SNTA1

Summary

SNTA1 (syntrophin alpha 1, HGNC:11167) is a protein-coding gene on chromosome 20q11.21, encoding Alpha-1-syntrophin (Q13424). Adapter protein that binds to and probably organizes the subcellular localization of a variety of membrane proteins.

Syntrophins are cytoplasmic peripheral membrane scaffold proteins that are components of the dystrophin-associated protein complex. This gene is a member of the syntrophin gene family and encodes the most common syntrophin isoform found in cardiac tissues. The N-terminal PDZ domain of this syntrophin protein interacts with the C-terminus of the pore-forming alpha subunit (SCN5A) of the cardiac sodium channel Nav1.5. This protein also associates cardiac sodium channels with the nitric oxide synthase-PMCA4b (plasma membrane Ca-ATPase subtype 4b) complex in cardiomyocytes. This gene is a susceptibility locus for Long-QT syndrome (LQT) - an inherited disorder associated with sudden cardiac death from arrhythmia - and sudden infant death syndrome (SIDS). This protein also associates with dystrophin and dystrophin-related proteins at the neuromuscular junction and alters intracellular calcium ion levels in muscle tissue.

Source: NCBI Gene 6640 — RefSeq curated summary.

At a glance

• Gene–disease (curated): long QT syndrome 12 (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 572 total
• Phenotypes (HPO): 16
• MANE Select transcript: NM_003098

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11167
Approved symbol	SNTA1
Name	syntrophin alpha 1
Location	20q11.21
Locus type	gene with protein product
Status	Approved
Aliases	TACIP1, LQT12
Ensembl gene	ENSG00000101400
Ensembl biotype	protein_coding
OMIM	601017
Entrez	6640

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 19 protein_coding

ENST00000217381, ENST00000880497, ENST00000880498, ENST00000880499, ENST00000880500, ENST00000880501, ENST00000880502, ENST00000880503, ENST00000953197, ENST00000953198, ENST00000953199, ENST00000953200, ENST00000953201, ENST00000953202, ENST00000953203, ENST00000953204, ENST00000953205, ENST00000953206, ENST00000953207

RefSeq mRNA: 3 — MANE Select: NM_003098 NM_001424413, NM_001424414, NM_003098

CCDS: CCDS13220

Canonical transcript exons

ENST00000217381 — 8 exons

Exon	Start	End
ENSE00000661324	33408701	33408888
ENSE00000661326	33412296	33412426
ENSE00000661327	33412575	33412782
ENSE00000661328	33417719	33417923
ENSE00000661329	33438841	33439026
ENSE00001153140	33410135	33410331
ENSE00001153165	33443311	33443763
ENSE00001952368	33407957	33408599

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 98.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.1852 / max 209.2381, expressed in 1642 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186957	9.7227	1597
186959	1.9251	860
186956	0.4453	187
186958	0.0921	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.92	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.50	gold quality
gastrocnemius	UBERON:0001388	97.95	gold quality
right atrium auricular region	UBERON:0006631	97.68	gold quality
heart left ventricle	UBERON:0002084	97.52	gold quality
cardiac ventricle	UBERON:0002082	97.38	gold quality
putamen	UBERON:0001874	97.31	gold quality
caudate nucleus	UBERON:0001873	97.20	gold quality
muscle of leg	UBERON:0001383	97.18	gold quality
nucleus accumbens	UBERON:0001882	97.11	gold quality
cardiac atrium	UBERON:0002081	97.04	gold quality
amygdala	UBERON:0001876	96.94	gold quality
muscle organ	UBERON:0001630	96.59	gold quality
right lobe of thyroid gland	UBERON:0001119	96.52	gold quality
heart	UBERON:0000948	96.49	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.31	gold quality
triceps brachii	UBERON:0001509	96.23	gold quality
right frontal lobe	UBERON:0002810	96.13	gold quality
left lobe of thyroid gland	UBERON:0001120	96.11	gold quality
cingulate cortex	UBERON:0003027	96.01	gold quality
anterior cingulate cortex	UBERON:0009835	95.98	gold quality
olfactory bulb	UBERON:0002264	95.79	gold quality
popliteal artery	UBERON:0002250	95.67	gold quality
tibial artery	UBERON:0007610	95.66	gold quality
thyroid gland	UBERON:0002046	95.31	gold quality
skeletal muscle tissue	UBERON:0001134	95.21	gold quality
vastus lateralis	UBERON:0001379	95.15	gold quality
quadriceps femoris	UBERON:0001377	95.02	gold quality
aorta	UBERON:0000947	94.92	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.70	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	11.46
E-ANND-3	no	3.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

43 targeting SNTA1, 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-12118	100.00	65.88	1270
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-135A-5P	99.36	71.85	1601
HSA-MIR-135B-5P	99.36	71.63	1613
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-7113-3P	98.75	65.71	1120
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-6867-3P	98.12	66.07	1305
HSA-MIR-6880-5P	98.08	65.59	1282

Literature-anchored findings (GeneRIF, showing 19)

• alpha1D-adrenergic receptors are regulated by syntrophins through a PDZ domain-mediated interaction (PMID:16533813)
• These results establish an SNTA1-based nNOS complex attached to SCN5A as a key regulator of sodium current and suggest that SNTA1 be considered a rare long QT syndrome-susceptibility gene. (PMID:18591664)
• SNTA1 is a new susceptibility gene for LQTS. A257G-SNTA1 can cause gain-of-function of Na(v)1.5 similar to the LQT3. (PMID:19684871)
• Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current. (PMID:20009079)
• In contrast to stomach, lung, colon and rectal cancers, SNTA1 protein was found to be downregulated in esophageal cancers and upregulated in breast cancer. (PMID:21091386)
• The combined mutations of A261V-SNTA1 plus R800L-SCN5A increase the INa current late/peak ratio and time constants of current decay. (PMID:23376825)
• Calcium homeostasis mishandling in Duchenne muscular dystrophy myotubes depends on store operated calcium entry under the influence alpha1-syntrophin regulation as well as TRPV2-dependant cation influx. (PMID:23426965)
• Ordered disorder of the astrocytic dystrophin-associated protein complex in the norm and pathology. (PMID:24014171)
• alpha-Syntrophin, which resides in nuclei of myocytes, functions as the upstream mediator of nuclear nNOS translocation and nNOS-dependent mitochondrial biogenesis. (PMID:24235139)
• our results present a possible mechanism of Rac1 activation involving SNTA1 and emphasise its role in ROS generation, cell migration, and acquisition of malignancy. (PMID:24434436)
• In a nonreferred nationwide Danish cohort of SIDS cases, up to 5/66 (7.5%) of SIDS cases can be explained by genetic variants in the sodium channel complex genes. (PMID:25757662)
• A novel SNTA1 variant is likely causative for drug induced long-QT syndrome by augmenting the late sodium current. (PMID:27028743)
• not associated with sudden infant death syndrome (PMID:28520217)
• Low SNTA expression is associated with non-alcoholic steatohepatitis but is unchanged in hepatocellular carcinoma. (PMID:28941732)
• Data (including data from studies conducted in knockout mice) suggest that SNTA1 is involved in regulation of expression of TUBA8 in hepatocytes (but not in hepatic stellate cells); here, SNTA1 protein levels are inversely related to TUBA8 protein expression in hepatocyte cell line. (SNTA1 = syntrophin alpha-1; TUBA8 = tubulin alpha-8 chain) (PMID:30033487)
• Soluble galectin-3 was, however, reduced upon SNTA knock-down and increased upon SNTA overexpression. (PMID:31881201)
• Jasplakinolide Attenuates Cell Migration by Impeding Alpha-1-syntrophin Protein Phosphorylation in Breast Cancer Cells. (PMID:33515365)
• alpha-Syntrophin alleviates ER stress to maintain protein homeostasis during myoblast differentiation. (PMID:33834492)
• SNTA1 gene rescues ion channel function and is antiarrhythmic in cardiomyocytes derived from induced pluripotent stem cells from muscular dystrophy patients. (PMID:35762211)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	SNTA1	ENSDARG00000098420
mus_musculus	Snta1	ENSMUSG00000027488
rattus_norvegicus	Snta1	ENSRNOG00000016062
drosophila_melanogaster	Syn1	FBGN0037130
caenorhabditis_elegans	stn-1	WBGENE00006062

Paralogs (4): SNTG1 (ENSG00000147481), SNTB2 (ENSG00000168807), SNTB1 (ENSG00000172164), SNTG2 (ENSG00000172554)

Protein

Protein identifiers

Alpha-1-syntrophin — Q13424 (reviewed: Q13424)

Alternative names: 59 kDa dystrophin-associated protein A1 acidic component 1, Pro-TGF-alpha cytoplasmic domain-interacting protein 1, Syntrophin-1

All UniProt accessions (1): Q13424

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that binds to and probably organizes the subcellular localization of a variety of membrane proteins. May link various receptors to the actin cytoskeleton and the extracellular matrix via the dystrophin glycoprotein complex. Plays an important role in synapse formation and in the organization of UTRN and acetylcholine receptors at the neuromuscular synapse. Binds to phosphatidylinositol 4,5-bisphosphate.

Subunit / interactions. Monomer and homodimer. Interacts with the other members of the syntrophin family SNTB1 and SNTB2; SGCG and SGCA of the dystrophin glycoprotein complex; NOS1; GRB2; the sodium channel proteins SCN4A and SCN5A; F-actin and calmodulin. Interacts with dystrophin protein DMD and related proteins DTNA and UTRN and with MAPK12, TGFA and GA. Interacts with MYOC; regulates muscle hypertrophy. Interacts with DTNB.

Subcellular location. Cell membrane. Sarcolemma. Cell junction. Cytoplasm. Cytoskeleton.

Tissue specificity. High expression in skeletal muscle and heart. Low expression in brain, pancreas, liver, kidney and lung. Not detected in placenta.

Post-translational modifications. Phosphorylated by CaM-kinase II. Phosphorylation may inhibit the interaction with DMD. Phosphorylated by SRC; phosphorylation mediates laminin-induced activation of RAC1 signaling.

Disease relevance. Long QT syndrome 12 (LQT12) [MIM:612955] A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The PH 1 domain mediates the oligomerization in a calcium dependent manner, and the association with the phosphatidylinositol 4,5-bisphosphate. The PDZ domain binds to the last three or four amino acids of ion channels and receptor proteins. The association with dystrophin or related proteins probably leaves the PDZ domain available to recruit proteins to the membrane. The SU domain binds calmodulin in a calcium-dependent manner.

Similarity. Belongs to the syntrophin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13424-1	1	yes
Q13424-2	2

RefSeq proteins (3): NP_001411342, NP_001411343, NP_003089* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR015482	Syntrophin	Family
IPR036034	PDZ_sf	Homologous_superfamily
IPR041428	PHsplit_syntrophin	Domain
IPR055108	Syntrophin_4th	Domain

Pfam: PF00169, PF00595, PF18012, PF23012

UniProt features (22 total): modified residue 5, domain 4, sequence conflict 4, region of interest 4, sequence variant 3, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13424-F1	80.00	0.52

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 (5): 184, 189, 193, 200, 101

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9913351	Formation of the dystrophin-glycoprotein complex (DGC)
R-HSA-1474244	Extracellular matrix organization
R-HSA-3000171	Non-integrin membrane-ECM interactions

MSigDB gene sets: 205 (showing top): GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, ENK_UV_RESPONSE_KERATINOCYTE_UP, AAGCCAT_MIR135A_MIR135B, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_SODIUM_ION_TRANSPORT, GTGCCTT_MIR506, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CELL_MEMBRANE_REPOLARIZATION, MODULE_120, GOBP_MUSCLE_CONTRACTION, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_REGULATION_OF_RAC_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_HEART_RATE

GO Biological Process (6): regulation of heart rate (GO:0002027), muscle contraction (GO:0006936), positive regulation of Rac protein signal transduction (GO:0035022), regulation of ventricular cardiac muscle cell membrane repolarization (GO:0060307), ventricular cardiac muscle cell action potential (GO:0086005), regulation of sodium ion transmembrane transport (GO:1902305)

GO Molecular Function (11): dystroglycan binding (GO:0002162), actin binding (GO:0003779), structural molecule activity (GO:0005198), calmodulin binding (GO:0005516), sodium channel regulator activity (GO:0017080), PDZ domain binding (GO:0030165), transmembrane transporter binding (GO:0044325), nitric-oxide synthase binding (GO:0050998), ATPase binding (GO:0051117), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (11): cytoskeleton (GO:0005856), plasma membrane (GO:0005886), dystrophin-associated glycoprotein complex (GO:0016010), syntrophin complex (GO:0016013), neuromuscular junction (GO:0031594), protein-containing complex (GO:0032991), sarcolemma (GO:0042383), anchoring junction (GO:0070161), cytoplasm (GO:0005737), membrane (GO:0016020), lateral plasma membrane (GO:0016328)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Non-integrin membrane-ECM interactions	1
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
cellular anatomical structure	3
molecular_function	2
enzyme binding	2
binding	2
plasma membrane protein complex	2
plasma membrane	2
regulation of heart contraction	1
regulation of biological quality	1
muscle system process	1
Rac protein signal transduction	1
regulation of Rac protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
regulation of cardiac muscle cell membrane repolarization	1
ventricular cardiac muscle cell membrane repolarization	1
cardiac muscle cell action potential involved in contraction	1
regulation of sodium ion transport	1
sodium ion transmembrane transport	1
regulation of monoatomic cation transmembrane transport	1
cytoskeletal protein binding	1
sodium channel activity	1
ion channel regulator activity	1
protein domain specific binding	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
glycoprotein complex	1
dystrophin-associated glycoprotein complex	1
synapse	1
cellular_component	1
cell junction	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

920 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SNTA1	DMD	P11532	966
SNTA1	CAV3	P56539	964
SNTA1	DTNA	Q9Y4J8	946
SNTA1	DAG1	Q14118	939
SNTA1	SCN5A	Q14524	927
SNTA1	SGCD	Q92629	887
SNTA1	SGCA	Q16586	880
SNTA1	SCN4B	Q8IWT1	871
SNTA1	SSPN	Q14714	863
SNTA1	UTRN	P46939	837
SNTA1	SGCG	Q13326	825
SNTA1	TRPC1	P48995	822
SNTA1	AKAP9	Q99996	814
SNTA1	KCNE2	Q9Y6J6	806
SNTA1	KCNE1	P15382	797

IntAct

450 interactions, top by confidence:

A	B	Type	Score
DTNB	DMD	psi-mi:“MI:0914”(association)	0.890
DMD	DTNB	psi-mi:“MI:0914”(association)	0.890
ADRA1D	SNTA1	psi-mi:“MI:0403”(colocalization)	0.860
ADRA1D	SNTA1	psi-mi:“MI:0914”(association)	0.860
SNTA1	ADRA1D	psi-mi:“MI:0914”(association)	0.860
SNTA1	ADRA1D	psi-mi:“MI:0915”(physical association)	0.860
ADRA1D	SNTA1	psi-mi:“MI:0915”(physical association)	0.860
ADRA1D	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.860
DMD	SNTA1	psi-mi:“MI:0915”(physical association)	0.800
ADRA1D	UTRN	psi-mi:“MI:0914”(association)	0.770
HMG20A	KDM1A	psi-mi:“MI:0914”(association)	0.730
PTEN	PTEN	psi-mi:“MI:0915”(physical association)	0.710
SNTB2	CASK	psi-mi:“MI:0914”(association)	0.670
ABCA1	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.660
SNTA1	SLC16A7	psi-mi:“MI:0407”(direct interaction)	0.620
SNTA1	GUCY1A2	psi-mi:“MI:0407”(direct interaction)	0.620
SNTA1	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.620
SNTA1	WWTR1	psi-mi:“MI:0407”(direct interaction)	0.620
SNTA1	CYSLTR2	psi-mi:“MI:0407”(direct interaction)	0.620
GUCY1A2	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.620
CYSLTR2	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.620
SLC16A7	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.620
E6	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.610
SNTA1	PTEN	psi-mi:“MI:0407”(direct interaction)	0.610

BioGRID (129): SNTA1 (Affinity Capture-MS), SNTA1 (Affinity Capture-MS), SNTA1 (Affinity Capture-MS), SNTA1 (Affinity Capture-MS), SNTA1 (Affinity Capture-MS), SNTA1 (Affinity Capture-MS), SNTA1 (Affinity Capture-MS), SNTA1 (Affinity Capture-MS), SNTA1 (Affinity Capture-Western), SNTA1 (Protein-peptide), PLEKHA2 (Affinity Capture-Western), SNTA1 (Affinity Capture-MS), XRCC6 (Two-hybrid), GLS (Reconstituted Complex), SNTA1 (Two-hybrid)

ESM2 similar proteins: A1L1G1, A2XUN8, B2RYJ8, D3ZAA9, F1MH07, O08764, O95382, P28562, P28563, P47823, P51432, P54760, P58404, P70218, P70268, Q01970, Q0P5E6, Q12851, Q13144, Q13424, Q13425, Q14168, Q28626, Q4ACU6, Q5R8E2, Q5ZLR4, Q61161, Q61234, Q61235, Q63433, Q64623, Q68G30, Q6P9Q4, Q7TQI7, Q7XK25, Q7ZVR8, Q8CHW4, Q8K0G8, Q8N961, Q8R0H9

Diamond homologs: A0A0G2K2P5, A0A8P0N4K0, C5IAW9, F1LW30, O08721, O08722, O08747, O62683, O95049, O95185, O97758, P39447, P57105, Q07157, Q0P5E6, Q13424, Q28626, Q32LE7, Q3T0C9, Q5EBL8, Q5ZIK2, Q61234, Q6NXB2, Q6QA76, Q6R653, Q6UXZ4, Q6ZN44, Q761X5, Q7KRY7, Q7T2Z5, Q80VW5, Q86UL8, Q8IV45, Q8IZJ1, Q8JGT4, Q8K1S2, Q8K1S3, Q8K1S4, Q95168, Q9CZG9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
SNTA1	up-regulates	NOS1	relocalization
SNTA1	“form complex”	DGC	binding
MAPK12	up-regulates	SNTA1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 155 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 dystrophin-glycoprotein complex (DGC)	5	15.1×	3e-03
Neurexins and neuroligins	5	9.7×	9e-03
G alpha (12/13) signalling events	7	9.4×	2e-03
Class B/2 (Secretin family receptors)	5	9.3×	9e-03
p75 NTR receptor-mediated signalling	5	9.2×	9e-03
Cardiac conduction	8	8.5×	2e-03
Muscle contraction	8	6.0×	4e-03
Signaling by GPCR	11	4.3×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of synaptic transmission, glutamatergic	6	27.1×	8e-05
non-canonical Wnt signaling pathway	5	21.1×	1e-03
positive regulation of excitatory postsynaptic potential	5	19.1×	2e-03
positive regulation of GTPase activity	5	10.0×	1e-02
transport across blood-brain barrier	6	7.8×	1e-02
phospholipase C-activating G protein-coupled receptor signaling pathway	7	6.7×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	288
Likely benign	203
Benign	13

Top pathogenic / likely-pathogenic (0)

SpliceAI

1537 predictions. Top by Δscore:

Variant	Effect	Δscore
20:33408695:A:AC	donor_gain	1.0000
20:33408696:C:CC	donor_gain	1.0000
20:33408699:A:AC	donor_gain	1.0000
20:33408700:C:CC	donor_gain	1.0000
20:33408700:CG:C	donor_gain	1.0000
20:33408700:CGAT:C	donor_gain	1.0000
20:33408719:T:TA	donor_gain	1.0000
20:33408884:GCAGG:G	acceptor_gain	1.0000
20:33408885:CAGG:C	acceptor_gain	1.0000
20:33408885:CAGGC:C	acceptor_gain	1.0000
20:33408886:AGG:A	acceptor_gain	1.0000
20:33408887:GG:G	acceptor_gain	1.0000
20:33408889:C:CC	acceptor_gain	1.0000
20:33408889:C:T	acceptor_loss	1.0000
20:33410146:T:TA	donor_gain	1.0000
20:33410262:CG:C	acceptor_gain	1.0000
20:33410266:C:CT	acceptor_gain	1.0000
20:33412427:C:CC	acceptor_gain	1.0000
20:33412570:GGTA:G	donor_loss	1.0000
20:33412571:GTACC:G	donor_loss	1.0000
20:33412572:TACCT:T	donor_loss	1.0000
20:33412573:A:T	donor_loss	1.0000
20:33412574:CCTG:C	donor_gain	1.0000
20:33412577:G:A	donor_gain	1.0000
20:33412780:TAC:T	acceptor_gain	1.0000
20:33412781:AC:A	acceptor_gain	1.0000
20:33412782:CC:C	acceptor_gain	1.0000
20:33412784:T:C	acceptor_loss	1.0000
20:33412790:C:CT	acceptor_gain	1.0000
20:33412793:A:T	acceptor_gain	1.0000

AlphaMissense

3207 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:33408561:G:C	F488L	1.000
20:33408561:G:T	F488L	1.000
20:33408563:A:G	F488L	1.000
20:33408574:T:A	K484I	1.000
20:33408834:A:G	F431S	1.000
20:33438846:A:G	L164P	1.000
20:33438869:C:A	K156N	1.000
20:33438869:C:G	K156N	1.000
20:33438873:A:G	L155P	1.000
20:33438873:A:T	L155H	1.000
20:33438893:A:C	H148Q	1.000
20:33438893:A:T	H148Q	1.000
20:33438895:G:C	H148D	1.000
20:33438933:A:C	I135S	1.000
20:33438933:A:G	I135T	1.000
20:33438933:A:T	I135N	1.000
20:33438937:C:G	A134P	1.000
20:33438939:T:A	D133V	1.000
20:33438939:T:C	D133G	1.000
20:33438939:T:G	D133A	1.000
20:33438940:C:G	D133H	1.000
20:33438942:C:A	G132V	1.000
20:33438942:C:T	G132E	1.000
20:33438951:A:G	L129P	1.000
20:33438951:A:T	L129H	1.000
20:33438969:G:T	A123D	1.000
20:33438983:G:C	F118L	1.000
20:33438983:G:T	F118L	1.000
20:33438984:A:C	F118C	1.000
20:33438984:A:G	F118S	1.000

dbSNP variants (sampled 300 via entrez): RS1000025851 (20:33440186 T>A,G), RS1000049732 (20:33436555 A>G,T), RS1000079854 (20:33409079 A>G), RS1000235708 (20:33418717 C>A,T), RS1000242553 (20:33411949 C>G), RS1000280563 (20:33442889 G>C,T), RS1000316199 (20:33443740 C>T), RS1000689948 (20:33443171 T>G), RS1000901333 (20:33415660 G>A), RS1000912025 (20:33408690 C>T), RS1001024161 (20:33422312 A>C,G,T), RS1001052197 (20:33422502 G>A), RS1001088710 (20:33423663 T>A,C,G), RS1001254207 (20:33420166 C>G,T), RS1001255213 (20:33413457 C>T)

Disease associations

OMIM: gene MIM:601017 | disease phenotypes: MIM:612955, MIM:603829, MIM:601144, MIM:192500, MIM:194200, MIM:300376, MIM:302045, MIM:310200, MIM:613688

GenCC curated gene-disease

Disease	Classification	Inheritance
long QT syndrome 12	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
long QT syndrome	Disputed	AD

Mondo (17): long QT syndrome (MONDO:0002442), long QT syndrome 12 (MONDO:0013062), ventricular fibrillation, paroxysmal familial, type 1 (MONDO:0011376), invasive ductal breast carcinoma (MONDO:0004953), Brugada syndrome (MONDO:0015263), ventricular fibrillation (MONDO:0000190), familial long QT syndrome (MONDO:0019171), Wolff-Parkinson-White syndrome (MONDO:0008685), sick sinus syndrome (MONDO:0001823), long QT syndrome 1 (MONDO:0100316), dilated cardiomyopathy (MONDO:0005021), ventricular tachycardia (MONDO:0005477), Becker muscular dystrophy (MONDO:0010311), dilated cardiomyopathy 3B (MONDO:0010542), Duchenne muscular dystrophy (MONDO:0010679)

Orphanet (9): Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768), Idiopathic ventricular fibrillation (Orphanet:228140), Brugada syndrome (Orphanet:130), Dilated cardiomyopathy (Orphanet:217604), Familial isolated dilated cardiomyopathy (Orphanet:154), Becker muscular dystrophy (Orphanet:98895), Duchenne muscular dystrophy (Orphanet:98896), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

16 total (19 of 16 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000365	Hearing impairment
HP:0001197	Abnormality of prenatal development or birth
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001645	Sudden cardiac death
HP:0001663	Ventricular fibrillation
HP:0001664	Torsade de pointes
HP:0001688	Sinus bradycardia
HP:0002900	Hypokalemia
HP:0004308	Ventricular arrhythmia
HP:0005135	Abnormal T-wave
HP:0005184	Prolonged QTc interval
HP:0012332	Abnormal autonomic nervous system physiology
HP:0025708	Early young adult onset
HP:0500018	Abnormal cardiac exercise stress test
HP:0001716	Wolff-Parkinson-White syndrome
HP:0001644	Dilated cardiomyopathy
HP:0005110	Atrial fibrillation

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007281_3	HDL cholesterol x physical activity interaction (1df test)	2.000000e-08
GCST007282_7	HDL cholesterol x physical activity interaction (2df test)	6.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0003940	physical activity
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007805	HDL cholesterol change measurement

MeSH disease descriptors (14)

Descriptor	Name	Tree numbers
D001281	Atrial Fibrillation	C14.280.067.198; C23.550.073.198
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D020388	Muscular Dystrophy, Duchenne	C05.651.534.500.300; C10.668.491.175.500.300; C16.320.322.562; C16.320.577.300
D012804	Sick Sinus Syndrome	C14.280.067.093.249; C14.280.067.558.536; C14.280.123.500.536; C23.550.073.093.249; C23.550.073.425.440
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
D014693	Ventricular Fibrillation	C14.280.067.922; C23.550.073.922
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C570377	Benign Pseudohypertrophic Muscular Dystrophy (supp.)
C580047	Dmd-Associated Dilated Cardiomyopathy (supp.)
C567842	Long Qt Syndrome 12 (supp.)
C563614	Long Qt Syndrome 2 (supp.)
C567851	Ventricular Fibrillation, Paroxysmal Familial, 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	3
FR900359	increases phosphorylation	1
pirinixic acid	affects binding, decreases expression, increases activity	1
entinostat	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Caffeine	increases phosphorylation	1
Cisplatin	decreases expression	1
Doxorubicin	increases expression	1
Estradiol	affects cotreatment, increases expression	1
Folic Acid	decreases expression	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Triclosan	decreases expression	1
Valproic Acid	increases expression, increases methylation	1
1-Methyl-4-phenylpyridinium	increases expression	1
Sodium Selenite	increases expression	1
Cadmium Chloride	increases expression	1
Vitamin K 3	affects expression	1

Cellosaurus cell lines

4 cell lines: 2 embryonic stem cell, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5EP	WAe009-A-50	Embryonic stem cell	Female
CVCL_C1S8	SCVIi061-A	Induced pluripotent stem cell	Female
CVCL_C1S9	SCVIi062-A	Induced pluripotent stem cell	Female
CVCL_C5TU	H9SNTA1KO	Embryonic stem cell	Female

Clinical trials (associated diseases)

249 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
NCT02201914	PHASE4	UNKNOWN	Clomiphene Citrate Plus Gonadotropins and GnRH Antagonist Versus Flexible GnRH Antagonist Protocol Versus Microdose GnRH Agonist Protocol in Poor Responders Undergoing IVF
NCT02651285	PHASE4	UNKNOWN	Use of G-CSF Supplemented IVF Medium in Patients Undergoing IVF
NCT04002635	PHASE4	WITHDRAWN	Letrozole for Frozen Embryo Transfer (FET) in Patients With Polycystic Ovary Syndrome (PCOS)
NCT04385342	PHASE4	UNKNOWN	FSH Followed by HMG vs FSH Plus HMG in IVF
NCT04487925	PHASE4	RECRUITING	Controlled Ovarian Stimulation Versus Modified Natural Cycles in Poor Responders
NCT04654741	PHASE4	UNKNOWN	The Rate of Embryo Euploidy in Progestin-primed Ovarian Stimulation Cycles
NCT04728659	PHASE4	UNKNOWN	Desogestrel Versus GnRH Antagonist in IVF/ICSI
NCT04993924	PHASE4	UNKNOWN	GnRH Antagonist Pre-treatment in the Early Follicular Phase for Resolution of a Baseline Functional Ovarian Cyst
NCT05071339	PHASE4	UNKNOWN	GnRH Antagonist Pre-treatment for the Prevention of Asynchronous Follicular Growth
NCT05321511	PHASE4	UNKNOWN	Comparison of Triggers in Double Ovarian Stimulation (DuoStim).
NCT05954962	PHASE4	COMPLETED	Efficacy of Micronized Natural Progesterone vs GnRH Antagonist in the Prevention of LH Peak During Ovarian Stimulation.
NCT06181305	PHASE4	UNKNOWN	Endometrial Preparation in Frozen Embryo Transfer Cycles
NCT06396390	PHASE4	NOT_YET_RECRUITING	Comparison of Progestin Primed Ovarian Stimulation (PPOS) vs.GnRH Antagonist Methods on IVF Outcomes
NCT07499804	PHASE4	RECRUITING	Effect of Tadalafil on Endometrial Thickness and Frozen Embryo Transfer Outcomes
NCT04414761	PHASE3	COMPLETED	Live Birth Rate Between PPOS and GnRH Antagonist Protocol in Patients With Anticipated High Ovarian Response
NCT04806919	PHASE3	COMPLETED	Luteal Support in Artificial Vitrified/Warmed Cycles With Low Progesterone
NCT05972902	PHASE3	UNKNOWN	Dydrogesterone, Cetrorelix Acetate and Triptorelin in Intra Cytoplasmic Sperm Injection Outcomes
NCT06048666	PHASE3	UNKNOWN	Platelet Rich Plasma on Ovarian Reserve Parameters and Intra Cytoplasmic Sperm Injection Outcomes in Patients With Diminished Ovarian Reserve
NCT06405204	PHASE3	NOT_YET_RECRUITING	of Myo-inositol, Melatonin and Co-enzyme q10 on Ovarian Reserve
NCT07499817	PHASE3	RECRUITING	Effect of Pentoxyfilline on Endometrial Thickness and Frozen Embryo Transfer Outcomes
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
NCT02677259	PHASE2	UNKNOWN	Luteal Phase Estradiol Support for In Vitro Fertilization/Intracytoplasmic Sperm Injection Cycles
NCT04524026	PHASE2	COMPLETED	RIOTC: Reducing the Impact of Ovarian Stimulation. Novel Approaches to Luteal Support in IVF-Study 2
NCT04778358	PHASE2	COMPLETED	Higher Dose of Rekovelle in Oocyte Donors
NCT06555575	PHASE2	RECRUITING	Ubiquinone vs. Ubiquinol Supplementation
NCT06997900	PHASE2	RECRUITING	Menopur And Rekovelle Combination Study Version 2.0
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
NCT04175990	PHASE1	COMPLETED	IVF Outcome Following Progestogen Ovarian Stimulation
NCT04283435	PHASE1	UNKNOWN	Endometrial Effects of Sildenafil in Frozen-Thawed Cycles in Women With Thin Endometrium