SHOX2

Summary

SHOX2 (SHOX homeobox 2, HGNC:10854) is a protein-coding gene on chromosome 3q25.32, encoding Short stature homeobox protein 2 (O60902). May be a growth regulator and have a role in specifying neural systems involved in processing somatosensory information, as well as in face and body structure formation.

This gene is a member of the homeobox family of genes that encode proteins containing a 60-amino acid residue motif that represents a DNA binding domain. Homeobox genes have been characterized extensively as transcriptional regulators involved in pattern formation in both invertebrate and vertebrate species. Several human genetic disorders are caused by aberrations in human homeobox genes. This locus represents a pseudoautosomal homeobox gene that is thought to be responsible for idiopathic short stature, and it is implicated in the short stature phenotype of Turner syndrome patients. This gene is considered to be a candidate gene for Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 6474 — RefSeq curated summary.

At a glance

• Gene–disease (curated): atrial fibrillation (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 64 total
• MANE Select transcript: NM_001163678

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10854
Approved symbol	SHOX2
Name	SHOX homeobox 2
Location	3q25.32
Locus type	gene with protein product
Status	Approved
Aliases	SHOT, OG12X, OG12
Ensembl gene	ENSG00000168779
Ensembl biotype	protein_coding
OMIM	602504
Entrez	6474

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000389589, ENST00000441443, ENST00000483851, ENST00000490689, ENST00000554685

RefSeq mRNA: 3 — MANE Select: NM_001163678 NM_001163678, NM_003030, NM_006884

CCDS: CCDS33884, CCDS43164, CCDS54664

Canonical transcript exons

ENST00000483851 — 5 exons

Exon	Start	End
ENSE00001928724	158105679	158106420
ENSE00003548634	158095905	158098284
ENSE00003695106	158099860	158099948
ENSE00003739072	158100254	158100311
ENSE00003744757	158102678	158102886

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 96.93.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0590 / max 250.6173, expressed in 440 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45320	0.9412	280
45322	0.6587	177
45321	0.2003	104
45325	0.1351	54
45323	0.0660	28
45324	0.0577	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.93	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.02	gold quality
saphenous vein	UBERON:0007318	95.25	gold quality
tendon of biceps brachii	UBERON:0008188	93.09	gold quality
sperm	CL:0000019	85.18	silver quality
tendon	UBERON:0000043	85.18	gold quality
popliteal artery	UBERON:0002250	84.86	gold quality
tibial artery	UBERON:0007610	84.85	gold quality
calcaneal tendon	UBERON:0003701	83.17	gold quality
dorsal root ganglion	UBERON:0000044	83.08	gold quality
male germ cell	CL:0000015	82.20	silver quality
tibial nerve	UBERON:0001323	81.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.28	gold quality
subcutaneous adipose tissue	UBERON:0002190	77.21	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.95	silver quality
synovial joint	UBERON:0002217	76.48	gold quality
aorta	UBERON:0000947	75.32	gold quality
endocervix	UBERON:0000458	75.29	gold quality
sural nerve	UBERON:0015488	75.27	gold quality
layer of synovial tissue	UBERON:0007616	74.41	gold quality
right coronary artery	UBERON:0001625	72.42	gold quality
thoracic mammary gland	UBERON:0005200	72.42	gold quality
mammary gland	UBERON:0001911	72.27	gold quality
dorsal plus ventral thalamus	UBERON:0001897	71.55	gold quality
vena cava	UBERON:0004087	70.91	silver quality
right atrium auricular region	UBERON:0006631	70.39	gold quality
mammary duct	UBERON:0001765	70.22	gold quality
upper leg skin	UBERON:0004262	69.65	gold quality
left coronary artery	UBERON:0001626	69.59	gold quality
minor salivary gland	UBERON:0001830	69.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7051	yes	121.96
E-GEOD-75688	yes	49.88
E-ANND-3	yes	4.83

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
ACAN	Unknown
ADRB3	Repression
ARX
BMP4
LMO1
NKX2-5	Repression
NPPB	Unknown
SHOX2

Upstream regulators (CollecTRI, top): ARX, SHOX2, TBX5

miRNA regulators (miRDB)

92 targeting SHOX2, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6508-5P	99.92	70.67	2465

Literature-anchored findings (GeneRIF, showing 39)

• work establishes a link between Tbx5, Shox2 and Bmp4 in the pacemaker region of the developing heart (PMID:20858598)
• SHOX2 DNA methylation is found in bronchial aspirates of lung cancer patients (PMID:21047392)
• Frequent gene amplification correlated with hypermethylation of the SHOX2 gene locus. (PMID:21426551)
• SHOX2 DNA methylation is associated with lung cancer. (PMID:21694641)
• A CE marked in vitro diagnostic test kit to quantify SHOX2 DNA methylation in bronchial aspirates was developed and characterized. (PMID:22108652)
• DNA methylation of PITX2 and SHOX2 is an independent prognostic biomarker for disease progression in non-small-cell lung cancer patients. (PMID:22555092)
• Shox2 regulates progression through chondrogenesis at two distinct stages–the onset of early differentiation and the transition to maturation and hypertrophy. (PMID:23038774)
• Elevated SHOX2 expression is associated with tumor recurrence of hepatocellular carcinoma. (PMID:23851611)
• The combination of EBUS-TBNA and SHOX2 methylation level strongly improves the assessment of the nodal status by identifying additional malignant lesions and confirming benign nodes and therefore avoiding invasive follow-up procedures. (PMID:24026539)
• The assay is based on quantification of methylated Short Stature Homeobox gene two (SHOX2) DNA in the specimen measured via multiplex real-time Polymerase Chain Reaction (PCR) on bisulfite-converted DNA. (PMID:24136974)
• prognostic value of SHOX2 and SEPT9 DNA methylation in benign, paramalignant and malignant pleural effusions (PMID:24386354)
• SHOX2, like SHOX, regulates NPPB directly whilst activates ACAN via its cooperation with the SOX trio. (PMID:24421874)
• miR-375/SHOX2 functional relationship regulates breast tumorigenesis by controlling the process of EMT. (PMID:24746361)
• SHOX2 DNA methylation identified 66% of the patients with cancer subsequent to a cytological equivocal diagnosis. SHOX2 complements the cytological diagnosis and the methylation marker panel. (PMID:25331797)
• SHOX2 overexpression favors differentiation of embryonic stem cells into cardiac pacemaker cells, improving biological pacing ability. (PMID:25533636)
• The longitudinal measurement of extracellular plasma mSHOX2 DNA yields information about the response to cytotoxic treatment and allows an early assessment of treatment response for lung cancer patients. (PMID:25675432)
• important role in the process of intervertebral disc degeneration (PMID:26697824)
• Whole-genome microarray mRNA-expression profiles of myofibroblasts and skin fibroblasts revealed four additional genes that are significantly differentially expressed in these two cell types: NKX2-3 and LRRC17 in myofibroblasts and SHOX2 and TBX5 in skin fibroblasts (PMID:27036009)
• these results suggest a genetic contribution of SHOX2 in early-onset atrial fibrillation (PMID:27138930)
• High SHOX2 methylation is associated with Lung cancer. (PMID:27544059)
• Study showed that SHOX2 methylation levels in adenomas and colorectal carcinomas (CRC) were significantly higher compared to those in normal control tissues. Histologic transition from adenomas to CRC was paralleled by amplification of the SEPT9 gene locus. (PMID:27660666)
• We have identified that SHOX2 expression or methylation are potent independent prognostic indicators for predicting LGG patient survival, and have potential to identify an important subset of LGG patients with IDHwt status with significantly better overall survival. (PMID:27840009)
• Study found SHOX2 and SEPT9 frequently methylated in biliary tract cancers. (PMID:27999621)
• Data suggest that the microRNA miR-375/short stature homeobox 2 protein (SHOX2) axis may be a novel therapeutic target for esophageal squamous cell carcinoma (ESCC). (PMID:28069583)
• the methylation positive rates of SHOX2 with RASSF1A in stage III were both higher than the other stages of lung cancer (PMID:28325362)
• Post-therapeutic SHOX2 and SEPT9 circulating cell-free DNA(ccfDNA) methylation levels correlated with UICC stage (all P <0.01). SEPT9 ccfDNA methylation further allowed for an accurate pre- and post-therapeutic detection of distant metastases. (PMID:29610456)
• the first report on the association of SHOX2 loss-of-function mutation with enhanced susceptibility to familial Atrial fibrillation (PMID:30443179)
• SHOX2 and PTGER4 methylation detection in blood plasma has certain value in the early diagnosis of lung cancer (PMID:31167696)
• SHOX2 is regulated by IGF2-AS in the gastric adenocarcinoma. (PMID:31183590)
• combined detection of RASSF1A and SHOX2 gene methylation was identified as an excellent method for the screening and surveillance of lung cancer that exhibits high sensitivity and specificity (PMID:32266538)
• lncRNA SNHG11 promotes the development of colorectal cancer by mediating miR-339-3p/SHOX2. (PMID:32683847)
• A Novel Diagnosis Method Based on Methylation Analysis of SHOX2 and Serum Biomarker for Early Stage Lung Cancer. (PMID:33167712)
• [Diagnostic Efficacy of SHOX2 Gene Hypermethylation for Lung Cancer: A Meta-Analysis]. (PMID:34275516)
• [SHOX2 promotes migration, invasion and stemness of bladder cancer cells in vitro]. (PMID:34308848)
• SHOX2 cooperates with STAT3 to promote breast cancer metastasis through the transcriptional activation of WASF3. (PMID:34465361)
• SHOX2 methylation in Vietnamese patients with lung cancer. (PMID:35088378)
• Association of the SHOX2 and RASSF1A methylation levels with the pathological evolution of early-stage lung adenocarcinoma. (PMID:38840077)
• A gene desert required for regulatory control of pleiotropic Shox2 expression and embryonic survival. (PMID:39389973)
• Downregulation of short-stature homeobox protein 2 suppresses gastric cancer cell growth and stemness in vitro and in vivo via inactivating wnt/beta-catenin signaling. (PMID:39415634)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	shox2	ENSDARG00000075713
mus_musculus	Shox2	ENSMUSG00000027833
rattus_norvegicus	Shox2	ENSRNOG00000012478

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Short stature homeobox protein 2 — O60902 (reviewed: O60902)

Alternative names: Homeobox protein Og12X, Paired-related homeobox protein SHOT

All UniProt accessions (2): O60902, A0A087WVB7

UniProt curated annotations — full annotation on UniProt →

Function. May be a growth regulator and have a role in specifying neural systems involved in processing somatosensory information, as well as in face and body structure formation.

Subcellular location. Nucleus.

Tissue specificity. Widely expressed, including in heart, skeletal muscle, liver, lung, bone marrow fibroblast, pancreas and placenta.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the paired homeobox family. Bicoid subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
O60902-1	1, SHOX2A, SHOTA	yes
O60902-2	2, SHOX2B, SHOTB, OG12XB
O60902-3	3

RefSeq proteins (3): NP_001157150, NP_003021, NP_006875 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000047	HTH_motif	Conserved_site
IPR001356	HD	Domain
IPR003654	OAR_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR052631	Paired_homeobox_Bicoid	Family

Pfam: PF00046, PF03826

UniProt features (13 total): sequence conflict 4, compositionally biased region 3, splice variant 2, chain 1, DNA-binding region 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60902-F1	61.50	0.20

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 308 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, YAATNRNNNYNATT_UNKNOWN, GOBP_REGULATION_OF_SKELETAL_MUSCLE_TISSUE_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, WWTAAGGC_UNKNOWN, GOBP_REGULATION_OF_MORPHOGENESIS_OF_A_BRANCHING_STRUCTURE, GOBP_CARTILAGE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, NKX25_02

GO Biological Process (33): negative regulation of transcription by RNA polymerase II (GO:0000122), skeletal system development (GO:0001501), osteoblast differentiation (GO:0001649), regulation of heart rate (GO:0002027), positive regulation of mesenchymal cell proliferation (GO:0002053), chondrocyte development (GO:0002063), sinoatrial node development (GO:0003163), sinoatrial valve development (GO:0003172), cardiac right atrium morphogenesis (GO:0003213), regulation of transcription by RNA polymerase II (GO:0006357), smoothened signaling pathway (GO:0007224), nervous system development (GO:0007399), mesenchymal cell proliferation (GO:0010463), regulation of chondrocyte differentiation (GO:0032330), embryonic forelimb morphogenesis (GO:0035115), positive regulation of smoothened signaling pathway (GO:0045880), embryonic digestive tract morphogenesis (GO:0048557), positive regulation of skeletal muscle fiber development (GO:0048743), positive regulation of axonogenesis (GO:0050772), embryonic skeletal joint morphogenesis (GO:0060272), cartilage development involved in endochondral bone morphogenesis (GO:0060351), muscle tissue morphogenesis (GO:0060415), cardiac pacemaker cell differentiation (GO:0060920), sinoatrial node cell development (GO:0060931), stem cell proliferation (GO:0072089), regulation of branching morphogenesis of a nerve (GO:2000172), positive regulation of stem cell proliferation (GO:2000648), chondrocyte differentiation (GO:0002062), heart valve development (GO:0003170), cardiac atrium morphogenesis (GO:0003209), regulation of DNA-templated transcription (GO:0006355), embryonic limb morphogenesis (GO:0030326), embryonic morphogenesis (GO:0048598)

GO Molecular Function (5): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
system development	2
chondrocyte differentiation	2
negative regulation of DNA-templated transcription	1
ossification	1
cell differentiation	1
regulation of heart contraction	1
regulation of biological quality	1
positive regulation of cell population proliferation	1
mesenchymal cell proliferation	1
regulation of mesenchymal cell proliferation	1
cell development	1
cardiac conduction system development	1
atrial cardiac muscle tissue development	1
heart valve development	1
cardiac atrium morphogenesis	1
regulation of DNA-templated transcription	1
cell surface receptor signaling pathway	1
cell population proliferation	1
regulation of cell differentiation	1
regulation of cartilage development	1
embryonic limb morphogenesis	1
forelimb morphogenesis	1
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1
positive regulation of signal transduction	1
digestive tract morphogenesis	1
embryonic organ morphogenesis	1
embryonic digestive tract development	1
positive regulation of cell development	1
positive regulation of skeletal muscle tissue development	1
skeletal muscle fiber development	1
regulation of skeletal muscle fiber development	1
positive regulation of striated muscle cell differentiation	1
axonogenesis	1
positive regulation of cell projection organization	1
positive regulation of neurogenesis	1
regulation of axonogenesis	1
embryonic skeletal system morphogenesis	1

Protein interactions and networks

STRING

1168 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHOX2	TBX18	O95935	748
SHOX2	HCN4	Q9Y3Q4	741
SHOX2	TBX3	O15119	716
SHOX2	IPO13	O94829	689
SHOX2	LMO1	P25800	654
SHOX2	SEPTIN9	Q9UHD8	644
SHOX2	HOXD13	P35453	633
SHOX2	ISL1	P20663	627
SHOX2	TBX5	Q99593	623
SHOX2	SALL1	Q9NSC2	612
SHOX2	NPPA	P01160	604
SHOX2	GJA5	P36382	564
SHOX2	RUNX2	Q13950	560
SHOX2	SALL2	Q9Y467	534
SHOX2	TBX15	Q96SF7	532

IntAct

4 interactions, top by confidence:

A	B	Type	Score
SHOX2	CDK4	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
SHOX2	HSPA8	psi-mi:“MI:0915”(physical association)	0.400
SHOX2	TRIM29	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (12): SHOX2 (Two-hybrid), SHOX2 (Two-hybrid), HSPA8 (Proximity Label-MS), SHOX2 (Proximity Label-MS), SHOX2 (Proximity Label-MS), SHOX2 (Proximity Label-MS), SHOX2 (Proximity Label-MS), SHOX2 (Proximity Label-MS), SHOX2 (Affinity Capture-MS), TRIM29 (Two-hybrid), SHOX2 (Affinity Capture-RNA), SHOX2 (Biochemical Activity)

ESM2 similar proteins: A0JPN1, A2A9A2, A6NHT5, A6YP92, A7MB54, E9PZZ1, M0R6D8, O02786, O08934, O35085, O35762, O42115, O60902, P09065, P13297, P23683, P28360, P42581, P49640, P49749, P50223, P70390, P78413, P78415, P81067, P97830, Q03828, Q14549, Q14774, Q1XID0, Q2NKI2, Q2VL76, Q2VL77, Q2VL78, Q2VL79, Q2VL80, Q2VL82, Q2VL83, Q2VL84, Q2VL85

Diamond homologs: A1A546, A1YEV8, A1YG25, A2T711, A6NJT0, A6NNA5, A6YP92, G5EC89, G5EDS1, L8E946, O08934, O09113, O14813, O15266, O18381, O35085, O35137, O35602, O35690, O35750, O42115, O42201, O42250, O42356, O42357, O42358, O42477, O42567, O60902, O70137, O73917, O95076, O97039, P0DMV5, P23759, P23760, P24610, P26367, P26630, P29506

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	52
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1003 predictions. Top by Δscore:

Variant	Effect	Δscore
3:158099945:ACAC:A	acceptor_gain	1.0000
3:158099946:CAC:C	acceptor_gain	1.0000
3:158099946:CACC:C	acceptor_gain	1.0000
3:158099949:C:CC	acceptor_gain	1.0000
3:158099958:G:C	acceptor_gain	1.0000
3:158099947:AC:A	acceptor_gain	0.9900
3:158099947:ACCTG:A	acceptor_gain	0.9900
3:158099948:CCT:C	acceptor_gain	0.9900
3:158099948:CCTG:C	acceptor_gain	0.9900
3:158099951:G:GC	acceptor_gain	0.9900
3:158099958:G:GC	acceptor_gain	0.9900
3:158100248:GCATA:G	donor_loss	0.9900
3:158100249:CATA:C	donor_loss	0.9900
3:158100250:ATAC:A	donor_loss	0.9900
3:158100251:TA:T	donor_loss	0.9900
3:158100252:A:AG	donor_loss	0.9900
3:158100253:C:CA	donor_loss	0.9900
3:158100309:AACC:A	acceptor_loss	0.9900
3:158100310:ACC:A	acceptor_loss	0.9900
3:158100311:CCT:C	acceptor_loss	0.9900
3:158100312:C:CA	acceptor_loss	0.9900
3:158100313:T:A	acceptor_loss	0.9900
3:158100319:T:C	acceptor_gain	0.9900
3:158100319:T:TC	acceptor_gain	0.9900
3:158102675:TAC:T	donor_loss	0.9900
3:158102676:ACCTG:A	donor_loss	0.9900
3:158102677:C:CT	donor_loss	0.9900
3:158102715:AGTT:A	donor_gain	0.9900
3:158105677:AC:A	donor_gain	0.9900
3:158105678:CC:C	donor_gain	0.9900

AlphaMissense

2039 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:158098050:G:C	H325D	1.000
3:158098058:G:T	A322D	1.000
3:158098059:C:G	A322P	1.000
3:158098060:T:A	K321N	1.000
3:158098060:T:G	K321N	1.000
3:158098064:A:G	L320P	1.000
3:158098066:T:A	R319S	1.000
3:158098066:T:G	R319S	1.000
3:158098067:C:A	R319I	1.000
3:158098067:C:G	R319T	1.000
3:158098068:T:C	R319G	1.000
3:158098070:A:C	L318R	1.000
3:158098070:A:G	L318P	1.000
3:158098070:A:T	L318H	1.000
3:158098071:G:A	L318F	1.000
3:158098079:A:C	I315S	1.000
3:158098079:A:G	I315T	1.000
3:158098079:A:T	I315N	1.000
3:158098081:G:C	S314R	1.000
3:158098081:G:T	S314R	1.000
3:158098083:T:G	S314R	1.000
3:158099894:A:T	V223D	1.000
3:158100276:T:A	K197N	1.000
3:158100276:T:G	K197N	1.000
3:158100277:T:A	K197I	1.000
3:158100278:T:C	K197E	1.000
3:158100279:T:A	R196S	1.000
3:158100279:T:G	R196S	1.000
3:158100280:C:A	R196I	1.000
3:158100280:C:G	R196T	1.000

dbSNP variants (sampled 300 via entrez): RS1000097517 (3:158106314 G>A), RS1000616472 (3:158104278 A>C,G), RS1001556020 (3:158104890 T>C), RS1001902752 (3:158101489 A>G), RS1001948848 (3:158096259 G>C), RS1002239466 (3:158107819 T>C,G), RS1002575062 (3:158104657 G>A), RS1002867126 (3:158108264 C>A,T), RS1003230125 (3:158106180 AGAG>A), RS1003738018 (3:158099599 C>CT), RS1004141073 (3:158096435 A>C), RS1004245373 (3:158106231 A>C,T), RS1004799686 (3:158106772 A>G), RS1005179989 (3:158096806 A>C), RS1005397018 (3:158103316 G>GC)

Disease associations

OMIM: gene MIM:602504 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
atrial fibrillation	Limited	Autosomal dominant
schizophrenia	No Known Disease Relationship	Unknown

Mondo (2): schizophrenia (MONDO:0005090), atrial fibrillation (MONDO:0004981)

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001956_18	Height	2.000000e-09
GCST002702_82	Height	4.000000e-07
GCST003996_42	Monobrow	1.000000e-15
GCST004747_6	Lung cancer in never smokers	7.000000e-06
GCST005232_8	Neuroticism	2.000000e-09
GCST005588_21	Idiopathic dilated cardiomyopathy	6.000000e-06
GCST005951_143	Body mass index	4.000000e-08
GCST006629_92	Pulse pressure	2.000000e-08
GCST006940_97	Neurociticism	4.000000e-08
GCST007576_48	Chronotype	4.000000e-08
GCST008839_127	Height	7.000000e-17
GCST010796_693	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST90000025_956	Appendicular lean mass	3.000000e-14

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007906	synophrys measurement
EFO:0007660	neuroticism measurement
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0004340	body mass index
EFO:0005763	pulse pressure measurement
EFO:0008328	chronotype measurement
EFO:0004327	electrocardiography
EFO:0004980	appendicular lean mass

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D001281	Atrial Fibrillation	C14.280.067.198; C23.550.073.198

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
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	4
Vorinostat	decreases expression, affects cotreatment, increases expression	2
Cisplatin	decreases expression, increases expression	2
Tretinoin	increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	decreases methylation, affects cotreatment	1
arsenite	increases methylation	1
sodium arsenite	affects methylation	1
beta-methylcholine	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
palbociclib	increases phosphorylation, affects binding, decreases reaction	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Calcitriol	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Hydralazine	affects cotreatment, decreases expression	1
Methotrexate	increases expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Polychlorinated Biphenyls	affects expression	1
Smoke	decreases expression	1
Triclosan	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Genistein	decreases expression	1

Cellosaurus cell lines

9 cell lines: 5 induced pluripotent stem cell, 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A0SZ	MRIi024-A	Induced pluripotent stem cell	Male
CVCL_A0TA	MRIi016-A	Induced pluripotent stem cell	Male
CVCL_D0E9	DPEDi001-A-1	Induced pluripotent stem cell	Male
CVCL_D0EA	MRIi016-A-1	Induced pluripotent stem cell	Male
CVCL_D0EB	MRIi016-A-2	Induced pluripotent stem cell	Male
CVCL_TL03	HAP1 SHOX2 (-) 1	Cancer cell line	Male
CVCL_TL04	HAP1 SHOX2 (-) 2	Cancer cell line	Male
CVCL_TL05	HAP1 SHOX2 (-) 3	Cancer cell line	Male
CVCL_TL06	HAP1 SHOX2 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety