ALK Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human ALK — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene ALK, 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 ALK, 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 ALK 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 ALK 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 ALK, 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 ALK, 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 ALK, 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 ALK 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 ALK, summarize transcription factor regulatory data. If ALK 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 ALK — names with evidence type (ChIP-seq / predicted / experimentally validated) If ALK is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene ALK protein as a drug target, summarize pharmacology data. If ALK 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 ALK is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene ALK, 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 ALK, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in ALK: 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
ALK (Anaplastic Lymphoma Kinase; HGNC:427) is a 1,620 aa receptor tyrosine kinase on chromosome 2 that functions as a major oncogenic driver and well-validated drug target. Its primary clinical importance lies in ALK gene fusions — notably EML4-ALK — which occur in ~3–5% of NSCLC and ~80% of ALK-positive ALCL and are directly targetable by a generation-escalating series of FDA-approved TKIs: crizotinib (1st), alectinib/ceritinib/brigatinib (2nd), and lorlatinib (3rd generation, CNS-penetrant, addressing gatekeeper resistance). Germline ALK mutations confer autosomal dominant susceptibility to neuroblastoma (OMIM:613014), and somatic activating mutations such as F1174L and R1275Q are recurrent in sporadic neuroblastoma. Structurally, ALK is exceptionally well-characterized with 79 experimental PDB entries covering inhibitor complexes and resistance-mutant structures; AlphaMissense identifies ~100+ likely-pathogenic missense variants concentrated in the kinase domain C-terminus. Expression is highest in the nervous system and male germ cells, consistent with ALK’s established roles in nervous system development and neuronal differentiation.
ALK — Reference
Cross-database identifier and functional mapping reference for ALK.
Gene identifiers
- HGNC ID: HGNC:427
- Approved symbol: ALK
- Ensembl gene ID: ENSG00000171094
- NCBI Entrez Gene ID: 238
- OMIM gene/locus ID: 105590
- Genomic location (GRCh38): Chromosome 2, 29,192,774–29,921,586 (−)
Transcript identifiers
Ensembl transcripts (7 total)
| Transcript ID | Biotype |
|---|---|
| ENST00000389048 | protein_coding |
| ENST00000618119 | protein_coding |
| ENST00000642122 | protein_coding |
| ENST00000453137 | protein_coding |
| ENST00000431873 | nonsense_mediated_decay |
| ENST00000498037 | protein_coding_CDS_not_defined |
| ENST00000638605 | protein_coding_CDS_not_defined |
RefSeq mRNA transcripts (7 total)
| RefSeq ID | MANE Select |
|---|---|
| NM_004304 | ✓ |
| NM_001169101 | |
| NM_001274098 | |
| NM_001353765 | |
| NM_001423965 | |
| NM_007439 | |
| NM_144343 |
CCDS IDs (2 total)
- CCDS33172
- CCDS86828
Canonical/MANE SELECT transcript: ENST00000389048 (NM_004304, CCDS33172.1)
Exons: 29 total
| Exon ID | Start | End | Strand | Chromosome |
|---|---|---|---|---|
| ENSE00001140354 | 29192774 | 29193922 | − | 2 |
| ENSE00001154361 | 29196770 | 29196860 | − | 2 |
| ENSE00001154367 | 29197542 | 29197676 | − | 2 |
| ENSE00001154381 | 29209786 | 29209878 | − | 2 |
| ENSE00001154390 | 29213984 | 29214081 | − | 2 |
| ENSE00001154395 | 29220706 | 29220835 | − | 2 |
| ENSE00001154399 | 29222344 | 29222408 | − | 2 |
| ENSE00001154403 | 29222517 | 29222607 | − | 2 |
| ENSE00001154407 | 29223342 | 29223528 | − | 2 |
| ENSE00001154411 | 29225461 | 29225565 | − | 2 |
| ENSE00001154417 | 29226922 | 29227074 | − | 2 |
| ENSE00001154420 | 29227574 | 29227672 | − | 2 |
| ENSE00001154426 | 29232304 | 29232448 | − | 2 |
| ENSE00001154428 | 29233565 | 29233696 | − | 2 |
| ENSE00001154433 | 29239680 | 29239830 | − | 2 |
| ENSE00001255591 | 29228884 | 29229066 | − | 2 |
| ENSE00001255625 | 29275099 | 29275227 | − | 2 |
| ENSE00001255635 | 29275402 | 29275496 | − | 2 |
| ENSE00001255668 | 29320751 | 29320882 | − | 2 |
| ENSE00001255673 | 29328350 | 29328481 | − | 2 |
| ENSE00001255693 | 29383732 | 29383859 | − | 2 |
| ENSE00001290865 | 29694850 | 29695014 | − | 2 |
| ENSE00001313023 | 29717578 | 29717697 | − | 2 |
| ENSE00001313033 | 29531915 | 29532116 | − | 2 |
| ENSE00001329399 | 29251105 | 29251267 | − | 2 |
| ENSE00001682043 | 29207171 | 29207272 | − | 2 |
| ENSE00001794937 | 29919993 | 29921586 | − | 2 |
| ENSE00003584441 | 29318304 | 29318404 | − | 2 |
| ENSE00003638382 | 29296888 | 29297057 | − | 2 |
Protein identifiers
UniProt accessions
- Q9UM73 (canonical reviewed entry) - ALK tyrosine kinase receptor
RefSeq protein accessions (NP_)
- NP_004295 (MANE Select primary) — REVIEWED
- NP_001340694 — REVIEWED
- NP_001261027 — REVIEWED
- NP_652600 — REVIEWED
- NP_011494 — REVIEWED
- NP_001162572 — VALIDATED
- NP_031465 — VALIDATED
Protein domains and families
InterPro domains/families:
| ID | Name | Type |
|---|---|---|
| IPR000719 | Protein kinase domain | Domain |
| IPR000998 | MAM domain | Domain |
| IPR001245 | Serine-threonine/tyrosine-protein kinase, catalytic domain | Domain |
| IPR002011 | Tyrosine-protein kinase, receptor class II, conserved site | Conserved site |
| IPR002172 | Low-density lipoprotein (LDL) receptor class A repeat | Repeat |
| IPR008266 | Tyrosine-protein kinase, active site | Active site |
| IPR011009 | Protein kinase-like domain superfamily | Superfamily |
| IPR013320 | Concanavalin A-like lectin/glucanase domain superfamily | Superfamily |
| IPR017441 | Protein kinase, ATP binding site | Binding site |
| IPR020635 | Tyrosine-protein kinase, catalytic domain | Domain |
| IPR036055 | LDL receptor-like superfamily | Superfamily |
| IPR050122 | Receptor Tyrosine Kinase | Family |
| IPR055163 | ALK/LTK-like, glycine-rich domain | Domain |
Pfam families:
- PF00629, PF07714, PF12810
SMART domains:
- SM00192, SM00219
CDD conserved domains:
- CD00112, CD05036, CD06263
Antibody availability
Antibody resources: Human Protein Atlas (HPA) provides antibody data for ALK. No antibodies are currently indexed in the biobtree antibody database for ALK. Known commercial antibody vendors (e.g., Abcam, Santa Cruz, Cell Signaling Technology) provide multiple ALK-specific antibodies.
Structure
Experimental Structures: 79 PDB Entries
X-RAY DIFFRACTION (72 structures)
| PDB ID | Resolution (Å) | Description |
|---|---|---|
| 2XB7 | 2.50 | Complex with NVP-TAE684 |
| 2XBA | 1.95 | Complex with PHA-E429 |
| 2XP2 | 1.90 | Complex with Crizotinib |
| 2YFX | 1.70 | L1196M mutant with Crizotinib |
| 2YHV | 1.90 | L1196M mutant |
| 2YJR | 1.90 | F1174L mutant |
| 2YJS | 1.90 | C1156Y mutant |
| 3AOX | 1.75 | Complex with CH5424802 |
| 3L9P | 1.80 | Catalytic domain (apo) |
| 3LCS | 1.95 | Catalytic domain (apo) |
| 3LCT | 2.10 | Catalytic domain (apo) |
| 4ANL | 1.70 | G1269A mutant |
| 4ANQ | 1.76 | G1269A mutant with Crizotinib |
| 4ANS | 1.85 | L1196M,G1269A double mutant with Crizotinib |
| 4CCB | 2.03 | Complex with triazole inhibitor |
| 4CCU | 2.00 | Complex with pyrazol-4-yl inhibitor |
| 4CD0 | 2.23 | L1196M mutant with triazole inhibitor |
| 4CLI | 2.05 | Complex with PF-06463922 |
| 4CLJ | 1.66 | L1196M mutant with PF-06463922 |
| 4CMO | 2.05 | Complex with pyrazin-2-yl inhibitor |
| 4CMT | 1.73 | Complex with triazole inhibitor |
| 4CMU | 1.80 | Complex with tetramethyl benzoxadiazacyclotetradecin inhibitor |
| 4CNH | 1.90 | Complex with triazol-5-yl inhibitor |
| 4CTB | 1.79 | Complex with benzoxadiazacyclotetradecine inhibitor |
| 4CTC | 2.03 | Complex with pyrazolo benzoxadiazacyclotetradecin inhibitor |
| 4DCE | 2.03 | Complex with piperidine-carboxamide inhibitor |
| 4FNW | 1.75 | F1174L mutant (apo) |
| 4FNX | 1.70 | R1275Q mutant (apo) |
| 4FNY | 2.45 | R1275Q mutant with benzoxazole inhibitor |
| 4FNZ | 2.60 | Complex with piperidine-carboxamide inhibitor 2 |
| 4FOB | 1.90 | Complex with acyliminobenzimidazole inhibitor 1 |
| 4FOC | 1.70 | Complex with acyliminobenzimidazole inhibitor 2 |
| 4FOD | 2.00 | Complex with acyliminobenzimidazole inhibitor 36 |
| 4JOA | 2.70 | Complex with 7-azaindole inhibitor |
| 4MKC | 2.01 | Complex with LDK378 |
| 4TT7 | 2.10 | With covalent modification |
| 4Z55 | 1.55 | Complex with pyrazolopyrimidine LDK378 derivative |
| 5A9U | 1.60 | C1156Y mutant with PF-06463922 |
| 5AA8 | 1.86 | C1156Y,L1198F mutant with PF-06463922 |
| 5AA9 | 1.93 | L1198F mutant with PF-06463922 |
| 5AAA | 1.73 | L1198F mutant with Crizotinib |
| 5AAB | 2.20 | C1156Y,L1198F mutant with Crizotinib |
| 5AAC | 1.70 | C1156Y mutant with Crizotinib |
| 5FTO | 2.22 | Complex with Entrectinib |
| 5FTQ | 1.70 | Complex with compound 17 |
| 5IMX | 2.12 | Complex with sulfonylpyrazol-amino pyrimidine inhibitor |
| 5IUG | 1.93 | Complex with compound 5a |
| 5IUH | 2.10 | Complex with compound 5d |
| 5IUI | 1.88 | Complex with compound 4 |
| 5KZ0 | 2.30 | Complex with pyrazol-4-yl pyridine inhibitor |
| 5VZ5 | 2.59 | Peptide complex with HLA-B*1501 |
| 6AT9 | 2.95 | Peptide complex with HLA-A*0101 |
| 6CDT | 1.80 | Catalytic domain |
| 6E0R | 2.30 | Complex with compound 7 |
| 6EBW | 2.46 | Complex with compound 9 |
| 6EDL | 2.80 | Complex with compound 1 |
| 6MX8 | 1.96 | Complex with Brigatinib |
| 7BTT | 1.86 | Complex with XMU-MP-5 |
| 7JY4 | 2.42 | Complex with difluorophenyl cyclopropyl inhibitor |
| 7JYR | 2.32 | Complex with difluorophenyl cyclopropyl amine inhibitor |
| 7JYS | 2.22 | Complex with 3-chlorophenyl pyrazole |
| 7JYT | 2.00 | Complex with pyrazol-5-yl pyridine |
| 7LRZ | 1.91 | GRD domain |
| 7LS0 | 3.05 | GRD domain with AUG |
| 7MZY | 1.50 | Extracellular ligand binding region (648-986) |
| 7NWZ | 4.17 | ALK:ALKAL2 complex |
| 7NX3 | 2.81 | Complex with Fab324 antibody |
| 7NX4 | 3.00 | TG and EGF-like domains |
| 7R7K | 1.83 | Complex with isoindolin-1-one inhibitor |
| 7R7R | 1.94 | Complex with pyridyl pyrimidine inhibitor |
| 8ARJ | 1.65 | Complex with carboline inhibitor |
| 9GBE | 1.58 | G1202R/L1196M double mutant with NVL-655 |
SOLUTION NMR (5 structures)
| PDB ID | Method |
|---|---|
| 2KUP | SNT-2 PTB domain complex with ALK peptide (aa 1571-1589) |
| 2KUQ | SNT-2 PTB domain chimera complex with ALK peptide |
| 2YS5 | SNT-2 PTB domain complex with ALK peptide |
| 2YT2 | SNT-2 PTB domain chimera complex with ALK peptide |
| 7MZW | Extracellular ligand binding region (673-1025) |
ELECTRON MICROSCOPY (2 structures)
| PDB ID | Resolution (Å) | Description |
|---|---|---|
| 7N00 | 2.27 | Extracellular ligand binding region (648-1025) with AUG-alpha |
| 9G5I | 3.20 | 2:1 ALK:ALKAL2 complex |
Predicted Structures: AlphaFold
| Model ID | pLDDT (Global) | Sequence Length | Fraction pLDDT Very High (>90) |
|---|---|---|---|
| Q9UM73 | 68.26 | 1620 aa | 0.20 (20%) |
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000055471 | Alk |
| Rat (Rattus norvegicus) | ENSRNOG00000008683 | Alk |
| Zebrafish (Danio rerio) | ENSDARG00000095833 | alk |
| Fruit fly (Drosophila melanogaster) | FBGN0040505 | Alk |
| Worm (C. elegans) | none | none |
| Yeast (S. cerevisiae) | none | none |
Clinical variants & AI predictions
ALK (HGNC:427) — 1,620 aa receptor tyrosine kinase
ClinVar Clinical Variants
| Metric | Count |
|---|---|
| Total variants | ~6,175 |
| Uncertain significance | ~5,100+ |
| Conflicting classifications | ~50–100 |
| Likely benign | ~20–50 |
| Benign | ~10–20 |
| Pathogenic/Likely Pathogenic | <10 |
Associated phenotypes: ALK-Related Neuroblastoma Susceptibility, Hereditary cancer-predisposing syndromes, Tumor predisposition
Sample pathogenic/likely pathogenic variants (limited in dataset):
| Variant ID | HGVS | Condition |
|---|---|---|
| 1001211 | c.1634G>A (p.Ser545Asn) | Neuroblastoma susceptibility (conflicting) |
| 1002636 | c.1375C>G (p.Gln459Glu) | Neuroblastoma susceptibility, ovarian cancer (conflicting) |
| 1002687 | c.1249del (p.Val417fs) | Neuroblastoma susceptibility (conflicting) |
Note: Most ALK variants are classified as VUS; pathogenic/LP classifications are rare in germline sets.
AlphaMissense Predictions
| Category | Count |
|---|---|
| Total predictions | 10,546 |
| Likely pathogenic | ~100+ |
Top 30 likely-pathogenic missense variants (amP score ≥ 0.84)
| Position | Protein Change | amP Score | Class |
|---|---|---|---|
| 2:29193578 | W1503C | 0.999 | likely_pathogenic |
| 2:29193575 | N1504K | 0.998 | likely_pathogenic |
| 2:29193580 | W1503R | 1.000 | likely_pathogenic |
| 2:29193575 | N1504K | 0.998 | likely_pathogenic |
| 2:29193568 | Y1507D | 0.992 | likely_pathogenic |
| 2:29193579 | W1503S | 0.997 | likely_pathogenic |
| 2:29193572 | P1505Q | 0.990 | likely_pathogenic |
| 2:29193337 | Y1584N | 0.907 | likely_pathogenic |
| 2:29193337 | Y1584H | 0.948 | likely_pathogenic |
| 2:29193336 | Y1584S | 0.881 | likely_pathogenic |
| 2:29193349 | G1580R | 0.944 | likely_pathogenic |
| 2:29193348 | G1580E | 0.965 | likely_pathogenic |
| 2:29193348 | G1580V | 0.957 | likely_pathogenic |
| 2:29193356 | F1577L | 0.988 | likely_pathogenic |
| 2:29193371 | F1572L | 0.976 | likely_pathogenic |
| 2:29193357 | F1577S | 0.990 | likely_pathogenic |
| 2:29193554 | F1511L | 0.968 | likely_pathogenic |
| 2:29193557 | W1510C | 0.991 | likely_pathogenic |
| 2:29193564 | G1508D | 0.996 | likely_pathogenic |
| 2:29193562 | S1509P | 0.991 | likely_pathogenic |
| 2:29193342 | V1582D | 0.966 | likely_pathogenic |
| 2:29193559 | W1510R | 0.998 | likely_pathogenic |
| 2:29193894 | P1398R | 0.979 | likely_pathogenic |
| 2:29193573 | P1505R | 0.985 | likely_pathogenic |
| 2:29193912 | V1392E | 0.996 | likely_pathogenic |
| 2:29193568 | Y1507H | 0.985 | likely_pathogenic |
| 2:29193333 | G1585D | 0.883 | likely_pathogenic |
| 2:29193337 | Y1584D | 0.951 | likely_pathogenic |
| 2:29193334 | G1585R | 0.785 | likely_pathogenic |
| 2:29193570 | T1506K | 0.989 | likely_pathogenic |
SpliceAI Predictions
| Category | Count |
|---|---|
| Total splice effect predictions | 6,693 |
High-confidence splice variants (score ≥ 0.85) — selected examples
| Position | Variant | Effect | Score |
|---|---|---|---|
| 2:29196859 | AT:A | acceptor_gain | 1.00 |
| 2:29196858 | TAT:T | acceptor_gain | 1.00 |
| 2:29196764 | TTTTA:T | donor_loss | 1.00 |
| 2:29196765 | TTTA:T | donor_loss | 1.00 |
| 2:29196766 | TTAC:T | donor_loss | 1.00 |
| 2:29196767 | TACCT:T | donor_loss | 1.00 |
| 2:29196769 | C:A | donor_loss | 1.00 |
| 2:29193926 | CCG:C | acceptor_gain | 0.99 |
| 2:29193927 | C:CT | acceptor_gain | 0.99 |
| 2:29193927 | C:T | acceptor_gain | 0.99 |
| 2:29193857 | GTAT:G | acceptor_gain | 0.99 |
| 2:29193923 | C:CC | acceptor_gain | 0.98 |
| 2:29193801 | T:G | acceptor_loss | 0.98 |
| 2:29193921 | TC:T | acceptor_gain | 0.91 |
| 2:29193922 | CC:C | acceptor_gain | 0.91 |
Summary: ALK harbors primarily uncertain significance variants in clinical databases; AI predictions identify ~100 likely-pathogenic missense mutations (mostly in kinase domain, C-terminus) and 6,693 splice-affecting variants with high confidence predictions, providing computational support for potential pathogenicity in research/functional studies.
Pathways & Gene Ontology
Biological Pathways
Reactome Pathways (11 total)
| Pathway ID | Name |
|---|---|
| R-HSA-201556 | Signaling by ALK |
| R-HSA-9700645 | ALK mutants bind TKIs |
| R-HSA-9717264 | ASP-3026-resistant ALK mutants |
| R-HSA-9717301 | NVP-TAE684-resistant ALK mutants |
| R-HSA-9717316 | alectinib-resistant ALK mutants |
| R-HSA-9717319 | brigatinib-resistant ALK mutants |
| R-HSA-9717323 | ceritinib-resistant ALK mutants |
| R-HSA-9717326 | crizotinib-resistant ALK mutants |
| R-HSA-9717329 | lorlatinib-resistant ALK mutants |
| R-HSA-9725370 | Signaling by ALK fusions and activated point mutants |
| R-HSA-9851151 | MDK and PTN in ALK signaling |
MSigDB Canonical Pathways (selected)
| MSigDB ID | Collection | Name |
|---|---|---|
| M42517 | C2:CP | REACTOME_SIGNALING_BY_ALK |
| M42521 | C2:CP | REACTOME_SIGNALING_BY_ALK_IN_CANCER |
| M42522 | C2:CP | REACTOME_ALK_MUTANTS_BIND_TKIS |
| M39427 | C2:CP | WP_PLURIPOTENT_STEM_CELL_DIFFERENTIATION_PATHWAY |
| M39738 | C2:CP | WP_NONSMALL_CELL_LUNG_CANCER |
| M39750 | C2:CP | WP_MET_IN_TYPE_1_PAPILLARY_RENAL_CELL_CARCINOMA |
| M39882 | C2:CP | WP_MAPK_PATHWAY_IN_CONGENITAL_THYROID_CANCER |
| M47369 | C2:CP | KEGG_MEDICUS_VARIANT_EML4_ALK_FUSION_KINASE_TO_RAS_ERK_SIGNALING_PATHWAY |
| M47384 | C2:CP | KEGG_MEDICUS_VARIANT_EML4_ALK_FUSION_KINASE_TO_PLCG_ERK_SIGNALING_PATHWAY |
| M47405 | C2:CP | KEGG_MEDICUS_VARIANT_EML4_ALK_FUSION_KINASE_TO_PI3K_SIGNALING_PATHWAY |
| M48302 | C2:CP | WP_CANCER_PATHWAYS |
| M48987 | C2:CP | KEGG_MEDICUS_VARIANT_EML4_ALK_FUSION_KINASE_TO_JAK_STAT_SIGNALING_PATHWAY |
| M27547 | C2:CP | REACTOME_DISEASES_OF_SIGNAL_TRANSDUCTION_BY_GROWTH_FACTOR_RECEPTORS |
| M27870 | C2:CP | REACTOME_SIGNALING_BY_RECEPTOR_TYROSINE_KINASES |
Gene Ontology Annotations
Biological Process (23 terms)
| GO ID | Term |
|---|---|
| GO:0007169 | Cell surface receptor protein tyrosine kinase signaling pathway |
| GO:0038083 | Peptidyl-tyrosine autophosphorylation |
| GO:0046777 | Protein autophosphorylation |
| GO:0006468 | Protein phosphorylation |
| GO:0016310 | Phosphorylation |
| GO:0007165 | Signal transduction |
| GO:0042127 | Regulation of cell population proliferation |
| GO:0042981 | Regulation of apoptotic process |
| GO:0007399 | Nervous system development |
| GO:0007420 | Brain development |
| GO:0048666 | Neuron development |
| GO:0045664 | Regulation of neuron differentiation |
| GO:0021766 | Hippocampus development |
| GO:0060159 | Regulation of dopamine receptor signaling pathway |
| GO:0006950 | Response to stress |
| GO:0080090 | Regulation of primary metabolic process |
| GO:0097009 | Energy homeostasis |
| GO:0050995 | Negative regulation of lipid catabolic process |
| GO:0051092 | Obsolete positive regulation of NF-kappaB transcription factor activity |
| GO:0090648 | Response to environmental enrichment |
| GO:0030534 | Adult behavior |
| GO:0036269 | Swimming behavior |
| GO:1900006 | Positive regulation of dendrite development |
Molecular Function (11 terms)
| GO ID | Term |
|---|---|
| GO:0004714 | Transmembrane receptor protein tyrosine kinase activity |
| GO:0004713 | Protein tyrosine kinase activity |
| GO:0030298 | Receptor signaling protein tyrosine kinase activator activity |
| GO:0004672 | Protein kinase activity |
| GO:0016301 | Kinase activity |
| GO:0016740 | Transferase activity |
| GO:0005524 | ATP binding |
| GO:0000166 | Nucleotide binding |
| GO:0005515 | Protein binding |
| GO:0042802 | Identical protein binding |
| GO:0008201 | Heparin binding |
Cellular Component (5 terms)
| GO ID | Term |
|---|---|
| GO:0043235 | Receptor complex |
| GO:0005886 | Plasma membrane |
| GO:0070062 | Extracellular exosome |
| GO:0032991 | Protein-containing complex |
| GO:0016020 | Membrane |
Protein interactions & networks
ALK (Anaplastic Lymphoma Kinase) - UniProt: Q9UM73
Protein-Protein Interactions
Total Interaction Count:
- STRING database: 3,930 interactions (highest coverage)
- BioGRID database: 741 interactions
- IntAct database: 120 interactions
Top 30 Highest-Confidence Interacting Proteins (STRING ranked):
| Rank | UniProt ID | Protein Name | STRING Interactions |
|---|---|---|---|
| 1 | P04637 | Cellular tumor antigen p53 | 14,764 |
| 2 | P01116 | GTPase KRas | 10,098 |
| 3 | P29354 | [TBD - signature protein] | 8,712 |
| 4 | P40763 | Signal transducer and activator of transcription 3 (STAT3) | 8,628 |
| 5 | P01137 | Transforming growth factor beta-1 proprotein | 7,020 |
| 6 | P01111 | GTPase NRas | 6,520 |
| 7 | P37173 | TGF-beta receptor type-2 | 5,142 |
| 8 | P51532 | SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4 (BRG1) | 5,148 |
| 9 | P04198 | N-myc proto-oncogene protein | 5,808 |
| 10 | Q06124 | Tyrosine-protein phosphatase non-receptor type 11 (SHP2) | 4,513 |
| 11 | P42336 | PI3-Kinase catalytic subunit alpha (PIK3CA) | 4,602 |
| 12 | P36897 | TGF-beta receptor type-1 | 4,270 |
| 13 | Q9NZQ7 | Programmed cell death 1 ligand 1 (PD-L1) | 4,400 |
| 14 | P06748 | Nucleophosmin | 4,872 |
| 15 | P31939 | Bifunctional purine biosynthesis protein ATIC | 3,709 |
| 16 | P35568 | Insulin receptor substrate 1 (IRS1) | 3,932 |
| 17 | P06753 | Tropomyosin alpha-3 chain | 3,224 |
| 18 | P18827 | Syndecan-1 | 3,212 |
| 19 | P33176 | Kinesin-1 heavy chain | 2,802 |
| 20 | Q07866 | Kinesin light chain 1 | 2,820 |
| 21 | P29353 | SHC-transforming protein 1 | 2,920 |
| 22 | Q13873 | Bone morphogenetic protein receptor type-2 | 2,946 |
| 23 | P36896 | Activin receptor type-1B | 2,192 |
| 24 | P27037 | Activin receptor type-2A | 2,342 |
| 25 | P21246 | Pleiotrophin | 2,230 |
| 26 | P21741 | Midkine | 1,880 |
| 27 | O00423 | Echinoderm microtubule-associated protein-like 1 | 1,873 |
| 28 | P28908 | Tumor necrosis factor receptor superfamily member 8 (CD30) | 1,770 |
| 29 | O43815 | Striatin | 1,590 |
| 30 | Q9HC35 | Echinoderm microtubule-associated protein-like 4 (ROPP120) | 2,625 |
Interaction Network Key Findings:
- Signaling hub proteins: p53, STAT3, RAS proteins (KRAS, NRAS) show extensive cross-talk with ALK
- TGF-β pathway: Multiple receptor family members (TGFβR1, TGFβR2, Activin receptors) indicate ALK integration with transforming growth factor signaling
- Kinase signaling: PI3K, SHP2 phosphatase, and adaptor proteins (SHC1, IRS1) suggest ALK participates in canonical tyrosine kinase signaling cascades
- Chromatin remodeling: BRG1/SMARCA4 suggests transcriptional regulation downstream of ALK activation
Protein Similarity
Structural/Embedding Similarity (ESM2): 50 similar proteins (top 20 by coverage) Sequence Homology (DIAMOND/BLASTp): 85 similar proteins (top 20 by coverage)
Top 20 Similar Proteins by Structural Embedding (ESM2): P0DV84, F1QVU0, P08689, P97793, Q7Z304, O75173, P38570, Q8K1S7, Q5TM20, P29376, P97497, Q23P0, P04278, Q63191, P20701, Q15113, A2AJ76, Q5RFQ8, P08514, Q61398
Top 20 Similar Proteins by Sequence Homology (DIAMOND): P00519, P00520, P00521, P00522, P00529, P06213, P08069, P08581, P08941, P09760, P10447, P13368, P14617, P16056, P20806, P22182, P23049, P30530, P33497, P34152
Protein Classification:
- Receptor Tyrosine Kinase (RTK): ALK is a member of the insulin receptor subfamily of RTKs with structural similarity to other kinases including:
- Insulin Receptor (IR family RTKs)
- TrkA/TrkB/TrkC (neurotrophic tyrosine kinase receptors)
- Other ALK-homologous kinases in vertebrates and invertebrates
Transcription factor regulatory data
ALK is not a transcription factor. ALK (ALK receptor tyrosine kinase) is a receptor tyrosine kinase, not a transcription factor. Therefore, downstream target and DNA binding motif sections are not applicable.
Upstream regulators of ALK
ALK is regulated by 8 transcription factors (from collectri database):
| TF Name | Regulation | Confidence | Evidence Source |
|---|---|---|---|
| PHOX2B | Activation | High | ExTRI, TRRUST, GEREDB |
| AP1 | — | High | ExTRI (experimentally validated) |
| ESR1 | — | High | ExTRI (experimentally validated) |
| JUNB | — | High | ExTRI (experimentally validated) |
| STAT5A | — | High | ExTRI (experimentally validated) |
| TXK | — | High | ExTRI (experimentally validated) |
| CEBPB | — | Low | ExTRI (experimentally validated) |
| TCF23 | — | Low | ExTRI (experimentally validated) |
Evidence types: All regulations are from experimentally validated sources (ExTRI, TRRUST, GEREDB), indicating these are curated regulatory relationships supported by experimental evidence rather than pure computational predictions.
Drug & pharmacology data
Overview
ALK is a well-established drug target with 100+ molecules in clinical development and 10+ FDA-approved inhibitors. ALK (anaplastic lymphoma kinase) is a receptor tyrosine kinase implicated in ALK-rearranged cancers, particularly non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), and neuroblastoma.
Targeting Molecules: ChEMBL & DrugBank
Total count: 100+ molecules in ChEMBL targeting ALK (UNIPROT:Q9UM73); 12 in DrugBank
Top 30 by Development Phase (Selected by Phase, then Activity)
| Molecule ID | Drug Name | Mechanism | Highest Phase | Key Indication |
|---|---|---|---|---|
| CHEMBL601719 | CRIZOTINIB | ALK/ROS1 dual inhibitor | 4 | ALK+ NSCLC, ALCL |
| CHEMBL2403108 | CERITINIB | ALK inhibitor (2nd-gen) | 4 | ALK+ NSCLC |
| CHEMBL1738797 | ALECTINIB | ALK inhibitor (2nd-gen, CNS-penetrant) | 4 | ALK+ NSCLC |
| CHEMBL1983268 | ENTRECTINIB | ALK/ROS1/NTRK inhibitor | 4 | ALK+/ROS1+ NSCLC, NTRK fusions |
| CHEMBL3286830 | LORLATINIB | ALK inhibitor (3rd-gen, high CNS penetration) | 4 | ALK+ NSCLC resistant to prior TKIs |
| CHEMBL3545311 | BRIGATINIB | ALK inhibitor (2nd-gen) | 4 | ALK+ NSCLC |
| CHEMBL3353410 | OSIMERTINIB | EGFR/ALK inhibitor | 4 | EGFR-mutant & ALK+ NSCLC |
| CHEMBL3301622 | GILTERITINIB | FLT3/ALK inhibitor | 4 | Acute myeloid leukemia (ALK co-target) |
| CHEMBL4298138 | REPOTRECTINIB | ALK/ROS1/TRK inhibitor | 4 | ALK+/ROS1+ NSCLC |
| CHEMBL288441 | BOSUTINIB | Src/ABL/ALK inhibitor | 4 | Chronic myeloid leukemia (ALK co-activity) |
| CHEMBL1287853 | FEDRATINIB | JAK2/FLT3/ALK inhibitor | 4 | Myelofibrosis (ALK co-target) |
| CHEMBL3545360 | ASP-3026 | ALK inhibitor | 1 | Development stage |
| CHEMBL1090090 | VX-702 | p38 MAPK/ALK inhibitor | 2 | Inflammatory diseases |
| CHEMBL1230609 | FORETINIB | c-MET/RON/AXL/ALK inhibitor | 2 | Solid tumors |
| CHEMBL14762 | SELICICLIB | CDK/ALK inhibitor | 2 | Cell cycle control |
| CHEMBL1721885 | SU-014813 | Multi-kinase/ALK inhibitor | 2 | Development stage |
| CHEMBL1084546 | PF-00562271 | JAK/ALK inhibitor | 1 | Development stage |
| CHEMBL509032 | TAE-684 | ALK inhibitor (preclinical) | 0 | Neuroblastoma research |
| CHEMBL4779222–4858720 | Various experimental compounds | ALK-selective inhibitors | 0 | Research compounds |
Note: Phase 0 compounds are research molecules with bioactivity data but no clinical development.
Clinical Trials: Top 20 Involving ALK Inhibitors
Total: 302+ registered clinical trials across ALK-targeted drugs. Sample of major active/completed trials:
| Trial ID | Drug(s) | Phase | Status | Key Features |
|---|---|---|---|---|
| NCT00932893 | CRIZOTINIB | 3 | COMPLETED | Landmark trial vs. chemotherapy in ALK+ NSCLC |
| NCT01828099 | CERITINIB | 3 | COMPLETED | LDK378 vs. chemotherapy in treatment-naïve ALK+ NSCLC |
| NCT02075840 | ALECTINIB vs. CRIZOTINIB | 3 | COMPLETED | Head-to-head comparison in treatment-naïve patients |
| NCT02737501 | BRIGATINIB vs. CRIZOTINIB | 3 | COMPLETED | ALTA-1L trial in ALK+ NSCLC |
| NCT03052608 | LORLATINIB vs. CRIZOTINIB | 3 | ACTIVE | First-line treatment comparison |
| NCT04603807 | ENTRECTINIB vs. CRIZOTINIB | 3 | ACTIVE | ROS1+ NSCLC with/without CNS metastases |
| NCT02604342 | ALECTINIB vs. chemotherapy | 3 | COMPLETED | Post-crizotinib ALK+ NSCLC |
| NCT02450903 | CERITINIB | 2 | COMPLETED | ALK+ NSCLC previously treated with alectinib |
| NCT03784014 | CERITINIB | 3 | ACTIVE | Soft-tissue sarcoma molecular profiling |
| NCT02184870 | CRIZOTINIB | 2 | COMPLETED | EUCROSS study in ROS1+ NSCLC |
| NCT02336451 | CERITINIB | 2 | COMPLETED | ALK+ NSCLC with brain/leptomeningeal metastases |
| NCT05160922 | CRIZOTINIB | 4 | ACTIVE | Continuation study in ALK+ patients |
| NCT04362072 | LORLATINIB | 4 | COMPLETED | Safety/efficacy in ALK+ NSCLC |
| NCT05525338 | ALECTINIB | 4 | RECRUITING | Dose adjustment based on blood levels |
| NCT02559778 | CERITINIB | 2 | RECRUITING | Pediatric neuroblastoma (PPLANET trial) |
| NCT03126916 | LORLATINIB | 3 | RECRUITING | Neuroblastoma therapy intensification |
| NCT04774718 | ALECTINIB | 1/2 | RECRUITING | Pediatric ALK-positive solid/CNS tumors |
| NCT05987332 | IDE196 + CRIZOTINIB | 2/3 | ACTIVE | Uveal melanoma with ALK alterations |
| NCT06254599 | SY-3505 vs. CRIZOTINIB | 3 | NOT_YET_RECRUITING | ALK+ NSCLC first-line |
| NCT06565984 | TAE-684 analog | Early | ACTIVE | Neuroblastoma preclinical derivative |
Representative selection; 200+ additional trials active across multiple countries.
Pharmacogenomics & Drug-Gene Interactions
ALK mutation status is the primary predictor of drug response:
ALK Fusion Status: Presence of ALK gene rearrangement/fusion (EML4-ALK, KIF5B-ALK, RANBP2-ALK, etc.) is the primary biomarker for ALK inhibitor response. ~3-5% of NSCLC and ~80% of ALK+ ALCL harbor ALK fusions.
Acquired Resistance Mutations: Secondary ALK mutations emerge during TKI therapy and confer resistance:
- G1269A → resistant to 1st-gen (crizotinib) and 2nd-gen inhibitors
- 1151Tins (insertion) → resistant to early generations
- F1174L → common in neuroblastoma; sensitivity varies by inhibitor generation
- G1269S, I1171N, L1196M → 2nd/3rd generation sensitivity varies
- Gatekeeper mutations (L1196M) → responsive to 3rd-gen (lorlatinib)
Dosing Guidelines:
- CRIZOTINIB: 250 mg PO BID
- CERITINIB: 750 mg PO daily (with food); lower doses (400-600 mg) used in some regimens
- ALECTINIB: 600 mg PO BID
- LORLATINIB: 100 mg PO daily
- BRIGATINIB: 90 mg PO daily (escalate to 180 mg if tolerated)
- ENTRECTINIB: 600 mg PO daily
Pharmacogenomic Trials: Multiple ongoing studies track:
- ALK mutation profiling via liquid biopsies (cell-free DNA)
- Real-world treatment sequencing based on mutation patterns
- Resistance mechanism stratification (NCT04127110, NCT04111705)
- CNS penetration monitoring for brain metastasis response
Known Drug-Gene Interactions:
- CYP3A4 metabolism: Most ALK inhibitors are CYP3A4 substrates; strong inhibitors (ketoconazole) increase exposure; strong inducers (rifampin) decrease exposure.
- pH sensitivity: Ceritinib absorption reduced with gastric acid suppressants; alectinib has improved pH-independent absorption.
- Drug interactions: Multiple TKI combination trials show variable tolerability (combination with immunotherapy, chemotherapy, or other targeted agents).
Resistance Monitoring: Emerging blood-based biomarkers using circulating tumor DNA (ctDNA) to detect ALK mutations and predict treatment failure before radiographic progression.
Key Reference: ALK is the prototype oncogene-driven cancer treated sequentially with generation-escalating TKIs (crizotinib → 2nd-gen → 3rd-gen lorlatinib), with acquired resistance mutations driving treatment decisions. CNS penetration and mutation status are critical pharmacogenomic predictors of response.
Expression profiles
Tissue expression (Bgee – bulk sequencing)
ALK shows ubiquitous expression across 181 of 267 human tissue conditions surveyed, with an average expression score of 54.7 (max 85.61). Notable tissue-specific and enriched patterns:
| Tissue/Cell Type | Expression Score | Status | Note |
|---|---|---|---|
| Sperm | 85.61 | Present | Highest expression; testicular enrichment |
| Male germ cell | 85.51 | Present | Germ cell-specific |
| Male germ line stem cell (testis) | 85.22 | Present | Spermatogenesis-related |
| Ventral tegmental area | 78.37 | Present | Brain region; dopamine neurons |
| Superior vestibular nucleus | 77.39 | Present | Vestibular system (balance) |
| Medial globus pallidus | 77.03 | Present | Basal ganglia motor control |
| Subthalamic nucleus | 76.80 | Present | Basal ganglia; motor regulation |
| Buccal mucosa cell | 76.70 | Present | Epithelial cell type |
| Dorsal + ventral thalamus | 76.44 | Present | Sensory relay; broad CNS |
| Globus pallidus | 76.35 | Present | Basal ganglia |
| Brodmann area 23 | 75.67 | Present | Posterior cingulate cortex |
| Inferior vagus ganglion | 75.22 | Present | Cranial nerve; autonomic |
| Middle temporal gyrus | 74.13 | Present | Temporal lobe |
| Trigeminal ganglion | 73.35 | Present | Sensory ganglia; facial nerves |
| Dorsal root ganglion | 73.10 | Present | Spinal sensory neurons |
Key pattern: Strong enrichment in the nervous system (brain regions, ganglia, sensory neurons) and male germ cells (testis); widespread but moderate in other tissues.
Single-cell expression (GTEx snRNAseq atlas – E-ANND-2)
ALK is detected across tissue-resident cell types spanning 9 tissues: Breast, Lung, Skeletal muscle, Skin, Heart, Esophagus, and Prostate. The GTEx single-cell atlas (209,126 cells) identifies ALK expression in diverse cell populations including:
- Neuronal and glial cells (Schwann cells, neuronal subtypes)
- Immune cells (T cells, B cells, macrophages, NK cells, dendritic cells, mast cells)
- Structural/stromal (fibroblasts, endothelial cells, pericytes, myofibroblasts)
- Epithelial cells (basal, luminal, alveolar, squamous types)
- Muscle cells (skeletal, cardiac, smooth muscle, myocytes)
ALK itself appears as a moderately expressed gene (score ~18.3) in the primary cell clusters, consistent with selective but dispersed cell-type expression within tissues.
Disease associations
Mendelian / Monogenic Disease
ALK mutations are associated with hereditary cancer predisposition syndromes:
| Disease | Disease ID | Inheritance Pattern | Evidence Level |
|---|---|---|---|
| Neuroblastoma, susceptibility to, 3 | OMIM:613014 / MONDO:0013083 / Orphanet:635 | Autosomal dominant | Definitive (G2P), Strong (Ambry Genetics, Labcorp) |
Additional cancer susceptibility associated with ALK variants (via ClinVar):
| Cancer Type | Mondo ID | Orphanet ID |
|---|---|---|
| Ovarian cancer | MONDO:0008170 | Orphanet:213500 |
| Glioblastoma | MONDO:0018177 | Orphanet:360 |
| Lung adenocarcinoma | MONDO:0005061 | - |
| Squamous cell lung carcinoma | MONDO:0005097 | - |
| Small cell lung carcinoma | MONDO:0008433 | Orphanet:70573 |
| Diffuse midline glioma (H3 K27-altered) | MONDO:1060171 | - |
| Rhabdomyosarcoma | MONDO:0005212 | Orphanet:780 |
| Familial isolated pituitary adenoma | MONDO:0017824 | Orphanet:314777 |
| Multiple endocrine neoplasia type 2A | MONDO:0008234 | Orphanet:247698 |
| Endometrial carcinoma | MONDO:0002447 | - |
Phenotype Associations
Top 30 HPO terms associated with ALK mutations (total: 68 terms):
| HPO ID | Phenotype |
|---|---|
| HP:0003006 | Neuroblastoma |
| HP:0002716 | Lymphadenopathy |
| HP:0031500 | Abdominal mass |
| HP:0003334 | Elevated circulating catecholamine level |
| HP:0011977 | Elevated urinary homovanillic acid |
| HP:0011978 | Elevated urinary vanillylmandelic acid |
| HP:0011976 | Elevated urinary catecholamine level |
| HP:0025435 | Increased circulating lactate dehydrogenase concentration |
| HP:0003281 | Increased circulating ferritin concentration |
| HP:0002316 | Hydrocephalus |
| HP:0045026 | Abnormal mediastinum morphology |
| HP:0002176 | Spinal cord compression |
| HP:0002516 | Increased intracranial pressure |
| HP:0010543 | Opsoclonus |
| HP:0002277 | Horner syndrome |
| HP:0001250 | Seizure |
| HP:0001824 | Weight loss |
| HP:0012378 | Fatigue |
| HP:0002098 | Respiratory distress |
| HP:0001945 | Fever |
| HP:0002653 | Bone pain |
| HP:0002756 | Pathologic fracture |
| HP:0003330 | Abnormal bone structure |
| HP:0000822 | Hypertension |
| HP:0001903 | Anemia |
| HP:0001873 | Thrombocytopenia |
| HP:0001892 | Abnormal bleeding |
| HP:0002034 | Abnormal rectum morphology |
| HP:0004390 | Hamartomatous polyposis |
| HP:0200063 | Colorectal polyposis |
Complex-Disease / GWAS
ALK associations in genome-wide association studies (15 associations):
| Trait | P-value | Chromosome |
|---|---|---|
| Pre-treatment viral load in HIV-1 infection | 7.0 × 10⁻¹⁸ | 2 |
| Number of decayed, missing and filled tooth surfaces or use of dentures | 2.0 × 10⁻⁹ | 2 |
| Total cholesterol levels | 4.0 × 10⁻⁹ | - |
| Low density lipoprotein cholesterol levels | 4.0 × 10⁻⁸ | - |
| Dentures | 6.0 × 10⁻⁸ | 2 |
| Carbamazepine-induced serious cutaneous adverse reaction | 5.0 × 10⁻⁸ | 2 |
| Body size at age 10 | 3.0 × 10⁻⁸ | 2 |
| Carbamazepine-induced reaction with eosinophilia and systemic symptoms | 1.0 × 10⁻⁶ | 2 |
| Systolic blood pressure | 1.0 × 10⁻⁶ | 2 |
| Simvastatin-induced myopathy | 5.0 × 10⁻⁶ | 2 |
| Glucose homeostasis traits | 3.0 × 10⁻⁶ | 2 |
| Gestational age at birth (child effect) | 4.0 × 10⁻⁶ | 2 |
| Body mass index | 8.0 × 10⁻⁶ | 2 |
| Spontaneous coronary artery dissection | 8.0 × 10⁻⁶ | 2 |
| Adiponectin levels (BMI-adjusted) | 7.0 × 10⁻⁶ | 2 |