ASCL1

Summary

ASCL1 (achaete-scute family bHLH transcription factor 1, HGNC:738) is a protein-coding gene on chromosome 12q23.2, encoding Achaete-scute homolog 1 (P50553). Transcription factor that plays a key role in neuronal differentiation: acts as a pioneer transcription factor, accessing closed chromatin to allow other factors to bind and activate neural pathways.

This gene encodes a member of the basic helix-loop-helix (BHLH) family of transcription factors. The protein activates transcription by binding to the E box (5’-CANNTG-3’). Dimerization with other BHLH proteins is required for efficient DNA binding. This protein plays a role in the neuronal commitment and differentiation and in the generation of olfactory and autonomic neurons. Mutations in this gene may contribute to the congenital central hypoventilation syndrome (CCHS) phenotype in rare cases.

Source: NCBI Gene 429 — RefSeq curated summary.

At a glance

• Gene–disease (curated): central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 61 total — 1 pathogenic
• Phenotypes (HPO): 19
• Transcription factor: yes — 75 downstream targets (CollecTRI)
• MANE Select transcript: NM_004316

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:738
Approved symbol	ASCL1
Name	achaete-scute family bHLH transcription factor 1
Location	12q23.2
Locus type	gene with protein product
Status	Approved
Aliases	ASH1, HASH1, bHLHa46
Ensembl gene	ENSG00000139352
Ensembl biotype	protein_coding
OMIM	100790
Entrez	429

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000266744

RefSeq mRNA: 1 — MANE Select: NM_004316 NM_004316

CCDS: CCDS31886

Canonical transcript exons

ENST00000266744 — 2 exons

Exon	Start	End
ENSE00000937687	102957674	102959002
ENSE00001216371	102959362	102960513

Expression profiles

Bgee: expression breadth ubiquitous, 143 present calls, max score 92.91.

FANTOM5 (CAGE): breadth broad, TPM avg 13.0590 / max 1447.0463, expressed in 380 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127686	11.2781	361
127690	1.0860	205
127688	0.2331	113
127691	0.2156	126
127687	0.1336	58
127689	0.1126	54

Top tissues by expression

265 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	92.91	gold quality
ventricular zone	UBERON:0003053	90.37	gold quality
CA1 field of hippocampus	UBERON:0003881	85.57	gold quality
entorhinal cortex	UBERON:0002728	84.90	gold quality
diaphragm	UBERON:0001103	83.70	gold quality
lateral globus pallidus	UBERON:0002476	83.46	gold quality
amygdala	UBERON:0001876	83.39	gold quality
primary visual cortex	UBERON:0002436	83.39	gold quality
postcentral gyrus	UBERON:0002581	83.18	gold quality
temporal lobe	UBERON:0001871	83.16	gold quality
embryo	UBERON:0000922	83.07	gold quality
ventral tegmental area	UBERON:0002691	82.83	gold quality
pituitary gland	UBERON:0000007	82.82	gold quality
globus pallidus	UBERON:0001875	82.60	gold quality
occipital lobe	UBERON:0002021	82.53	gold quality
medial globus pallidus	UBERON:0002477	82.40	gold quality
parietal lobe	UBERON:0001872	82.16	gold quality
adenohypophysis	UBERON:0002196	81.86	gold quality
Ammon’s horn	UBERON:0001954	81.20	gold quality
inferior vagus X ganglion	UBERON:0005363	81.15	gold quality
subthalamic nucleus	UBERON:0001906	80.43	gold quality
substantia nigra	UBERON:0002038	80.07	gold quality
superior frontal gyrus	UBERON:0002661	79.90	gold quality
midbrain	UBERON:0001891	79.83	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	79.43	gold quality
cerebral cortex	UBERON:0000956	79.41	gold quality
dorsal plus ventral thalamus	UBERON:0001897	79.26	gold quality
thymus	UBERON:0002370	78.94	gold quality
lateral nuclear group of thalamus	UBERON:0002736	78.90	gold quality
forebrain	UBERON:0001890	78.84	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	1321.83
E-GEOD-93593	yes	817.33
E-HCAD-5	yes	18.16
E-MTAB-8894	no	1074.02
E-ANND-3	no	0.81

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

75 targets.

Target	Regulation
ACHE
ACTA2
ACTG2
ASCL1
AVPR2
AXIN2	Activation
BCL2	Activation
BTG2	Activation
BUB1	Repression
CCND2
CEL
CENPJ	Activation
CGA
CHGA	Unknown
CHRNA3	Unknown
CHRNA5	Unknown
CHRNB4	Unknown
CKM	Activation
CLN3
DBH	Unknown
DKK1	Repression
DLL1	Activation
DLL3	Activation
DLL4	Activation
DLX5	Activation
EFNA5	Activation
EHD1
EZH2
GAD1	Activation
GADD45A

JASPAR motifs

Motif	Name	Family
MA1100.1	ASCL1	MyoD/ASC-related factors
MA1100.2	ASCL1	MyoD/ASC-related factors
MA1100.3	ASCL1	MyoD/ASC-related factors
MA1631.1	ASCL1	MyoD/ASC-related factors
MA1631.2	ASCL1	MyoD/ASC-related factors

JASPAR matrix evidence (PMIDs): PMID:31086315, PMID:20382226

Upstream regulators (CollecTRI, top): ASCL1, ASCL2, CHD8, CREB1, CTNNB1, DNMT1, DNMT3A, DNMT3B, EED, EZH2, FGF19, FMR1, FOXN4, GLI2, HES1, HES4, HES5, HES6, HNRNPR, ID1, LMO3, MEF2C, MEIS1, MYCN, NEUROG1, NEUROG2, NHLH2, NOTCH1, NOTCH2, PAX6, RBPJ, SOX10, SP1, TFCP2, ZNF699

miRNA regulators (miRDB)

109 targeting ASCL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-557	99.96	70.01	1640
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• HASH1 mRNA expression levels in SCLC clinical samples were 1,000-fold higher than in the NSCLC samples, and this method could contribute to diagnosis based on molecular profiling of tumors. (PMID:11948117)
• We also studied the proneural HASH-1 gene and identified a heterozygous nucleotide substitution in three CCHS patients (PMID:14532329)
• HASH1 appears to be important in the endocrine phenotype of medullary thyroid carcinoma (MTC) tumors and may serve as a molecular target for the treatment of patients with MTC. (PMID:14668716)
• ASH1 is a neuroendocrine marker whose expression is largely conserved in normal and neoplastic pituitary cells. (PMID:14759067)
• the hASH1 mRNA level might represent a useful tool for distinguishing esthesioneuroblastoma from poorly differentiated tumors of the sinonasal region (PMID:15272537)
• Up-Regulation of ASCL1 is associated with gastrointestinal neuroendocrine carcinomas (PMID:15701827)
• The present genetic data may thus suggest that polyglutamine length polymorphisms in ASCL1 could influence predispositions to PD through the fine-tuning of LC integrity. (PMID:16021468)
• RaF-1 activation causes cessation of hASH-1 expression (PMID:16029117)
• Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma (PMID:16103883)
• Knockdown of ASH1 gene in lung neoplasm cells in vitro suppressed growth by increasing apoptosis. (PMID:17507989)
• In prostate cancers with neuroendocrine differentiation…hASH1 transcript levels in androgen deprivation-treated compared with untreated patients (PMID:18311112)
• ASH1 functions as a dual transcription factor by activating neuroendocrine differentiation markers and also repressing putative tumor suppressors. (PMID:18339843)
• lack of nuclear expression of HES1 may contribute to the abundance of ASCL1 and to tumorigenesis in the endocrine pancreas. (PMID:18491256)
• The Ascl1 cell lineage generates Purkinje cells, deep cerebellar nuclei interneurons and oligodendrocytes at specific stages in the transgenic mouse cerebellum. (PMID:18585058)
• Tumor marker mASH1 was highly (sensitivity of 71%) and specifically (specificity of 95%) expressed in poorly differentiated neuroendocrine carcinoma. (PMID:18587321)
• MASH1 is a useful adjunct marker for differentiating small cell carcinoma of the lung from Merkel cell carcinoma. (PMID:18587322)
• Mash1 has a role in regulation of prenatal human retinal neurosphere growth and cell fate potential by retinal pigment epithelium (PMID:18802035)
• By overexpressing ASCL1, neurogenesis from human neural progenitor cells was regained, which produced larger neurons with more neurites than hNPC but no fully mature dopamine neurons. (PMID:19008346)
• Improved translation efficiency of ASH1 mRNA by FMRP may represent an important regulatory switch in neuronal differentiation. (PMID:19097999)
• Findings suggest that a broad range of SCLC cells has tumorigenic capacity rather than a small discrete population. Intrinsic tumor cell heterogeneity, including variation in key regulatory factors such as ASCL1, can modulate tumorigenicity in SCLC. (PMID:19176379)
• Expression of DKK1 and TPH1 were negatively regulated by ASCL1 in pancreatic endocrine tumours. (PMID:19744316)
• these support the role of the polyglutamine length variants in the MASH1 gene in Parkinson’s disease susceptibility. (PMID:20097173)
• Our data indicate a specific role for ASCL1 in regulating the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. This regulation may contribute to the predicted role that ASCL1 plays in SCLC tumorigenesis. (PMID:20124469)
• report the analysis of 9 highly conserved putative enhancers in a 64kb interval encompassing the human ASCL1 locus (PMID:20206680)
• Supratentorial PNETs expressed significantly higher levels of SOX2, NOTCH1, ID1, and ASCL-1 transcripts. (PMID:20515335)
• deletional rearrangement of the TCR delta gene disrupted the hypothetical gene C12orf42 and brought the Achaete-scute complex homolog 1 gene into proximity of the TRA enhancer, which is overexpressed in thyroid and lung cancers (PMID:20659153)
• hASH1 is a new kind of highly specific markers of pulmonary neuroendocrine tumours, and may be applied to clinical pathology diagnosis of the pulmonary neuroendocrine tumors. (PMID:20677557)
• ASCL1-pathway is responsible for the up-regulation of IGF2 during neuroblastoma differentiation. (PMID:20842449)
• HASH1 down-regulation is associated with cell proliferation, thereby resulting in uterine carcinogenesis. (PMID:21495212)
• The present results suggest that a transcriptional complex of LMO3 and HEN2 may contribute to the genesis and malignant phenotype of neuroblastoma by inhibiting HES1 which suppresses the transactivation of Mash1. (PMID:21573214)
• Among human primary tumors, 2/2 SCLC, 5/5 pulmonary carcinoids, and 10/41 non-SCLC (only 4 of which had NE features) were positive for hASH1 by immunohistochemistry and RNA-RNA in situ hybridization. (PMID:21684625)
• The ASCL1 knock-down gene set also classified the 171 adenocarcinomas into three subtypes and this NE subtype also had the poorest prognosis. (PMID:21737174)
• miR-375 is a key downstream effector of ASH1 function in lung cancer cells (PMID:21856745)
• Dual-luciferase assays showed that ASCL1 activated the expression of miR-375 by binding to the three E-box elements in the miR-375 promoter. These results imply a role of ASCL1 in SCLC via the upregulation of miR-375. (PMID:22172490)
• hASH-1 expression occurs in breast cancers with neuroendocrine differentiation regardless of the extent of the NE cell population, and it is restricted to a subset of tumor cells having a low proliferative potential. (PMID:22422124)
• Ascl1 directly regulates expression of matrix metalloproteinase-7 and O(6)-methylguanine-DNA methyltransferase. (PMID:23300791)
• Achaete-scute homolog 1 may be proposed as a diagnostic marker of poor differentiation and may help to differentiate neuroendocrine carcinomas from neuroendocrine tumors in difficult cases. (PMID:23375646)
• BRN2 is a higher level regulator than ASCL1 and ND1 and BRN2 might be involved in aggressiveness of small cell lung cancer. (PMID:23530560)
• ASH1 overexpression in prostate cancer cells promotes neuroendocrine differentiation and increased cell viability. (PMID:23657976)
• ASCL1 Promotes Wnt Signaling Directly by Repressing DKK1. (PMID:23707066)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ascl1a	ENSDARG00000038386
mus_musculus	Ascl1	ENSMUSG00000020052
rattus_norvegicus	Ascl1	ENSRNOG00000085519
drosophila_melanogaster	ac	FBGN0000022
drosophila_melanogaster	ase	FBGN0000137

Paralogs (4): ASCL3 (ENSG00000176009), ASCL2 (ENSG00000183734), ASCL4 (ENSG00000187855), ASCL5 (ENSG00000232237)

Protein

Protein identifiers

Achaete-scute homolog 1 — P50553 (reviewed: P50553)

Alternative names: Class A basic helix-loop-helix protein 46

All UniProt accessions (1): P50553

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that plays a key role in neuronal differentiation: acts as a pioneer transcription factor, accessing closed chromatin to allow other factors to bind and activate neural pathways. Directly binds the E box motif (5’-CANNTG-3’) on promoters and promotes transcription of neuronal genes. The combination of three transcription factors, ASCL1, POU3F2/BRN2 and MYT1L, is sufficient to reprogram fibroblasts and other somatic cells into induced neuronal (iN) cells in vitro. Plays a role at early stages of development of specific neural lineages in most regions of the CNS, and of several lineages in the PNS. Essential for the generation of olfactory and autonomic neurons. Acts synergistically with FOXN4 to specify the identity of V2b neurons rather than V2a from bipotential p2 progenitors during spinal cord neurogenesis, probably through DLL4-NOTCH signaling activation. Involved in the regulation of neuroendocrine cell development in the glandular stomach.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with TCF3.

Subcellular location. Nucleus.

Disease relevance. Genetic variations in ASCL1 may play a role in disorders of the neurocristopathy spectrum manifesting with features of Hirschsprung disease, congenital central hypoventilation syndrome, dysautonomia, in addition to neurodevelopmental issues.

RefSeq proteins (1): NP_004307* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR015660	MASH1/Ascl1a-like	Family
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00010

UniProt features (11 total): compositionally biased region 3, region of interest 2, sequence variant 2, chain 1, domain 1, sequence conflict 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50553-F1	68.22	0.25

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 156

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-9031628	NGF-stimulated transcription
R-HSA-162582	Signal Transduction
R-HSA-166520	Signaling by NTRKs
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-198725	Nuclear Events (kinase and transcription factor activation)
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 343 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, BENPORATH_ES_WITH_H3K27ME3, SP3_Q3, GOBP_LUNG_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, GOBP_GLIAL_CELL_DEVELOPMENT

GO Biological Process (68): negative regulation of transcription by RNA polymerase II (GO:0000122), noradrenergic neuron development (GO:0003358), noradrenergic neuron fate commitment (GO:0003359), Notch signaling pathway (GO:0007219), regulation of mitotic cell cycle (GO:0007346), neuroblast fate determination (GO:0007400), neuroblast proliferation (GO:0007405), sensory organ development (GO:0007423), heart development (GO:0007507), regulation of gene expression (GO:0010468), oligodendrocyte development (GO:0014003), spinal cord association neuron differentiation (GO:0021527), spinal cord oligodendrocyte cell fate specification (GO:0021530), vestibular nucleus development (GO:0021750), cerebral cortex GABAergic interneuron differentiation (GO:0021892), commitment of neuronal cell to specific neuron type in forebrain (GO:0021902), central nervous system neuron development (GO:0021954), cerebral cortex development (GO:0021987), neurogenesis (GO:0022008), neuron differentiation (GO:0030182), regulation of epithelial cell differentiation (GO:0030856), response to retinoic acid (GO:0032526), negative regulation of apoptotic process (GO:0043066), positive regulation of neuron apoptotic process (GO:0043525), negative regulation of neuron differentiation (GO:0045665), positive regulation of neuron differentiation (GO:0045666), positive regulation of Notch signaling pathway (GO:0045747), positive regulation of cell cycle (GO:0045787), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), cell maturation (GO:0048469), sympathetic nervous system development (GO:0048485), neuron fate commitment (GO:0048663), neuron fate specification (GO:0048665), neuron development (GO:0048666), peripheral nervous system neuron development (GO:0048935), regulation of neurogenesis (GO:0050767), positive regulation of neurogenesis (GO:0050769), musculoskeletal movement, spinal reflex action (GO:0050883), response to folic acid (GO:0051593)

GO Molecular Function (16): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), nucleic acid binding (GO:0003676), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), identical protein binding (GO:0042802), bHLH transcription factor binding (GO:0043425), protein dimerization activity (GO:0046983), E-box binding (GO:0070888), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), double-stranded DNA binding (GO:0003690), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), neuronal cell body (GO:0043025), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Nuclear Events (kinase and transcription factor activation)	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by NTRKs	1
Signaling by NTRK1 (TRKA)	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
binding	3
regulation of transcription by RNA polymerase II	2
noradrenergic neuron differentiation	2
neuron development	2
generation of neurons	2
animal organ development	2
central nervous system neuron differentiation	2
cell differentiation	2
transcription cis-regulatory region binding	2
protein binding	2
DNA binding	2
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
neuron fate commitment	1
cell surface receptor signaling pathway	1
mitotic cell cycle	1
regulation of cell cycle	1
cell fate determination	1
neuroblast fate commitment	1
neural precursor cell proliferation	1
circulatory system development	1
gene expression	1
regulation of macromolecule biosynthetic process	1
glial cell development	1
oligodendrocyte differentiation	1
cell differentiation in spinal cord	1
dorsal spinal cord development	1
spinal cord oligodendrocyte cell differentiation	1
oligodendrocyte cell fate specification	1
pons development	1
medulla oblongata development	1
neural nucleus development	1
cerebral cortex neuron differentiation	1
GABAergic neuron differentiation	1
forebrain neuron fate commitment	1
pallium development	1
anatomical structure development	1
nervous system development	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

2326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASCL1	NEUROG2	Q9H2A3	971
ASCL1	POU3F2	P20265	968
ASCL1	MYT1L	Q9UL68	961
ASCL1	DLX2	Q07687	926
ASCL1	POU3F3	P20264	923
ASCL1	ID4	P47928	900
ASCL1	PHOX2B	Q99453	892
ASCL1	PHOX2A	O14813	877
ASCL1	NEUROG1	Q92886	870
ASCL1	DLX1	P56177	864
ASCL1	NKX2-2	O95096	851
ASCL1	ATOH1	Q92858	838
ASCL1	HES6	Q96HZ4	822
ASCL1	LMX1A	Q8TE12	800
ASCL1	LMX1B	O60663	792

IntAct

53 interactions, top by confidence:

A	B	Type	Score
ASCL1	TCF4	psi-mi:“MI:0915”(physical association)	0.720
ASCL1	TCF4	psi-mi:“MI:0407”(direct interaction)	0.720
TCF4	ASCL1	psi-mi:“MI:0915”(physical association)	0.720
ASCL1	TCF3	psi-mi:“MI:0915”(physical association)	0.630
TCF3	ASCL1	psi-mi:“MI:0915”(physical association)	0.630
USP20	ASCL1	psi-mi:“MI:0915”(physical association)	0.560
ASCL1	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
ASCL1	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
ASCL1	ARID1A	psi-mi:“MI:0914”(association)	0.500
SMARCC1	ASCL1	psi-mi:“MI:0915”(physical association)	0.500
ASCL1	ARID1A	psi-mi:“MI:0915”(physical association)	0.500
ASCL1		psi-mi:“MI:0407”(direct interaction)	0.440
ASCL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
ASCL1	SMARCC2	psi-mi:“MI:2364”(proximity)	0.270
ASCL1	SMARCB1	psi-mi:“MI:2364”(proximity)	0.270
BRAF	ASCL1	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	ASCL1	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	ASCL1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (43): ASCL1 (Two-hybrid), TCF3 (Affinity Capture-Western), ASCL1 (Affinity Capture-Western), ASCL1 (Co-localization), ASCL1 (Affinity Capture-Western), ASCL1 (Two-hybrid), ASCL1 (Two-hybrid), UBQLN2 (Two-hybrid), TCF4 (Reconstituted Complex), TCF4 (Two-hybrid), MEF2A (Affinity Capture-Western), ASCL1 (Reconstituted Complex), POF1B (Affinity Capture-MS), PLA2G4E (Affinity Capture-MS), TGM1 (Affinity Capture-MS)

ESM2 similar proteins: A3KMR8, A7Z017, D3ZNT6, O02754, O42290, O57342, O75444, P09631, P19359, P23091, P29775, P50553, P51179, P54841, P54842, P54843, P54844, P54846, P61295, P61296, Q02067, Q05826, Q0V9K1, Q0V9X5, Q13562, Q2PFS4, Q4U1U2, Q4V5A3, Q504L8, Q566X8, Q5IS79, Q60430, Q60867, Q61039, Q64289, Q6DE84, Q6PFG8, Q789F3, Q8CF90, Q8NHW3

Diamond homologs: A8E5T6, M0QWB7, O35437, O35885, O43680, O60682, O73615, O73823, O88940, O93507, O96004, O96642, P09774, P09775, P10083, P10084, P10627, P13903, P17542, P19359, P19360, P22091, P24899, P26687, P27792, P34555, P46581, P48985, P50553, P57100, P57101, P57102, P59101, P61295, P61296, P79782, P97831, P97832, Q02067, Q02575

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
DTX1	down-regulates	ASCL1	binding
NHLH2	“up-regulates quantity by expression”	ASCL1	“transcriptional regulation”
HES1	“down-regulates quantity by repression”	ASCL1	“transcriptional regulation”
LMO3	“up-regulates quantity by expression”	ASCL1	“transcriptional regulation”
ASCL1	“down-regulates quantity by repression”	DKK1	“transcriptional regulation”
HES5	“down-regulates quantity by repression”	ASCL1	“transcriptional regulation”
ASCL1	up-regulates	Neurogenesis
CHD8	“down-regulates quantity”	ASCL1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of the embryonic stem cell BAF (esBAF) complex	5	150.3×	2e-08
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	5	114.2×	4e-08
Regulation of endogenous retroelements	5	92.1×	1e-07
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	5	75.1×	2e-07
Regulation of MITF-M-dependent genes involved in pigmentation	5	66.4×	4e-07
MITF-M-dependent gene expression	7	63.4×	3e-09
Transcriptional regulation by RUNX1	6	43.9×	2e-07
MITF-M-regulated melanocyte development	7	40.0×	3e-08

GO biological processes:

GO term	Partners	Fold	FDR
nucleosome disassembly	5	174.4×	3e-08
regulation of G0 to G1 transition	5	146.5×	3e-08
regulation of nucleotide-excision repair	5	130.8×	4e-08
regulation of mitotic metaphase/anaphase transition	5	107.8×	9e-08
positive regulation of T cell differentiation	5	99.0×	1e-07
regulation of G1/S transition of mitotic cell cycle	6	79.9×	3e-08
positive regulation of myoblast differentiation	5	79.6×	3e-07
positive regulation of double-strand break repair	5	74.8×	4e-07

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

61 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	38
Likely benign	10
Benign	5

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3244235	NC_000012.11:g.(?103232953)(103352733_?)del	Pathogenic

SpliceAI

79 predictions. Top by Δscore:

Variant	Effect	Δscore
12:102958999:GCAG:G	donor_gain	1.0000
12:102959003:GTAG:G	donor_loss	1.0000
12:102959003:G:GG	donor_gain	0.9900
12:102958998:AGCAG:A	donor_gain	0.9800
12:102958999:GCAGG:G	donor_gain	0.9800
12:102959360:AG:A	acceptor_gain	0.9800
12:102959361:GG:G	acceptor_gain	0.9800
12:102959361:GGGT:G	acceptor_gain	0.9700
12:102959354:T:G	acceptor_gain	0.9600
12:102959360:A:AG	acceptor_gain	0.9600
12:102959360:AGGGT:A	acceptor_gain	0.9600
12:102959361:G:GG	acceptor_gain	0.9600
12:102959361:GGGTG:G	acceptor_gain	0.9600
12:102959357:TATA:T	acceptor_loss	0.9500
12:102959359:TA:T	acceptor_loss	0.9500
12:102959360:A:C	acceptor_loss	0.9500
12:102959001:AG:A	donor_gain	0.9400
12:102959002:GG:G	donor_gain	0.9400
12:102959353:AT:A	acceptor_gain	0.9400
12:102959358:ATAG:A	acceptor_gain	0.9400
12:102959354:T:TA	acceptor_gain	0.9200
12:102959360:AGG:A	acceptor_gain	0.9100
12:102959361:GGG:G	acceptor_gain	0.9100
12:102959000:CAGGT:C	donor_gain	0.9000
12:102959001:AGGTA:A	donor_gain	0.9000
12:102959353:A:AG	acceptor_gain	0.9000
12:102959000:CAG:C	donor_gain	0.8800
12:102959359:T:G	acceptor_gain	0.8600
12:102958996:G:GT	donor_gain	0.8500
12:102959003:GTA:G	donor_gain	0.8500

AlphaMissense

1526 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:102958608:C:A	R122S	1.000
12:102958611:C:A	R123S	1.000
12:102958611:C:G	R123G	1.000
12:102958611:C:T	R123C	1.000
12:102958612:G:A	R123H	1.000
12:102958612:G:C	R123P	1.000
12:102958612:G:T	R123L	1.000
12:102958614:A:G	N124D	1.000
12:102958615:A:T	N124I	1.000
12:102958616:C:A	N124K	1.000
12:102958616:C:G	N124K	1.000
12:102958620:C:A	R126S	1.000
12:102958620:C:T	R126C	1.000
12:102958621:G:A	R126H	1.000
12:102958621:G:C	R126P	1.000
12:102958623:G:A	E127K	1.000
12:102958623:G:C	E127Q	1.000
12:102958624:A:C	E127A	1.000
12:102958624:A:G	E127G	1.000
12:102958624:A:T	E127V	1.000
12:102958625:G:C	E127D	1.000
12:102958625:G:T	E127D	1.000
12:102958626:C:A	R128S	1.000
12:102958626:C:G	R128G	1.000
12:102958626:C:T	R128C	1.000
12:102958627:G:A	R128H	1.000
12:102958627:G:C	R128P	1.000
12:102958627:G:T	R128L	1.000
12:102958632:C:A	R130S	1.000
12:102958632:C:G	R130G	1.000

dbSNP variants (sampled 300 via entrez): RS1000278727 (12:102958174 T>TC), RS1000616080 (12:102957146 A>C,G), RS1000689447 (12:102956786 A>G), RS1001497783 (12:102957884 A>G,T), RS1001597724 (12:102956531 A>G), RS1001833281 (12:102956774 G>A), RS1002384218 (12:102958226 T>C), RS1004389952 (12:102958142 C>T), RS1004455717 (12:102956106 A>C), RS1004783072 (12:102957709 G>T), RS1004891067 (12:102955840 G>T), RS1004992987 (12:102960081 G>A,T), RS1005158382 (12:102959467 A>G), RS1005328234 (12:102958395 C>CAGA,CAGG,CAGT), RS1006379109 (12:102960961 G>C,T)

Disease associations

OMIM: gene MIM:100790 | disease phenotypes: MIM:209880, MIM:261600

GenCC curated gene-disease

Disease	Classification	Inheritance
central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease	Moderate	Autosomal dominant
Haddad syndrome	Supportive	Autosomal dominant
neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (5): central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (MONDO:0800026), central hypoventilation syndrome, congenital (MONDO:0800031), Haddad syndrome (MONDO:0020493), phenylketonuria (MONDO:0009861), neurodevelopmental disorder (MONDO:0700092)

Orphanet (3): Congenital central hypoventilation syndrome (Orphanet:661), Haddad syndrome (Orphanet:99803), Phenylketonuria (Orphanet:716)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001508	Failure to thrive
HP:0001518	Small for gestational age
HP:0001522	Death in infancy
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001562	Oligohydramnios
HP:0002020	Gastroesophageal reflux
HP:0002251	Aganglionic megacolon
HP:0003005	Ganglioneuroma
HP:0003006	Neuroblastoma
HP:0005957	Breathing dysregulation
HP:0007110	Central hypoventilation
HP:0010536	Central sleep apnea
HP:0012332	Abnormal autonomic nervous system physiology

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000965_10	C-reactive protein levels	2.000000e-11
GCST005312_11	Menopause (age at onset)	1.000000e-16
GCST007382_21	Plasma free amino acid levels (adjusted for twenty other PFAAs)	3.000000e-25
GCST007385_10	Plasma free amino acid levels	3.000000e-12
GCST007614_17	C-reactive protein levels	2.000000e-20
GCST007615_35	C-reactive protein levels	2.000000e-16

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement
EFO:0004704	age at menopause
EFO:0005001	phenylalanine measurement
EFO:0005134	amino acid measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
D010661	Phenylketonurias	C10.228.140.163.100.687; C16.320.565.100.766; C16.320.565.189.687; C18.452.132.100.687; C18.452.648.100.766; C18.452.648.189.687

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

50 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	5
trichostatin A	affects cotreatment, increases expression	3
Estradiol	affects binding, increases expression, affects cotreatment, decreases expression	3
afimoxifene	decreases expression, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
MRK 003	increases expression	2
Resveratrol	decreases expression, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression, affects cotreatment	2
Tretinoin	decreases expression, increases expression	2
methylmercuric chloride	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
tributyltin	affects cotreatment, increases expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, decreases expression	1
propionic acid	decreases expression	1
naphthalene	decreases expression, decreases reaction, increases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
beta-methylcholine	affects expression	1
deguelin	increases expression	1
Chir 99021	decreases expression, affects cotreatment, increases expression, affects binding	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol Z	increases expression	1
XAV939	affects binding, affects cotreatment, decreases expression	1
3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid	decreases expression	1
LDN 193189	increases expression, affects cotreatment	1
3-(4-pyridyl)-1H-indole	affects cotreatment, increases expression	1
Bosentan	affects expression	1
Eucalyptol	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0D0	SEES3-1V human ASCL1, clone1	Embryonic stem cell	Male
CVCL_A0D1	SEES3-1V human ASCL1, clone2	Embryonic stem cell	Male
CVCL_A0D2	SEES3-1V human ASCL1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

382 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT01082328	PHASE4	COMPLETED	Response to Kuvan® in Subjects With Phenylketonuria (PKU) in a 4 Weeks Testing Period
NCT01617070	PHASE4	COMPLETED	Effects of Kuvan on Melatonin Secretion
NCT01965912	PHASE4	COMPLETED	Kuvan®’s Effect on the Cognition of Children With Phenylketonuria
NCT02677870	PHASE4	COMPLETED	The Effectiveness of Kuvan in Amish PKU Patients
NCT03788343	PHASE4	COMPLETED	Phenylalanine and Its Impact on Cognition
NCT04227080	PHASE4	UNKNOWN	BH4 Responsiveness in PAH Deficiency PKU Patients
NCT06780332	PHASE4	ACTIVE_NOT_RECRUITING	Rapid Drug Desensitization Study in Adults Experiencing Hypersensitivity Reactions to Palynziq
NCT06901323	PHASE4	ACTIVE_NOT_RECRUITING	Effect of L-carnitine Supplementation on Phenylalanine and Brain-derived Neurotrophic Factor Levels in Infants and Children With Phenylketonuria
NCT07477691	PHASE4	NOT_YET_RECRUITING	Immune Modulation During Palynziq® Treatment in Adults (IMPALA)
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00104247	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Phenoptin™ in Subjects With Phenylketonuria Who Have Elevated Phenylalanine Levels
NCT00225615	PHASE3	COMPLETED	A Phase 3, Multicenter, Open-Label Extension Study of Phenoptin in Subjects With PKU Who Have Elevated Phenylalanine Levels
NCT00272792	PHASE3	COMPLETED	Study of Phenoptin to Increase Phenylalanine Tolerance in Phenylketonuric Children on a Phenylalanine-restricted Diet
NCT00332189	PHASE3	COMPLETED	Study of Phenoptin in Subjects With Phenylketonuria Who Participated in Protocols PKU-004 or PKU-006
NCT00838435	PHASE3	COMPLETED	Effect of Kuvan on Neurocognitive Function, Blood Phenylalanine Level, Safety, and Pharmacokinetics in Children With PKU
NCT01114737	PHASE3	COMPLETED	Safety and Therapeutic Effects of Sapropterin Dihydrochloride on Neuropsychiatric Symptoms in Phenylketonuria (PKU) Patients
NCT01376908	PHASE3	COMPLETED	Kuvan® in Phenylketonuria Patients Less Than 4 Years Old
NCT01732471	PHASE3	COMPLETED	Phase 3 Open-label Study to Evaluate the Response and Safety of Kuvan® in Subjects With Phenylketonuria
NCT01819727	PHASE3	COMPLETED	An Open-Label Phase 3 Study of BMN 165 for Adults With PKU Not Previously Treated w/ BMN 165
NCT01889862	PHASE3	COMPLETED	Phase 3 Study to Evaluate the Efficacy & Safety of Self-Administered Injections of BMN165 by Adults With PKU
NCT03694353	PHASE3	COMPLETED	Safety and Efficacy of Self Administered Injections of Pegvaliase (>40mg/Day Dose) in Adults With PKU
NCT05099640	PHASE3	COMPLETED	A Study of PTC923 in Participants With Phenylketonuria
NCT05166161	PHASE3	ACTIVE_NOT_RECRUITING	A Long-Term Safety Study of PTC923 in Participants With Phenylketonuria
NCT05270837	PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate the Safety and Efficacy of Pegvaliase in Adolescents (Ages 12-17) With Phenylketonuria
NCT05764239	PHASE3	TERMINATED	Efficacy and Safety of SYNB1934 in Patients With PKU (SYNPHENY-3)
NCT06302348	PHASE3	RECRUITING	A Study of Sepiapterin in Participants With Phenylketonuria (PKU)
NCT06628128	PHASE3	RECRUITING	A Long-Term Study of JNT-517 in Participants With Phenylketonuria
NCT06971731	PHASE3	RECRUITING	A Study of JNT-517 in Participants With Phenylketonuria (PKU)
NCT01500473	PHASE2	TERMINATED	Therapeutic Effect of Desogestrel on Ventilatory Control in Patients With Congenital Central Hypoventilation Syndrome
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00104260	PHASE2	COMPLETED	Study to Evaluate the Response to and Safety of an 8-Day Course of Phenoptin™ Treatment in Subjects With Phenylketonuria
NCT00260000	PHASE2	COMPLETED	Study of BH4, a New and Simple Treatment of Mild PKU
NCT00841100	PHASE2	COMPLETED	Kuvan Therapy in Phenylketonuria (PKU): The Effect of Blood Phenylalanine Concentration on Kuvan Response