Neuroblastoma, susceptibility to, 3

Summary

Neuroblastoma, susceptibility to, 3 (MONDO:0013083) is a disease caused by ALK (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: ALK (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 4,800

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuroblastoma, susceptibility to, 3
Mondo ID	MONDO:0013083
OMIM	613014
UMLS	C2751681
MedGen	414083
GARD	0027831
Is cancer (heuristic)	no

Also known as: ALK neuroblastoma · NBLST3 · neuroblastoma caused by mutation in ALK · neuroblastoma, susceptibility to, 3 · neuroblastoma, susceptibility to, type 3

Data availability: 4,800 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › neuroblastoma, susceptibility to, 3

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

272 uncertain significance, 252 likely benign, 55 conflicting classifications of pathogenicity, 15 benign/likely benign, 6 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1001211	NM_004304.5(ALK):c.1634G>A (p.Ser545Asn)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002636	NM_004304.5(ALK):c.1375C>G (p.Gln459Glu)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002687	NM_004304.5(ALK):c.1249del (p.Val417fs)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003201	NM_004304.5(ALK):c.3067+9G>T	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1006725	NM_004304.5(ALK):c.487G>A (p.Val163Met)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1006905	NM_004304.5(ALK):c.4826T>C (p.Leu1609Pro)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007159	NM_004304.5(ALK):c.474dup (p.Gly159fs)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011652	NM_004304.5(ALK):c.110C>T (p.Pro37Leu)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014087	NM_004304.5(ALK):c.4405C>T (p.Pro1469Ser)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1015251	NM_004304.5(ALK):c.4780G>A (p.Glu1594Lys)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1016794	NM_004304.5(ALK):c.3712_3715del (p.Gln1238fs)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1021741	NM_004304.5(ALK):c.3406T>G (p.Ser1136Ala)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1022772	NM_004304.5(ALK):c.1155T>C (p.Gly385=)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1022941	NM_004304.5(ALK):c.1229G>A (p.Gly410Glu)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1024392	NM_004304.5(ALK):c.776G>C (p.Arg259Pro)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1024948	NM_004304.5(ALK):c.1669C>T (p.Arg557Cys)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1035164	NM_004304.5(ALK):c.825G>T (p.Glu275Asp)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038015	NM_004304.5(ALK):c.4586_4587delinsTG (p.Asp1529Val)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038235	NM_004304.5(ALK):c.536G>T (p.Arg179Leu)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043248	NM_004304.5(ALK):c.254C>T (p.Pro85Leu)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043891	NM_004304.5(ALK):c.208G>A (p.Asp70Asn)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1047180	NM_004304.5(ALK):c.2501T>A (p.Val834Glu)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1052901	NM_004304.5(ALK):c.989A>G (p.Lys330Arg)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1053663	NM_004304.5(ALK):c.881C>T (p.Pro294Leu)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1054700	NM_004304.5(ALK):c.1084A>G (p.Ile362Val)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1056325	NM_004304.5(ALK):c.4566A>G (p.Ile1522Met)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1056340	NM_004304.5(ALK):c.1021A>G (p.Ser341Gly)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1061256	NM_004304.5(ALK):c.4074-13CTT[2]	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1061494	NM_004304.5(ALK):c.107C>A (p.Pro36Gln)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1062679	NM_004304.5(ALK):c.2738G>A (p.Trp913Ter)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ALK	Definitive	Autosomal dominant	neuroblastoma, susceptibility to, 3	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALK	Orphanet:146	Differentiated thyroid carcinoma
ALK	Orphanet:178342	Inflammatory myofibroblastic tumor
ALK	Orphanet:251877	Ganglioneuroblastoma
ALK	Orphanet:251992	Ganglioneuroma
ALK	Orphanet:300895	ALK-positive anaplastic large cell lymphoma
ALK	Orphanet:364043	ALK-positive large B-cell lymphoma
ALK	Orphanet:626	Large/giant congenital melanocytic nevus
ALK	Orphanet:635	Neuroblastoma

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALK	HGNC:427	ENSG00000171094	Q9UM73	ALK tyrosine kinase receptor	gencc,clinvar
UBASH3A	HGNC:12462	ENSG00000160185	P57075	Ubiquitin-associated and SH3 domain-containing protein A	clinvar
CLIP4	HGNC:26108	ENSG00000115295	Q8N3C7	CAP-Gly domain-containing linker protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALK	ALK tyrosine kinase receptor	Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system.
UBASH3A	Ubiquitin-associated and SH3 domain-containing protein A	Interferes with CBL-mediated down-regulation and degradation of receptor-type tyrosine kinases.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Phosphatase	1	28.0×	0.106
Kinase	1	9.2×	0.157
Scaffold/PPI	1	5.8×	0.164

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALK	Kinase	yes	2.7.10.1	Prot_kinase_dom, MAM_dom, Ser-Thr/Tyr_kinase_cat_dom
UBASH3A	Phosphatase	yes		SH3_domain, UBA-like_sf, His_Pase_superF_clade-1
CLIP4	Scaffold/PPI	no		CAP-Gly_domain, Ankyrin_rpt, Ankyrin_rpt-contain_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
sperm	1
blood	1
granulocyte	1
lymph node	1
secondary oocyte	1
skeletal muscle tissue of biceps brachii	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALK	181	broad	marker	sperm, male germ cell, male germ line stem cell (sensu Vertebrata) in testis
UBASH3A	133	broad	marker	granulocyte, blood, lymph node
CLIP4	269	ubiquitous	marker	secondary oocyte, upper leg skin, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALK	4,792
UBASH3A	1,757
CLIP4	764

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALK	Q9UM73	79
UBASH3A	P57075	2
CLIP4	Q8N3C7	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Drug resistance of ALK mutants	1	11420.0×	2e-04	ALK
ASP-3026-resistant ALK mutants	1	11420.0×	2e-04	ALK
NVP-TAE684-resistant ALK mutants	1	11420.0×	2e-04	ALK
alectinib-resistant ALK mutants	1	11420.0×	2e-04	ALK
brigatinib-resistant ALK mutants	1	11420.0×	2e-04	ALK
ceritinib-resistant ALK mutants	1	11420.0×	2e-04	ALK
crizotinib-resistant ALK mutants	1	11420.0×	2e-04	ALK
lorlatinib-resistant ALK mutants	1	11420.0×	2e-04	ALK
MDK and PTN in ALK signaling	1	2855.0×	7e-04	ALK
ALK mutants bind TKIs	1	951.7×	0.002	ALK
Signaling by ALK	1	571.0×	0.003	ALK
Signaling by ALK in cancer	1	271.9×	0.005	ALK
Signaling by ALK fusions and activated point mutants	1	150.3×	0.009	ALK
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.021	ALK
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.022	ALK
Disease	1	13.1×	0.081	ALK
Signal Transduction	1	10.2×	0.098	ALK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to environmental enrichment	1	2808.7×	0.007	ALK
regulation of dopamine receptor signaling pathway	1	1404.3×	0.007	ALK
swimming behavior	1	1123.5×	0.007	ALK
response to stress	1	802.5×	0.007	ALK
peptidyl-tyrosine autophosphorylation	1	624.1×	0.007	ALK
phosphorylation	1	432.1×	0.008	ALK
positive regulation of dendrite development	1	330.4×	0.010	ALK
negative regulation of lipid catabolic process	1	280.9×	0.010	ALK
regulation of neuron differentiation	1	244.2×	0.010	ALK
adult behavior	1	156.0×	0.014	ALK
negative regulation of T cell receptor signaling pathway	1	122.1×	0.016	UBASH3A
cytoplasmic microtubule organization	1	114.6×	0.016	CLIP4
energy homeostasis	1	90.6×	0.018	ALK
neuron development	1	85.1×	0.018	ALK
regulation of cytokine production	1	82.6×	0.018	UBASH3A
hippocampus development	1	77.0×	0.018	ALK
obsolete positive regulation of NF-kappaB transcription factor activity	1	68.5×	0.019	ALK
cell surface receptor protein tyrosine kinase signaling pathway	1	57.9×	0.021	ALK
protein autophosphorylation	1	48.4×	0.024	ALK
regulation of cell population proliferation	1	38.5×	0.028	ALK
regulation of apoptotic process	1	27.8×	0.037	ALK
signal transduction	1	5.3×	0.176	ALK

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ALK	CERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALK	61	4
UBASH3A	0	0
CLIP4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CERITINIB	4	ALK
BOSUTINIB	4	ALK
CRIZOTINIB	4	ALK
ALECTINIB	4	ALK
ENTRECTINIB	4	ALK
LORLATINIB	4	ALK
GILTERITINIB	4	ALK
OSIMERTINIB	4	ALK
BRIGATINIB	4	ALK
REPOTRECTINIB	4	ALK
FEDRATINIB	4	ALK
RUXOLITINIB	4	ALK
INFIGRATINIB PHOSPHATE	4	ALK
INFIGRATINIB	4	ALK
PALBOCICLIB	4	ALK
VANDETANIB	4	ALK
UPADACITINIB	4	ALK
PAZOPANIB	4	ALK
NINTEDANIB	4	ALK
SUNITINIB	4	ALK
ERLOTINIB	4	ALK
MIDOSTAURIN	4	ALK
DACTOLISIB	3	ALK
LINIFANIB	3	ALK
SEMAXANIB	3	ALK
CANERTINIB	3	ALK
ROCILETINIB	3	ALK
ALVOCIDIB	3	ALK
CEDIRANIB	3	ALK
QUERCETIN	3	ALK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ALK	1,815	Binding:1801, Functional:13, ADMET:1
UBASH3A	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALK	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ALK	1,815

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CERITINIB	4	ALK
BOSUTINIB	4	ALK
CRIZOTINIB	4	ALK
ALECTINIB	4	ALK
ENTRECTINIB	4	ALK
LORLATINIB	4	ALK
GILTERITINIB	4	ALK
OSIMERTINIB	4	ALK
BRIGATINIB	4	ALK
REPOTRECTINIB	4	ALK
FEDRATINIB	4	ALK
RUXOLITINIB	4	ALK
INFIGRATINIB PHOSPHATE	4	ALK
INFIGRATINIB	4	ALK
PALBOCICLIB	4	ALK
VANDETANIB	4	ALK
UPADACITINIB	4	ALK
PAZOPANIB	4	ALK
NINTEDANIB	4	ALK
SUNITINIB	4	ALK
ERLOTINIB	4	ALK
MIDOSTAURIN	4	ALK
DACTOLISIB	3	ALK
LINIFANIB	3	ALK
SEMAXANIB	3	ALK
CANERTINIB	3	ALK
ROCILETINIB	3	ALK
ALVOCIDIB	3	ALK
CEDIRANIB	3	ALK
QUERCETIN	3	ALK

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ALK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	UBASH3A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CLIP4

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
UBASH3A	1	—
CLIP4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.