ASCL2

Summary

ASCL2 (achaete-scute family bHLH transcription factor 2, HGNC:739) is a protein-coding gene on chromosome 11p15.5, encoding Achaete-scute homolog 2 (Q99929). Transcription factor.

This gene is a member of the basic helix-loop-helix (BHLH) family of transcription factors. It activates transcription by binding to the E box (5’-CANNTG-3’). Dimerization with other BHLH proteins is required for efficient DNA binding. Involved in the determination of the neuronal precursors in the peripheral nervous system and the central nervous system.

Source: NCBI Gene 430 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 50 total — 3 pathogenic, 1 likely-pathogenic
• Transcription factor: yes — 10 downstream targets (CollecTRI)
• MANE Select transcript: NM_005170

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:739
Approved symbol	ASCL2
Name	achaete-scute family bHLH transcription factor 2
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	ASH2, HASH2, bHLHa45
Ensembl gene	ENSG00000183734
Ensembl biotype	protein_coding
OMIM	601886
Entrez	430

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000331289

RefSeq mRNA: 1 — MANE Select: NM_005170 NM_005170

CCDS: CCDS7732

Canonical transcript exons

ENST00000331289 — 2 exons

Exon	Start	End
ENSE00001320943	2269733	2270588
ENSE00001324898	2268498	2269126

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 89.67.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3228 / max 218.1221, expressed in 366 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118201	0.8223	326
118198	0.3152	117
118200	0.1364	79
118199	0.0489	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	89.67	gold quality
parotid gland	UBERON:0001831	86.44	gold quality
decidua	UBERON:0002450	84.91	gold quality
leukocyte	CL:0000738	81.76	gold quality
monocyte	CL:0000576	81.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.63	silver quality
gingival epithelium	UBERON:0001949	77.44	silver quality
mucosa of transverse colon	UBERON:0004991	77.15	gold quality
placenta	UBERON:0001987	76.60	gold quality
palpebral conjunctiva	UBERON:0001812	76.51	gold quality
gingiva	UBERON:0001828	75.27	silver quality
ileal mucosa	UBERON:0000331	74.98	gold quality
blood	UBERON:0000178	73.73	gold quality
nasal cavity mucosa	UBERON:0001826	73.35	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	73.00	gold quality
amniotic fluid	UBERON:0000173	72.71	silver quality
skin of abdomen	UBERON:0001416	72.67	gold quality
mucosa of sigmoid colon	UBERON:0004993	72.26	gold quality
colonic mucosa	UBERON:0000317	72.22	gold quality
nasal cavity epithelium	UBERON:0005384	71.62	gold quality
jejunal mucosa	UBERON:0000399	71.24	gold quality
upper arm skin	UBERON:0004263	71.20	gold quality
zone of skin	UBERON:0000014	70.98	gold quality
skin of leg	UBERON:0001511	70.61	gold quality
duodenum	UBERON:0002114	70.17	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	69.40	gold quality
skin of hip	UBERON:0001554	67.72	silver quality
seminal vesicle	UBERON:0000998	67.01	silver quality
epithelium of nasopharynx	UBERON:0001951	66.27	gold quality
small intestine	UBERON:0002108	66.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	1060.91
E-GEOD-125970	yes	312.03
E-ANND-3	yes	4.76

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

10 targets.

Target	Regulation
ASCL1	Activation
CKM	Activation
CXCR4	Unknown
CYP19A1	Repression
EGR1	Unknown
EPHB3
FGFR1
FGFR3
ME3
PCSK6	Repression

Upstream regulators (CollecTRI, top): HAND1, HES1, MYC, NCOR1, USF1, USF2

miRNA regulators (miRDB)

20 targeting ASCL2, 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-340-5P	100.00	72.50	4437
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-508-5P	99.41	64.25	1248
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-6529-3P	98.68	66.76	1020
HSA-MIR-4780	98.57	64.75	611
HSA-MIR-4660	97.79	67.44	1328
HSA-MIR-938	97.41	68.28	656
HSA-MIR-2467-5P	97.36	67.71	991
HSA-MIR-4435	95.90	65.47	1201
HSA-MIR-6781-5P	94.61	59.49	155
HSA-MIR-4707-5P	90.95	65.69	110
HSA-MIR-6774-3P	89.14	65.20	68
HSA-MIR-6784-5P	84.56	60.91	126

Literature-anchored findings (GeneRIF, showing 30)

• These findings suggest that increased protein levels and DNA binding of USF1 and USF2 mediate the inhibitory effects of hypoxia and of Mash-2 on CYP19 gene expression in human placenta (PMID:12917334)
• These results suggest that PACE4 expression is down-regulated by Hash-2/Mash-2 in both human and rat placenta and that many bioactive proteins might be regulated by PACE4 activity. (PMID:14561729)
• ascl2 is a putative regulator of proliferation that is overexpressed in intestinal neoplasia (PMID:16568095)
• Negative expression of HASH2 in complete hydatidiform moles (CM) but positive expression in malignant tumors suggests the presence of a specific mechanism for inactivation of the HASH2 gene in CM and reactivation in invasive moles or choriocarcinoma (PMID:17165436)
• a stem cell specific transcription signature promoted by ASCL2 has been identified to be upregulated in a subset of liver metastases, those characterised by an 11p15.5 gain (PMID:20479215)
• Ascl2 knockdown results in tumor growth arrest by miRNA-302b-related inhibition of colon cancer progenitor cells (PMID:22384170)
• These results suggest that ASCL2 might play an important role in gastric tumor growth and chemoresistance. (PMID:23181270)
• Ascl2 directly initiates follicular T-helper cell development (PMID:24463518)
• SNAIL1 combines competitive displacement of ASCL2 and epigenetic mechanisms to rapidly silence the EPHB3 tumor suppressor in colorectal cancer. (PMID:25277775)
• ASCL2 gene expression is regulated by miR-200a/b/c, miR-141 and miR429 levels in colon cancer. (PMID:25371200)
• SEMA3F functions as a suppressor of colorectal cancer metastasis by down-regulating the ASCL2-CXCR4 signaling axis. (PMID:25866254)
• Ascl2 over-expression is associated with colorectal neoplasms. (PMID:26307678)
• expression of ASCL2 may identify an aggressive subgroup in lung squamous cell carcinoma (PMID:26483561)
• WiNTRLINC1 interacts with TCF4/beta-catenin to mediate the juxtaposition of its promoter with the regulatory regions of ASCL2. (PMID:27292638)
• this study shows that Ascl2 level was higher in peripheral blood mononuclear cells from Sjogren’s syndrome patients compared with those from healthy controls (PMID:28728856)
• A novel HIF-1alpha/Ascl2/miR-200b regulatory feedback circuit in modulating EMT-MET plasticity of CRC cells, which could serve as a possible therapeutic target. (PMID:28899657)
• We address this paradox using basic helix-loop-helix (bHLH) transcription factors ASCL1, ASCL2, and MYOD1, crucial mediators of lineage specification..Although the ASCL factors and MYOD1 have some distinct DNA motif preference, it is not sufficient to explain the extent of the differential binding. All three factors can bind inaccessible chromatin and induce changes in chromatin accessibility and H3K27ac (PMID:29500235)
• ASCL2 increase by L1 overexpression enhanced its expression, cell motility, tumorigenesis and metastasis, similar to L1 overexpression. Its suppression in cells expressing L1 blocked these tumorigenic properties. In CRC tissue, ASCL2 was detected in the nuclei of cells at invasive areas of the tumor that also expressed L1. Results suggest that increased ASCL2 expression is a critical step in L1-mediated CRC progression. (PMID:29551399)
• Study uncovers that SMYD3 controls Wnt induced activation of ASCL2 in cancer stem cells (CSCs) by regulating H3K4me3 status. These findings suggest that Wnt signals through a SMYD3-mediated epigenetic switch to promote ASCL2 expression and CSC maintenance in human gastric carcinoma (GC). Overexpression of SMYD3 and ASCL2 are associated with poor prognosis in GC patients. (PMID:29746925)
• R-spondin1/Wnt activated Ascl2 expression dose-dependently in the CD133(+)CD44(+) colorectal cancer population. (PMID:29886802)
• SNP rs1335532 associated with multiple sclerosis is located in active CD58 enhancer region and creates a strong functional Ascl2-binding site. (PMID:30006149)
• ASCL2 was able to downregulate the expression level of miR223, contribute to Epithelial-Mesenchymal Transition and promote gastric tumor metastasis. (PMID:30106147)
• High ASCL2 expression is associated with Drug Resistance in Colorectal Cancer. (PMID:30706227)
• Ascl2 negatively modulates pathogenic Th17cell differentiation via promoting IL-10 production, and alleviates intestinal inflammation. (PMID:30722992)
• High ASCL2 expression is associated with colon cancer. (PMID:31549316)
• Potential Mechanism of Immune Evasion Associated with the Master Regulator ASCL2 in Microsatellite Stability in Colorectal Cancer. (PMID:33628843)
• ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development. (PMID:33649217)
• TET2-BCLAF1 transcription repression complex epigenetically regulates the expression of colorectal cancer gene Ascl2 via methylation of its promoter. (PMID:35660018)
• ASCL2 Affects the Efficacy of Immunotherapy in Colon Adenocarcinoma Based on Single-Cell RNA Sequencing Analysis. (PMID:35774798)
• Achaete-scute complex-like 2 regulated inflammatory mechanism through Toll-like receptor 4 activating in stomach adenocarcinoma. (PMID:36008864)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	ascl1a	ENSDARG00000038386
danio_rerio	ascl1b	ENSDARG00000101628
mus_musculus	Ascl2	ENSMUSG00000009248
rattus_norvegicus	Ascl2	ENSRNOG00000020434
drosophila_melanogaster	ac	FBGN0000022
drosophila_melanogaster	ase	FBGN0000137
drosophila_melanogaster	l(1)sc	FBGN0002561
drosophila_melanogaster	sc	FBGN0004170
caenorhabditis_elegans		WBGENE00001958

Paralogs (4): ASCL1 (ENSG00000139352), ASCL3 (ENSG00000176009), ASCL4 (ENSG00000187855), ASCL5 (ENSG00000232237)

Protein

Protein identifiers

Achaete-scute homolog 2 — Q99929 (reviewed: Q99929)

Alternative names: Class A basic helix-loop-helix protein 45, Mash2

All UniProt accessions (1): Q99929

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor. Binds to E-box motifs 5’-CANNTG-3’ in the regulatory elements of target genes, probably as a heterodimer with another basic helix-loop-helix (bHLH) protein such as the transcription factor TCF3. May bind both open and closed chromatin, acting as a pioneer transcription factor to allow other factors to bind and activate lineage-specific genes. Required during post-implantation development for the generation of some differentiated trophoblast cell types. Transcriptional activity of ASCL2 may be antagonised in a subset of trophoblast cells by bHLH transcription factor HAND1, perhaps by competing for dimerization with other bHLH proteins. Involved in differentiation and function of follicular T-helper (Tfh) cells, thereby playing a role in germinal center responses; probably modulates expression of genes involved in Tfh cell function, such as BCL6. May also act as a suppressor of Th1-, Th2- and Th17-cell differentiation. Induces the formation of stem cells in intestinal crypts in vitro, synergistically activating transcription of target genes, such as SOX9, together with TCF4/beta-catenin. May form a bistable transcriptional switch, controlling expression of its own gene together with Wnt/R-spondin signaling, and thereby maintaining stem cell characteristics. Modulates expression of target genes, including perhaps down-regulating EGR1/Krox24 and chemokine CXCL10/Mob-1 and up-regulating CXCR4 and CDKN1C/p57kip2, in Schwann cells. May play a role in reducing proliferation of Schwann cells, perhaps acting via modulation of expression of CDKN1C. May be dispensable for blastocyst formation and later embryonic function. May be involved in the determination of neuronal precursors.

Subunit / interactions. Efficient DNA binding requires dimerization with another basic helix-loop-helix (bHLH) protein. Forms heterodimers with bHLH transcription factor TCF3. May not heterodimerise with bHLH protein HAND1.

Subcellular location. Nucleus.

Tissue specificity. Expressed in the placenta at a stage between the first and second trimesters and when it matures, at about 32-36 weeks. Expressed in the extravillous trophoblasts, the intermediate trophoblasts, and at lower levels in the cytotrophoblasts and stroma of chorionic villi of the developing placenta. Expressed in follicular T-helper (Tfh) cells.

Miscellaneous. In contrast to the mouse ortholog, the ASCL2 locus is not imprinted in human placenta.

RefSeq proteins (1): NP_005161* (*=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 (6 total): region of interest 3, chain 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99929-F1	71.97	0.35

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 273 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, MYAATNNNNNNNGGC_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, BENPORATH_ES_WITH_H3K27ME3, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_GLIOGENESIS, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_LYMPHOCYTE_MIGRATION, MAZ_Q6

GO Biological Process (22): negative regulation of transcription by RNA polymerase II (GO:0000122), response to hypoxia (GO:0001666), placenta development (GO:0001890), sensory organ development (GO:0007423), negative regulation of Schwann cell proliferation (GO:0010626), neuron differentiation (GO:0030182), somatic stem cell population maintenance (GO:0035019), negative regulation of T-helper 1 cell differentiation (GO:0045626), negative regulation of T-helper 2 cell differentiation (GO:0045629), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of neurogenesis (GO:0050767), spongiotrophoblast layer development (GO:0060712), chorionic trophoblast cell development (GO:0060719), T follicular helper cell differentiation (GO:0061470), negative regulation of T-helper 17 cell differentiation (GO:2000320), positive regulation of T cell migration (GO:2000406), in utero embryonic development (GO:0001701), regulation of transcription by RNA polymerase II (GO:0006357), nervous system development (GO:0007399), stem cell population maintenance (GO:0019827), cell differentiation (GO:0030154), T cell differentiation (GO:0030217)

GO Molecular Function (12): 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), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), 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), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), cytoplasm (GO:0005737), RNA polymerase II transcription regulator complex (GO:0090575)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
negative regulation of immune effector process	3
negative regulation of T-helper cell differentiation	3
animal organ development	2
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
response to stress	1
response to decreased oxygen levels	1
regulation of Schwann cell proliferation	1
Schwann cell proliferation	1
negative regulation of glial cell proliferation	1
cell differentiation	1
generation of neurons	1
stem cell population maintenance	1
negative regulation of T-helper 1 type immune response	1
T-helper 1 cell differentiation	1
regulation of T-helper 1 cell differentiation	1
negative regulation of type 2 immune response	1
T-helper 2 cell differentiation	1
regulation of T-helper 2 cell differentiation	1
positive regulation of DNA-templated transcription	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
embryonic placenta development	1
tissue development	1
cell development	1
chorionic trophoblast cell differentiation	1
T-helper cell differentiation	1
T-helper 17 cell differentiation	1
negative regulation of T-helper 17 type immune response	1
regulation of T-helper 17 cell differentiation	1
T cell migration	1
positive regulation of lymphocyte migration	1
regulation of T cell migration	1

Protein interactions and networks

STRING

1498 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASCL2	PHLDA2	Q53GA4	902
ASCL2	SLC67A1	Q96BI1	791
ASCL2	KCNQ1	P51787	789
ASCL2	LGR5	O75473	781
ASCL2	TSSC4	Q9Y5U2	780
ASCL2	OLFM4	Q6UX06	775
ASCL2	CDKN1C	P49918	768
ASCL2	IGF2	P01344	738
ASCL2	AXIN2	Q9Y2T1	631
ASCL2	LRIG1	Q96JA1	629
ASCL2	TSPAN32	Q96QS1	628
ASCL2	TCF3	P15883	621
ASCL2	KDM4A	O75164	605
ASCL2	NAP1L4	Q99733	595
ASCL2	GCM1	Q9NP62	590

IntAct

0 interactions, top by confidence:

BioGRID (12): TUBA1A (Affinity Capture-Western), ASCL2 (Affinity Capture-MS), ASCL2 (Co-purification), ASCL2 (Co-purification), NCOA6 (Affinity Capture-Western), ASCL2 (Affinity Capture-Western), ASCL2 (Affinity Capture-Western), RBBP5 (Affinity Capture-Western), ASCL2 (Affinity Capture-MS), ASCL2 (Affinity Capture-MS), ASCL2 (Affinity Capture-Western), ASCL2 (Affinity Capture-Western)

ESM2 similar proteins: A0A286YF58, A0A494C0N9, A0A494C0Y3, A0A7I2V3R4, A2VDX9, A6NIN4, D3YXK1, G3UXB3, O15370, O15522, O35392, O70218, O70220, O89113, P0DPE3, P12980, P17542, P22091, P28283, P82976, Q04890, Q05916, Q05917, Q13461, Q14V87, Q15270, Q19A40, Q5T230, Q5VY09, Q63244, Q6F5E0, Q6SPE9, Q6SPF0, Q7RTU7, Q80WY3, Q8TD94, Q8WY41, Q8WZ71, Q91XV7, Q96Q04

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	44
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
146876	GRCh38/hg38 11p15.5-15.4(chr11:1975511-2888695)x3	Pathogenic
154397	GRCh38/hg38 11p15.5-15.4(chr11:1132899-3213923)x1	Pathogenic
2684632	GRCh37/hg19 11p15.5-15.4(chr11:192764-3362853)x3	Pathogenic
1340828	GRCh37/hg19 11p15.5(chr11:1719815-2321109)x3	Likely pathogenic

SpliceAI

187 predictions. Top by Δscore:

Variant	Effect	Δscore
11:2269497:C:CA	donor_gain	0.9800
11:2269729:TTACC:T	donor_loss	0.9800
11:2269731:ACCT:A	donor_loss	0.9800
11:2269127:C:CC	acceptor_gain	0.9700
11:2269214:T:TA	donor_gain	0.9700
11:2269215:C:A	donor_gain	0.9700
11:2269122:TGAGG:T	acceptor_gain	0.9600
11:2269125:GG:G	acceptor_gain	0.9600
11:2269125:GGCTG:G	acceptor_loss	0.9500
11:2269126:GC:G	acceptor_loss	0.9500
11:2269127:C:CA	acceptor_loss	0.9500
11:2269128:T:A	acceptor_loss	0.9500
11:2269732:CCT:C	donor_gain	0.9500
11:2269764:A:T	donor_gain	0.9500
11:2269124:AGG:A	acceptor_gain	0.9200
11:2269216:C:A	donor_gain	0.9200
11:2269123:GAGG:G	acceptor_gain	0.8700
11:2269731:A:AC	donor_gain	0.8600
11:2269732:C:CC	donor_gain	0.8600
11:2269489:C:CT	donor_gain	0.8500
11:2269490:T:TT	donor_gain	0.8500
11:2269130:C:CT	acceptor_gain	0.8400
11:2269237:T:A	donor_gain	0.8400
11:2269131:G:T	acceptor_gain	0.8200
11:2269482:C:A	donor_gain	0.8200
11:2269123:GAGGC:G	acceptor_gain	0.8100
11:2269126:GCTGC:G	acceptor_gain	0.8100
11:2269734:T:TA	donor_gain	0.8100
11:2269766:CCAG:C	donor_gain	0.8100
11:2269768:A:T	donor_gain	0.8000

AlphaMissense

1187 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:2270069:C:A	K88N	1.000
11:2270069:C:G	K88N	1.000
11:2270071:T:G	K88Q	0.999
11:2270123:G:C	F70L	0.999
11:2270123:G:T	F70L	0.999
11:2270124:A:C	F70C	0.999
11:2270124:A:G	F70S	0.999
11:2270125:A:G	F70L	0.999
11:2270049:G:T	A95D	0.998
11:2270070:T:A	K88M	0.998
11:2270071:T:C	K88E	0.998
11:2270132:G:C	N67K	0.998
11:2270132:G:T	N67K	0.998
11:2270149:G:T	R62S	0.998
11:2270155:G:T	R60S	0.998
11:2270156:C:A	E59D	0.998
11:2270156:C:G	E59D	0.998
11:2270037:A:G	I99T	0.997
11:2270073:C:A	S87I	0.997
11:2270149:G:A	R62C	0.997
11:2270158:C:T	E59K	0.997
11:2270037:A:T	I99N	0.996
11:2270058:A:G	L92P	0.996
11:2270058:A:T	L92Q	0.996
11:2270072:G:C	S87R	0.996
11:2270072:G:T	S87R	0.996
11:2270074:T:G	S87R	0.996
11:2270161:G:T	R58S	0.996
11:2270040:T:C	Y98C	0.995
11:2270115:A:T	L73Q	0.995

dbSNP variants (sampled 300 via entrez): RS1000096186 (11:2269833 G>A), RS1000388123 (11:2268028 G>C), RS1000454285 (11:2271411 T>G), RS1000798370 (11:2268967 G>A), RS1001147555 (11:2268630 G>C), RS1002399430 (11:2270086 T>C,G), RS1002431424 (11:2268870 C>G,T), RS1002936848 (11:2272163 C>T), RS1003364579 (11:2270926 A>G), RS1003440276 (11:2271888 G>C), RS1003679147 (11:2271041 G>A,T), RS1004060034 (11:2271783 T>C), RS1004414727 (11:2269585 G>C,T), RS1004499287 (11:2270624 T>A,G), RS1004594827 (11:2270857 G>A,T)

Disease associations

OMIM: gene MIM:601886 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): long QT syndrome (MONDO:0002442)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002112_1	Celiac disease	7.000000e-06
GCST002560_9	Type 2 diabetes	1.000000e-07
GCST006196_4	Type 1 diabetes in high risk HLA genotype individuals (time to event)	5.000000e-06
GCST008833_17	Type 2 diabetes	4.000000e-10
GCST010725_20	Malaria	4.000000e-69
GCST010725_33	Malaria	2.000000e-67
GCST010725_51	Malaria	1.000000e-55
GCST012020_166	Serum metabolite levels	2.000000e-27
GCST012020_582	Serum metabolite levels	2.000000e-12
GCST012021_91	Serum metabolite levels	2.000000e-27
GCST012021_99	Serum metabolite levels	2.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0000409	disease free survival

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Estradiol	increases expression, affects cotreatment, decreases expression, decreases reaction	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
tungsten carbide	affects cotreatment, increases expression	1
deoxynivalenol	increases expression	1
sodium arsenate	increases abundance, decreases expression	1
trichostatin A	affects expression, decreases reaction	1
beta-lapachone	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
(+)-JQ1 compound	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	decreases expression, increases abundance	1
Bezafibrate	decreases expression	1
Cadmium	increases expression	1
Cobalt	affects cotreatment, increases expression	1
Nickel	affects expression, decreases reaction	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Asbestos, Serpentine	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Copper Sulfate	decreases expression	1
Linoleic Acid	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_A0D3	SEES3-1V human ASCL2, clone1	Embryonic stem cell	Male
CVCL_A0D4	SEES3-1V human ASCL2, clone2	Embryonic stem cell	Male
CVCL_A0D5	SEES3-1V human ASCL2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes
NCT03678311	Not specified	COMPLETED	Long QT Syndrome and Sleep Apnea