Neuroblastoma, susceptibility to, 2

Summary

Neuroblastoma, susceptibility to, 2 (MONDO:0700041) is a disease caused by PHOX2B (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PHOX2B (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 131

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuroblastoma, susceptibility to, 2
Mondo ID	MONDO:0700041
OMIM	613013
UMLS	C2751682
MedGen	416607
GARD	0028008
Is cancer (heuristic)	no

Also known as: NBLST2 · neuroblastoma, susceptibility to, type 2 · susceptibility to neuroblastoma 2

Data availability: 131 ClinVar variants · 2 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, 2

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, 3, 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, 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

131 retrieved; paginated sample, class counts are floors:

77 uncertain significance, 18 conflicting classifications of pathogenicity, 14 benign, 12 benign/likely benign, 7 pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2500070	NM_003924.4(PHOX2B):c.775_776insGGCGGCAGCGGCAGCGGCGGC (p.Ala259delinsGlyArgGlnArgGlnArgArgPro)	LOC110011216	Pathogenic	criteria provided, single submitter
452239	NM_003924.4(PHOX2B):c.756_776dup (p.Ala254_Ala260dup)	LOC110011216	Pathogenic	criteria provided, multiple submitters, no conflicts
505021	NM_003924.4(PHOX2B):c.753_767dup (p.Ala256_Ala260dup)	LOC110011216	Pathogenic	criteria provided, multiple submitters, no conflicts
1032169	NM_003924.4(PHOX2B):c.945A>C (p.Ter315Cys)	PHOX2B	Pathogenic	criteria provided, single submitter
1072410	NM_003924.4(PHOX2B):c.691_698dup (p.Gly234fs)	PHOX2B	Pathogenic	criteria provided, multiple submitters, no conflicts
2500068	NM_003924.4(PHOX2B):c.778_779insGGCGGCGGCGGCAGCGGCAGCGGCGGCAGC (p.Ala260delinsGlyArgArgArgGlnArgGlnArgArgGlnPro)	PHOX2B	Pathogenic	criteria provided, single submitter
987239	NM_003924.4(PHOX2B):c.866dup (p.Pro290fs)	PHOX2B	Pathogenic	criteria provided, multiple submitters, no conflicts
2500234	NM_003924.4(PHOX2B):c.745_746insGGCGGCCGCGGC (p.Ala249delinsGlyArgProArgPro)	LOC110011216	Likely pathogenic	criteria provided, single submitter
1515387	NM_003924.4(PHOX2B):c.241+1G>A	PHOX2B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677755	NM_003924.4(PHOX2B):c.712A>T (p.Lys238Ter)	PHOX2B	Likely pathogenic	criteria provided, single submitter
348809	NM_003924.4(PHOX2B):c.773C>A (p.Ala258Glu)	LOC110011216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
901291	NM_003924.4(PHOX2B):c.741C>G (p.Ala247=)	LOC110011216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135034	NM_003924.4(PHOX2B):c.617C>G (p.Pro206Arg)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239594	NM_003924.4(PHOX2B):c.760G>A (p.Ala254Thr)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239596	NM_003924.4(PHOX2B):c.832G>A (p.Gly278Ser)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
348803	NM_003924.4(PHOX2B):c.*60G>A	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
348807	NM_003924.4(PHOX2B):c.*19C>A	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
348808	NM_003924.4(PHOX2B):c.*18G>A	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
348810	NM_003924.4(PHOX2B):c.729A>G (p.Ala243=)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
406405	NM_003924.4(PHOX2B):c.242-5_242-2dup	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
467725	NM_003924.4(PHOX2B):c.391C>G (p.Leu131Val)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
467748	NM_003924.4(PHOX2B):c.796G>T (p.Ala266Ser)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
576023	NM_003924.4(PHOX2B):c.865G>A (p.Gly289Ser)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6011	NM_003924.4(PHOX2B):c.299G>T (p.Arg100Leu)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
640568	NM_003924.4(PHOX2B):c.932G>A (p.Ser311Asn)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
948497	NM_003924.4(PHOX2B):c.649G>A (p.Gly217Arg)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
467719	NM_003924.4(PHOX2B):c.146C>A (p.Thr49Asn)	PHOX2B-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
486030	NM_003924.4(PHOX2B):c.227G>C (p.Ser76Thr)	PHOX2B-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1346897	NM_003924.4(PHOX2B):c.770C>T (p.Ala257Val)	LOC110011216	Uncertain significance	criteria provided, multiple submitters, no conflicts
2186948	NM_003924.4(PHOX2B):c.745G>T (p.Ala249Ser)	LOC110011216	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 4 · 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
PHOX2B	Definitive	Autosomal dominant	neuroblastoma, susceptibility to, 2	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PHOX2B	Orphanet:2151	Hirschsprung disease-ganglioneuroblastoma syndrome
PHOX2B	Orphanet:635	Neuroblastoma
PHOX2B	Orphanet:661	Congenital central hypoventilation syndrome
PHOX2B	Orphanet:99803	Haddad syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PHOX2B	HGNC:9143	ENSG00000109132	Q99453	Paired mesoderm homeobox protein 2B	gencc,clinvar
PHOX2B-AS1	HGNC:40457	ENSG00000250467		PHOX2B antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PHOX2B	Paired mesoderm homeobox protein 2B	Involved in the development of several major noradrenergic neuron populations, including the locus coeruleus.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PHOX2B	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
PHOX2B-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
dorsal motor nucleus of vagus nerve	1
muscle layer of sigmoid colon	1
adrenal gland	1
left adrenal gland	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PHOX2B	53	tissue_specific	marker	muscle layer of sigmoid colon, buccal mucosa cell, dorsal motor nucleus of vagus nerve
PHOX2B-AS1	35	tissue_specific	yes	adrenal gland, left adrenal gland, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PHOX2B	1,215
PHOX2B-AS1	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PHOX2B	Q99453	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
medullary reticular formation development	1	16852.0×	5e-04	PHOX2B
parasympathetic nervous system development	1	16852.0×	5e-04	PHOX2B
efferent axon development in a lateral line nerve	1	16852.0×	5e-04	PHOX2B
retrotrapezoid nucleus neuron differentiation	1	16852.0×	5e-04	PHOX2B
cellular response to carbon dioxide	1	8426.0×	7e-04	PHOX2B
cell differentiation in hindbrain	1	5617.3×	7e-04	PHOX2B
hindbrain tangential cell migration	1	5617.3×	7e-04	PHOX2B
autonomic nervous system development	1	5617.3×	7e-04	PHOX2B
negative regulation of type B pancreatic cell proliferation	1	5617.3×	7e-04	PHOX2B
noradrenergic neuron development	1	3370.4×	1e-03	PHOX2B
respiratory system development	1	3370.4×	1e-03	PHOX2B
noradrenergic neuron differentiation	1	2407.4×	0.001	PHOX2B
brainstem development	1	2106.5×	0.001	PHOX2B
sympathetic ganglion development	1	1872.4×	0.001	PHOX2B
neural crest cell migration involved in autonomic nervous system development	1	1872.4×	0.001	PHOX2B
motor neuron migration	1	1685.2×	0.001	PHOX2B
regulation of respiratory gaseous exchange by nervous system process	1	1296.3×	0.002	PHOX2B
enteric nervous system development	1	991.3×	0.002	PHOX2B
sympathetic nervous system development	1	936.2×	0.002	PHOX2B
glial cell differentiation	1	887.0×	0.002	PHOX2B
type B pancreatic cell proliferation	1	887.0×	0.002	PHOX2B
dopaminergic neuron differentiation	1	624.1×	0.003	PHOX2B
positive regulation of G2/M transition of mitotic cell cycle	1	601.9×	0.003	PHOX2B
cellular response to BMP stimulus	1	561.7×	0.003	PHOX2B
membrane depolarization	1	510.7×	0.003	PHOX2B
inner ear development	1	374.5×	0.004	PHOX2B
skeletal muscle cell differentiation	1	343.9×	0.004	PHOX2B
response to activity	1	324.1×	0.004	PHOX2B
negative regulation of neuron differentiation	1	271.8×	0.005	PHOX2B
neuron development	1	255.3×	0.005	PHOX2B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PHOX2B	0	0
PHOX2B-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	PHOX2B, PHOX2B-AS1

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)
PHOX2B	0	—
PHOX2B-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.