ALK

Chr 2

ALK receptor tyrosine kinase

Also known as: ALK1, CD246, NBLST3

NCBI Gene: 238ENSG00000171094UniProt: Q9UM73

This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]

Primary Disease Associations & Inheritance

{Neuroblastoma, susceptibility to, 3}MIM #613014
UniProtNeuroblastoma 3
465
ClinVar variants
1
Pathogenic / LP
0.00
pLI score
12
Active trials
Clinical Summary— ALK
🧬
Gene-Disease Validity (ClinGen)
neuroblastoma, susceptibility to, 3 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
1 Pathogenic / Likely Pathogenic· 288 VUS of 465 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.45LOEUF
pLI 0.000
Z-score 5.56
OE 0.32 (0.23–0.45)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.01Z-score
OE missense 1.00 (0.95–1.05)
919 obs / 919.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.32 (0.23–0.45)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.00 (0.95–1.05)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.17
0≤1.21.6
LoF obs/exp: 25 / 78.0Missense obs/exp: 919 / 919.9Syn Z: -2.65

ClinVar Variant Classifications

465 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1
VUS288
Likely Benign173
Benign2
Conflicting1
1
Pathogenic
288
VUS
173
Likely Benign
2
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
1
0
1
Likely Pathogenic
0
0
0
0
0
VUS
22
239
22
5
288
Likely Benign
17
10
58
88
173
Benign
0
0
2
0
2
Conflicting
—1
Total392498393465

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ALK · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ALK-related neuroblastoma, susceptibility to

definitive
ADGain Of FunctionUncertain
Cancer
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Neuroblastoma, susceptibility to, 3}

MIM #613014

Molecular basis of disorder known

📖
GeneReview available — ALK
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Brigatinib Versus Crizotinib in ALK Inhibitor-Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial.
Camidge DR et al.·J Thorac Oncol
2021
GUK1 activation is a metabolic liability in lung cancer.
Schneider JL et al.·Cell
2025
EML4-ALK biology and drug resistance in non-small cell lung cancer: a new phase of discoveries.
Elshatlawy M et al.·Mol Oncol
2023Review
EML4-ALK Variant-Specific Genetic Interactions Shape Lung Tumorigenesis.
Diaz-Jimenez A et al.·Cancer Discov
2026
Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer.
Yoda S et al.·Cancer Discov
2018
Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC.
Zhang SS et al.·Lung Cancer
2021Review
Stargardt's Disease: Molecular Pathogenesis and Current Therapeutic Landscape.
Dayma K et al.·Int J Mol Sci
2025Review
Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non-Small Cell Lung Cancer in the Global Phase III ALEX Study.
Camidge DR et al.·J Thorac Oncol
2019Clinical trial
Frequency and Clinical Significance of Clonal and Subclonal Driver Mutations in High-Risk Neuroblastoma at Diagnosis: A Children's Oncology Group Study.
Berko ER et al.·J Clin Oncol
2025Clinical trial
Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations.
Bearz A et al.·J Thorac Oncol
2023Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Lung CancerNon Small Cell Lung Cancer

Amivantamab With Tyrosine Kinase Inhibitors (TKI) for Advanced NSCLC With ALK, ROS1, or RET Alterations

ACTIVE NOT RECRUITING
NCT05845671Phase PHASE1, PHASE2University of Colorado, DenverStarted 2023-07-17
Amivantamab 1050mgAmivantamab 1400mgAmivantamab (to be determined)
Carcinoma, Non-Small-Cell Lung

MYLUNG Consortium Part 3: Observational Study

RECRUITING
NCT05885698US Oncology ResearchStarted 2023-01-30
Non Small Cell Lung Cancer

A Study to Investigate the Family History of Cancer in Patients With Non-small Cell Lung Cancer (FAHIC - Lung).

RECRUITING
NCT06196424Fondazione Policlinico Universitario Campus Bio-MedicoStarted 2023-11-02
study questionnaire to investigate family history
Solid TumorsCNS Tumors

Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options

ACTIVE NOT RECRUITING
NCT02650401Phase PHASE1, PHASE2Hoffmann-La RocheStarted 2016-05-03
Entrectinib
ALK PositiveLocally Advanced Malignant Solid NeoplasmMetastatic Malignant Solid Neoplasm

Ceritinib and Everolimus in Treating Patients With Locally Advanced or Metastatic Solid Tumors or Stage IIIB-IV Non-small Cell Lung Cancer

ACTIVE NOT RECRUITING
NCT02321501Phase PHASE1M.D. Anderson Cancer CenterStarted 2016-06-22
CeritinibEverolimusLaboratory Biomarker Analysis
Non Small Cell Lung Cancer MetastaticALK Gene Mutation

A Study to Evaluate the Combination of Platinum-pemetrexed Based Chemotherapy Plus Lorlatinib in ALK Positive Non-Small Cell Lung Cancer (NSCLC) With Exclusively Extracranial Disease Progression on Lorlatinib

RECRUITING
NCT06378892Phase PHASE2Centro di Riferimento Oncologico - AvianoStarted 2024-03-15
Lorlatinib
Non-small Cell Lung Cancer (NSCLC)Anaplastic Lymphoma Kinase (ALK) Positive

A Study of Gilteritinib in Adults With Advanced ALK-positive Non-small Cell Lung Cancer (NSCLC)

RECRUITING
NCT07140016Phase PHASE1Astellas Pharma Global Development, Inc.Started 2025-09-22
gilteritinib
Non-squamous Non-small-cell Lung CancerStage IV Non-small Cell Lung CancerROS1 Gene Rearrangement

Study of Crizotinib for ROS1 and MET Activated Lung Cancer

RECRUITING
NCT04084717Phase PHASE2University Health Network, TorontoStarted 2019-12-03
Crizotinib
Non-small Cell Lung Cancer (NSCLC)

A Study to Learn About Brigatinib Treatment Information Available in Chinese Participants With Non-Small-cell Lung Cancer (NSCLC)

ACTIVE NOT RECRUITING
NCT05721950TakedaStarted 2024-01-17
Brigatinib
Radiotherapy Side EffectNon-small Cell Lung CancerALK Gene Mutation

Alectinib Followed by Concomitant Consolidation Radiation Therapy in Advanced NSCLC With ALK-rearrangement (A-SAB)

RECRUITING
NCT05724004Phase NAKarolinska University HospitalStarted 2023-10-05
SBRT/SRS/radiation therapy
ALK Gene MutationNSCLC Stage IVALK Sensitizing Mutation

Longitudinal Assessment of Genomic Alterations and Clonal Evolution in ALK-positive NSCLC (Galileo Project)

RECRUITING
NCT06234579Fondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2021-07-12
Biopsy (tissue or liquid)
Solid TumorAdvanced Solid TumorMetastatic Cancer

KPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II

RECRUITING
NCT05525858Seoul National University Bundang HospitalStarted 2022-09-28
AlectinibAtezolizumabErlotinib

External Resources

Links to major genomics databases and tools