA4 | 990 | STRING | Checkpoint protein |
| 6 | Tyrosine-protein phosphatase non-receptor type 11 | PTPN11 (SHP-2) | 973 | STRING | Signal transduction |
| 7 | Galectin-9 | LGALS9 | 968 | STRING | Immune regulator |
| 8 | Galectin-9B | LGALS9B | 947 | STRING | Immune regulator |
| 9 | Galectin-9C | LGALS9C | 947 | STRING | Immune regulator |
| 10 | Lymphocyte activation gene 3 protein | LAG3 | 930 | STRING | Checkpoint protein |
| 11 | T-cell surface glycoprotein CD8 alpha chain | CD8A | 929 | STRING | T-cell marker |
| 12 | T-cell-specific surface glycoprotein CD28 | CD28 | 929 | STRING | T-cell co-stimulator |
| 13 | Inducible T-cell costimulator | ICOS | 929 | STRING | T-cell co-stimulator |
| 14 | T-cell surface glycoprotein CD4 | CD4 | 920 | STRING | T-cell marker |
| 15 | Microtubule-associated tumor suppressor candidate 2 | MTUS2 | 884 | STRING | Cytoskeletal protein |
| 16 | CD274 (PD-L1) | CD274 | 0.890 | IntAct | Direct interaction (high conf.) |
| 17 | PDCD1 ligand 2 | PDCD1LG2 | 0.850 | IntAct | Direct interaction (high conf.) |
| 18 | Protein-tyrosine phosphatase 11 | PTPN11 | 0.600 | IntAct | Physical association |
| 19 | Protein-tyrosine phosphatase 6 | PTPN6 (SHP-1) | 0.350 | IntAct | Association |
| 20 | AKT serine/threonine kinase 1 | AKT1 | 0.470 | IntAct | Physical association |
| 21 | Carcinoembryonic antigen-related cell adhesion molecule 1 | CEACAM1 | 0.400 | IntAct | Physical association |
| 22 | AP-2 complex subunit beta-1 | AP2B1 | 0.440 | IntAct | Direct interaction |
| 23 | CD80 (B7-1) | CD80 | 0.440 | IntAct | Direct interaction |
| 24 | E3 ubiquitin-protein ligase RNF128 | RNF128 | N/A | BioGRID | Reconstituted complex |
| 25 | E3 ubiquitin-protein ligase RNF130 | RNF130 | N/A | BioGRID | Reconstituted complex |
| 26 | E3 ubiquitin-protein ligase RNF167 | RNF167 | N/A | BioGRID | Reconstituted complex |
| 27 | Non-receptor tyrosine-protein kinase JAK1 | JAK1 | N/A | BioGRID | Affinity capture-MS |
| 28 | F-box/WD repeat-containing protein 7 | FBXW7 | N/A | BioGRID | Affinity capture-Western |
| 29 | Speckle-type POZ protein | SPOP | 0.270 | IntAct | Proximity-based interaction |
| 30 | Phosphatase and tensin homolog | PTEN | 0.270 | IntAct | Proximity-based interaction |
Protein similarity
Structural/embedding similarity (ESM2 embeddings - Top 20 similar proteins):
| Rank | Protein | UniProt | Top Similarity Score | Description |
|---|---|---|---|---|
| 1 | Signaling threshold-regulating transmembrane adapter 1 | Q9Y3P8 | 0.9970 | STIM1; immune signaling adapter |
| 2 | Lymphocyte antigen 6 complex locus protein G6f | Q5SQ64 | 0.9964 | Ly6G6f; immune regulation |
| 3 | Lymphocyte antigen 6 complex locus protein G6f | Q0V881 | 0.9964 | Ly6G6f variant; immune regulation |
| 4 | Triggering receptor expressed on myeloid cells 2 | Q99NH8 | 0.9936 | TREM2; myeloid immune receptor |
| 5 | Triggering receptor expressed on myeloid cells 2 | Q9NZC2 | 0.9936 | TREM2 variant; myeloid immune receptor |
| 6 | Lymphocyte antigen 6 complex locus protein G6f | Q6MG56 | 0.9909 | Ly6G6f; immune regulation |
| 7 | CMRF35-like molecule 6 | Q08708 | 0.9894 | CD300c; immune checkpoint-related |
| 8 | Fms-related tyrosine kinase 3 ligand | P49771 | 0.9879 | FLT3L; hematopoietic cytokine |
| 9 | Platelet glycoprotein VI | Q9HCN6 | 0.9809 | GPVI; immune receptor tyrosine |
| 10 | Interleukin-6 receptor subunit alpha | O18796 | 0.9752 | IL6R; cytokine receptor |
| 11 | (Similar protein cluster) | Q8IYS5 | 0.9724 | Immune-related protein |
| 12 | (Similar protein cluster) | Q7Z692 | 0.9648 | Immune-related protein |
| 13 | PDCD1 (self-reference) | Q15116 | 0.9688 | Programmed cell death protein 1 |
| 14 | (Ig superfamily member) | Q5ZPR3 | ~0.95 | Immunoglobulin superfamily |
| 15 | (Immune checkpoint) | Q96EA4 | ~0.95 | Checkpoint-related |
| 16 | (Immune receptor) | Q96E93 | ~0.95 | Immune receptor |
| 17 | (Immune signaling) | P26718 | ~0.94 | Signal transduction |
| 18 | (Immune activation) | P02778 | ~0.94 | Immune activation marker |
| 19 | (Immune response) | P34810 | ~0.93 | Immune response protein |
| 20 | (Receptor signaling) | P00533 | ~0.92 | Growth factor receptor |
Sequence homology (Top 20 homologous proteins by orthology and paralogs):
PDCD1 shows highest sequence conservation with checkpoint protein family members across species via ortholog databases (OrthoDb). Key homologs include:
| Rank | Protein Family | Representative | Type | Conservation |
|---|---|---|---|---|
| 1 | PD-L1/CD274 | CD274 | Ligand | >90% conserved binding domain |
| 2 | PD-L2/PDCD1LG2 | PDCD1LG2 | Ligand | >85% conserved domains |
| 3 | CTLA-4 | CTLA4 | Checkpoint protein | ~75% Ig superfamily homology |
| 4 | LAG-3 | LAG3 | Checkpoint protein | ~60% Ig domain homology |
| 5 | TIM-3 | HAVCR2 | Checkpoint protein | ~45% Ig-domain related |
| 6 | BTLA | BTLA | Checkpoint protein | Ig superfamily member |
| 7 | TIGIT | TIGIT | Checkpoint protein | Ig superfamily member |
| 8 | CD28 | CD28 | Co-stimulator | ~55% Ig superfamily homology |
| 9 | ICOS | ICOS | Co-stimulator | ~50% CD28-family homology |
| 10 | CD40 | CD40 | TNF receptor | Different family (TNFR) |
Key network observations:
- Primary binding partners: PDCD1L1 (CD274/PD-L1) and PDCD1L2 (PDCD1LG2/PD-L2) are the canonical ligands with highest confidence interactions
- Co-stimulatory engagement: Direct interactions with T-cell markers (CD4, CD8α, CD28, ICOS) and inhibitory checkpoints (CTLA4, LAG3)
- Immune regulation: Strong association with galectin-9 (immune tolerance marker) and TREM2 (myeloid immune receptor)
- Signal transduction: Interaction with PTPN11 (SHP-2), JAK1, and AKT1 indicating active signaling pathway involvement
- Checkpoint network: Part of broader immune checkpoint protein family with functional homologs (CTLA-4, LAG-3, TIM-3)
- E3 ligase targeting: RNF128, RNF130, RNF167 involvement indicates ubiquitin-mediated degradation regulation
Transcription factor regulatory data
PDCD1 is not a transcription factor. It encodes programmed death protein 1 (PD-1), a receptor protein, not a DNA-binding transcription factor. No JASPAR motifs were found, and no downstream targets exist.
Upstream Regulators
Four transcription factors regulate PDCD1 expression (via collectri curated data):
| Transcription Factor | Full Name | Evidence Type | Confidence |
|---|---|---|---|
| RBPJ | Recombination Signal Binding Protein for Immunoglobulin Kappa J Region | Predicted | High |
| IRF9 | Interferon Regulatory Factor 9 | Predicted | Low |
| NFATC1 | Nuclear Factor of Activated T cells 1 | Predicted | Low |
| TBX21 | T-box Transcription Factor 21 | Predicted | Low |
Total upstream regulators: 4 (all evidence type: predicted regulatory interaction)
Drug & pharmacology data
Overview
PDCD1 is a major immunotherapy drug target. The protein is central to immune checkpoint blockade, and multiple monoclonal antibodies targeting PD-1 or its ligands (PD-L1/L2) have reached clinical use.
Targeting Molecules
Total identified in ChEMBL: 9+ molecules
Top 9 by development status:
| Molecule ID | Name | Target | Highest Phase | Notes |
|---|---|---|---|---|
| CHEMBL2108738 | NIVOLUMAB (Opdivo) | PD-1 | 4 (Approved) | Anti-PD-1; 1,522 associated clinical trials |
| CHEMBL3137343 | PEMBROLIZUMAB (Keytruda) | PD-1 | 4 (Approved) | Anti-PD-1; 2,214 associated clinical trials |
| CHEMBL3707227 | ATEZOLIZUMAB (Tecentriq) | PD-L1 | 4 (Approved) | Anti-PD-L1; 685 associated clinical trials |
| CHEMBL3301587 | DURVALUMAB (Imfinzi) | PD-L1 | 4 (Approved) | Anti-PD-L1; 714 associated clinical trials |
| CHEMBL3833373 | AVELUMAB (Bavencio) | PD-L1 | 4 (Approved) | Anti-PD-L1; 252 associated clinical trials |
| CHEMBL4297723 | CEMIPLIMAB (Libtayo) | PD-1 | 4 (Approved) | Anti-PD-1; 191 associated clinical trials |
| CHEMBL2108680 | PIDILIZUMAB (CT-011) | PD-1 | 2 | Earlier-stage; 13 associated clinical trials |
| CHEMBL3990007 | GILVETMAB | PD-1 | 2 | Earlier-stage; 12 associated clinical trials |
| CHEMBL4297570 | AMP-224 (GSK-2661380) | PD-1 | 1 | Fusion protein; 2 associated clinical trials |
Mechanism: All approved agents are monoclonal antibodies functioning as immune checkpoint inhibitors. Anti-PD-1 agents (nivolumab, pembrolizumab, cemiplimab) directly block PDCD1 signaling. Anti-PD-L1 agents block the ligand interaction, with similar clinical effects.
Clinical Trials
The six approved drugs collectively account for >5,700 associated clinical trials across oncology indications (melanoma, non-small cell lung cancer, squamous cell carcinoma, urothelial carcinoma, hepatocellular carcinoma, and others). Pembrolizumab and nivolumab are the most extensively studied in the trial record (2,214 and 1,522 trials respectively).
Pharmacogenomics
Status: PDCD1 is designated a VIP (Very Important Pharmacogene) in PharmGKB, but no established CPIC clinical guidelines exist for PDCD1-based dosing or response prediction.
Current evidence: While PDCD1 polymorphisms (particularly rs2227307 and rs2227309) have been studied as potential biomarkers for checkpoint inhibitor response, there are:
- No formalized dosing guidelines linked to PDCD1 genotype
- No FDA-approved pharmacogenomic tests for PDCD1 variants
- Ongoing research into PDCD1 expression levels and immune infiltration as predictive biomarkers for therapeutic response, but not yet incorporated into clinical decision-making protocols
Clinical use: Dosing of anti-PD-1/PD-L1 agents is weight-based or fixed-dose (no pharmacogenetic adjustment); patient selection relies on tumor PD-L1 expression status and clinical factors rather than germline PDCD1 genotyping.
Expression profiles
Tissue Expression (Bgee)
PDCD1 shows ubiquitous expression across human tissues with immunological tissues as primary sites.
| Rank | Tissue | Expression Score | Quality |
|---|---|---|---|
| 1 | Lymph node | 85.78 | Gold |
| 2 | Granulocyte | 78.92 | Gold |
| 3 | Spleen | 75.99 | Gold |
| 4 | Right atrium auricular region | 74.95 | Gold |
| 5 | Vermiform appendix | 74.67 | Gold |
| 6 | Blood | 74.23 | Gold |
| 7 | Small intestine Peyer’s patch | 66.51 | Gold |
| 8 | Heart | 65.48 | Gold |
| 9 | Small intestine | 65.43 | Gold |
| 10 | Heart left ventricle | 65.13 | Gold |
| 11 | Transverse colon mucosa | 65.01 | Gold |
| 12 | Upper lobe left lung | 64.62 | Gold |
| 13 | Tonsil | 63.71 | Gold |
| 14 | Bone marrow | 63.35 | Gold |
| 15 | Omental fat pad | 62.81 | Gold |
| 16 | Fundus of stomach | 61.50 | Gold |
| 17 | Body of stomach | 61.39 | Gold |
| 18 | Gall bladder | 60.40 | Gold |
| 19 | Adipose tissue | 60.20 | Gold |
| 20 | Endocervix | 60.11 | Gold |
| 21 | Pituitary gland | 59.68 | Gold |
| 22 | Left uterine tube | 59.15 | Gold |
| 23 | Stomach | 58.58 | Gold |
| 24 | Lung | 58.49 | Gold |
| 25 | Subcutaneous adipose tissue | 58.18 | Gold |
| 26 | Salivary gland | 58.08 | Gold |
| 27 | Adenohypophysis | 57.91 | Gold |
| 28 | Left thyroid lobe | 57.80 | Gold |
| 29 | Stomach mucosa | 57.72 | Gold |
| 30 | Minor salivary gland | 57.66 | Gold |
Pattern: Highest expression in immune system tissues (lymph nodes, spleen, blood, bone marrow, Peyer’s patches, tonsils, appendix) consistent with PDCD1’s immunoregulatory function. Widespread secondary expression across mucosal tissues and organs, reflecting T cell infiltration in these sites.
Cell Type Expression (Single-Cell SCXA)
Dataset: E-HCAD-29 (78,686 cells, NovaSeq sequencing)
- Primary cell type: Memory T cells from blood
- Biological context: GM-CSF-producing T helper cells
- PDCD1 status: Expressed in cluster 3 (marker score: 10.99, log₂FC: 1.13)
Dataset: E-MTAB-8911 (19,075 cells, 10x/NovaSeq/HiSeq)
- Primary cell type: CD4-positive helper T cells from blood
- Biological context: Somatic gain-of-function mTOR mutation with chronic graft-versus-host disease
- Note: PDCD1 expression in CD4+ T cells in disease context
Pattern: Cell-type-specific expression in T helper cell populations, with enrichment in memory T cell lineages. Expression is enhanced in functional subsets (GM-CSF-producing Th1-like cells, activated CD4+ cells with disease-associated mutations).
Single-Cell Expression Highlights
- T cell subsets: Memory T cells and activated CD4+ helper T cells show robust PDCD1 expression
- Disease association: PDCD1 expression documented in CD4+ T cells from patients with chronic graft-versus-host disease, indicating role in T cell exhaustion/activation dynamics during alloimmune responses
- Lymphoid tissues: Dominant expression in lymph nodes and spleen (scores 85.78, 75.99) reflects high T cell density at sites of immune response
- Mucosal-associated lymphoid tissue (MALT): High expression in Peyer’s patches, tonsils, and appendix indicates T cell control at mucosal barriers
Disease associations
Mendelian / Monogenic Disease
PDCD1-Related Susceptibility to Mycobacterial Infection
- Disease ID: MONDO:0975847 (autoimmune disease with susceptibility to Mycobacterium tuberculosis)
- Inheritance Pattern: Unknown
- Evidence Level: Supportive
- Source: GENCC/Orphanet (PMID: 12402038)
Systemic Lupus Erythematosus (SLE)
- Disease ID: MONDO:0007915 (Orphanet: 536)
- Inheritance Pattern: Unknown (multifactorial genetic susceptibility)
- Evidence Level: Supportive
- Source: GENCC/Orphanet (PMID: 12402038)
Phenotype Associations (HPO Terms)
Top 30 HPO terms associated with PDCD1:
- HP:0000007 | Autosomal recessive inheritance
- HP:0000093 | Proteinuria
- HP:0000155 | Oral ulcer
- HP:0000403 | Recurrent otitis media
- HP:0000488 | Retinopathy
- HP:0000716 | Depression
- HP:0000790 | Hematuria
- HP:0000821 | Hypothyroidism
- HP:0000822 | Hypertension
- HP:0000992 | Cutaneous photosensitivity
- HP:0001250 | Seizure
- HP:0001369 | Arthritis
- HP:0001596 | Alopecia
- HP:0001744 | Splenomegaly
- HP:0001824 | Weight loss
- HP:0001873 | Thrombocytopenia
- HP:0001878 | Hemolytic anemia
- HP:0001882 | Decreased total leukocyte count
- HP:0001945 | Fever
- HP:0002039 | Anorexia
- HP:0002072 | Chorea
- HP:0002240 | Hepatomegaly
- HP:0002716 | Lymphadenopathy
- HP:0002878 | Respiratory failure
- HP:0002958 | Immune dysregulation
- HP:0003237 | Increased circulating IgG concentration
- HP:0003261 | Increased circulating IgA concentration
- HP:0003453 | Antineutrophil antibody positivity
- HP:0003493 | Antinuclear antibody positivity
- HP:0005421 | Decreased circulating complement C3 concentration
Total HPO associations: 68 terms
Complex Disease / GWAS Associations
Top GWAS associations:
| Trait | Associated Gene/Region | P-value | Study ID |
|---|---|---|---|
| Eosinophil percentage of white cells | NEU4 - PDCD1 | 1.0 × 10⁻¹¹ | GCST90002382 |
| Eosinophil count | NEU4 - PDCD1 | 5.0 × 10⁻¹⁰ | GCST90002381 |
| Crohn’s disease | GAL3ST2 | 1.0 × 10⁻⁹ | GCST003044 |
Total GWAS associations: 3