STOX2

Summary

STOX2 (storkhead box 2, HGNC:25450) is a protein-coding gene on chromosome 4q35.1, encoding Storkhead-box protein 2 (Q9P2F5).

This gene encodes a Storkhead-box_winged-helix domain containing protein. This protein is differentially expressed in decidual tissue and may be involved in the susceptibility to pre-eclampsia with fetal growth restriction. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 56977 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 136 total
• MANE Select transcript: NM_020225

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25450
Approved symbol	STOX2
Name	storkhead box 2
Location	4q35.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp762K222
Ensembl gene	ENSG00000173320
Ensembl biotype	protein_coding
OMIM	617359
Entrez	56977

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000308497, ENST00000506529, ENST00000511250, ENST00000512520, ENST00000513034, ENST00000883698

RefSeq mRNA: 1 — MANE Select: NM_020225 NM_020225

CCDS: CCDS47167

Canonical transcript exons

ENST00000308497 — 4 exons

Exon	Start	End
ENSE00001199807	184009158	184011423
ENSE00001199822	184017089	184023526
ENSE00001199827	183905307	183906956
ENSE00003555355	184001325	184001477

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 97.30.

FANTOM5 (CAGE): breadth broad, TPM avg 3.1149 / max 124.5431, expressed in 464 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50803	2.2026	418
50811	0.3618	169
50810	0.2067	119
50804	0.1865	92
50805	0.0906	45
50806	0.0668	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	97.30	gold quality
buccal mucosa cell	CL:0002336	96.60	gold quality
parietal lobe	UBERON:0001872	94.96	gold quality
postcentral gyrus	UBERON:0002581	94.90	gold quality
middle temporal gyrus	UBERON:0002771	94.61	gold quality
cerebellar vermis	UBERON:0004720	94.54	gold quality
entorhinal cortex	UBERON:0002728	94.37	gold quality
sural nerve	UBERON:0015488	94.32	gold quality
endothelial cell	CL:0000115	94.29	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.97	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.81	gold quality
superior frontal gyrus	UBERON:0002661	92.63	gold quality
ventral tegmental area	UBERON:0002691	92.39	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.24	gold quality
occipital lobe	UBERON:0002021	92.18	gold quality
inferior vagus X ganglion	UBERON:0005363	91.59	gold quality
subthalamic nucleus	UBERON:0001906	91.45	gold quality
primary visual cortex	UBERON:0002436	91.17	gold quality
superior vestibular nucleus	UBERON:0007227	90.99	gold quality
medulla oblongata	UBERON:0001896	90.62	gold quality
ventricular zone	UBERON:0003053	90.60	gold quality
lateral globus pallidus	UBERON:0002476	90.26	gold quality
pons	UBERON:0000988	90.21	gold quality
corpus callosum	UBERON:0002336	89.71	gold quality
substantia nigra pars compacta	UBERON:0001965	89.38	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.34	gold quality
epithelial cell of pancreas	CL:0000083	88.92	silver quality
caput epididymis	UBERON:0004358	88.13	gold quality
mucosa of paranasal sinus	UBERON:0005030	87.77	gold quality
gingival epithelium	UBERON:0001949	86.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	1426.55
E-CURD-119	yes	17.69
E-ANND-3	yes	5.45
E-MTAB-6058	no	208.49
E-HCAD-5	no	2.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

389 targeting STOX2, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548N	99.98	71.94	4170

Literature-anchored findings (GeneRIF, showing 3)

• STOX2 shows significantly lower expression in deciduas from pregnancies complicated by both pre-eclampsia and FGR as compared with controls. (PMID:20643876)
• Our results suggest that MIA-STOX2 signaling may be a useful diagnostic and therapeutic target in oral squamous cell carcinoma (PMID:27050375)
• A long non-coding RNA within intron 3 of the STOX2 gene on 4q35.1 acts as a permissive cis-acting regulator of alternative splicing of STOX2.Non-coding RNA-directed splicing of STOX2 is affected in Finnish pre-eclamptic patients. (PMID:27555360)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	stox2a	ENSDARG00000070162
danio_rerio	stox2b	ENSDARG00000078572
mus_musculus	Stox2	ENSMUSG00000038143
rattus_norvegicus	Stox2	ENSRNOG00000009590
drosophila_melanogaster	CG33285	FBGN0053285

Paralogs (1): STOX1 (ENSG00000165730)

Protein

Protein identifiers

Storkhead-box protein 2 — Q9P2F5 (reviewed: Q9P2F5)

All UniProt accessions (4): D6RDA5, H0Y8U0, H0YA59, Q9P2F5

Isoforms (2)

UniProt ID	Names	Canonical?
Q9P2F5-1	1	yes
Q9P2F5-2	2

RefSeq proteins (1): NP_064610* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019391	Storkhead-box_WHD	Domain
IPR040126	STOX1/2	Family

Pfam: PF10264

UniProt features (21 total): compositionally biased region 11, region of interest 7, splice variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2F5-F1	50.30	0.08

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 176 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, PEREZ_TP63_TARGETS, CADWELL_ATG16L1_TARGETS_DN, chr4q35, LIAO_METASTASIS, GOBP_MULTI_MULTICELLULAR_ORGANISM_PROCESS, PEREZ_TP53_AND_TP63_TARGETS, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, GOBP_MATERNAL_PROCESS_INVOLVED_IN_FEMALE_PREGNANCY, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_EMBRYO_DEVELOPMENT, VECCHI_GASTRIC_CANCER_EARLY_DN, GOBP_PLACENTA_DEVELOPMENT, GOBP_MATERNAL_PLACENTA_DEVELOPMENT

GO Biological Process (4): maternal placenta development (GO:0001893), regulation of transcription by RNA polymerase II (GO:0006357), response to bacterium (GO:0009617), embryo development ending in birth or egg hatching (GO:0009792)

GO Molecular Function (2): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity (GO:0003700)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
placenta development	1
developmental process involved in reproduction	1
anatomical structure development	1
maternal process involved in female pregnancy	1
transcription by RNA polymerase II	1
response to other organism	1
embryo development	1
transcription regulator activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

694 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STOX2	MAIP1	Q8WWC4	559
STOX2	RMP64	Q6NW34	521
STOX2	TRAPPC11	Q7Z392	505
STOX2	TMEM145	Q8NBT3	497
STOX2	FAM149A	A5PLN7	474
STOX2	CDKN2AIP	Q9NXV6	461
STOX2	PRSS56	P0CW18	457
STOX2	ARHGAP42	A6NI28	451
STOX2	FBXO21	O94952	443
STOX2	UVSSA	Q2YD98	430
STOX2	MEIOC	A2RUB1	428
STOX2	CFAP96	A7E2U8	419
STOX2	DQX1	Q8TE96	408
STOX2	EIF2S2	P20042	407
STOX2	TSPAN10	Q9H1Z9	406

IntAct

24 interactions, top by confidence:

A	B	Type	Score
CSNK1E	PER1	psi-mi:“MI:0914”(association)	0.840
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
DCAF8	TCP1	psi-mi:“MI:0914”(association)	0.530
CSNK1E	ZSWIM8	psi-mi:“MI:0914”(association)	0.530
Csnk1e		psi-mi:“MI:0915”(physical association)	0.400
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
CSNK1D	TMEM131L	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
MCC	CIBAR1	psi-mi:“MI:0914”(association)	0.350
NXF2B	MEIOC	psi-mi:“MI:0914”(association)	0.350
DNAL4	WDR91	psi-mi:“MI:0914”(association)	0.350
DNAL4	ZMPSTE24	psi-mi:“MI:0914”(association)	0.350
SFN	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
YWHAB	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAE	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAH	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAQ	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAZ	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAG	E2F8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (23): STOX2 (Affinity Capture-MS), STOX2 (Affinity Capture-MS), STOX2 (Affinity Capture-RNA), STOX2 (Affinity Capture-MS), STOX2 (Affinity Capture-MS), STOX2 (Affinity Capture-MS), STOX2 (Affinity Capture-MS), STOX2 (Affinity Capture-MS), STOX2 (Affinity Capture-MS), STOX2 (Affinity Capture-MS), STOX2 (Proximity Label-MS), STOX2 (Affinity Capture-MS), STOX2 (Proximity Label-MS), STOX2 (Proximity Label-MS), STOX2 (Proximity Label-MS)

ESM2 similar proteins: A0A140LFM6, A0A1B0GVH6, A0A1L8H8C0, A0A2K1JJ00, A0JMD2, A2ARZ3, A2AWL7, A4IGV6, A6H5Y1, D3ZJ47, E9Q309, F1QPR4, F5H4B4, H0WFA5, O14513, O35413, O94875, P0CAX8, P48437, Q12912, Q15468, Q1LXZ9, Q1X8D7, Q28FG2, Q3UTJ2, Q3ZBS1, Q499E5, Q49A88, Q4V7H1, Q5T5U3, Q5VT06, Q62417, Q62770, Q69Z38, Q6DFB0, Q80TY4, Q8BLN6, Q8CB14, Q8IWI9, Q8K0T7

Diamond homologs: B2RQL2, G5EEC5, Q499E5, Q6ZVD7, Q95K63, Q9P2F5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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
Activation of BAD and translocation to mitochondria	7	266.5×	9e-15
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	235.1×	1e-14
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	235.1×	1e-14
Activation of BH3-only proteins	7	173.8×	1e-13
RHO GTPases activate PKNs	7	111.0×	3e-12
Intrinsic Pathway for Apoptosis	7	102.5×	5e-12
FOXO-mediated transcription	5	84.0×	2e-08
SARS-CoV-1-host interactions	7	61.5×	2e-10

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	73.3×	7e-07
intracellular protein localization	8	33.5×	1e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	119
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2119 predictions. Top by Δscore:

Variant	Effect	Δscore
4:184009154:TCAGG:T	acceptor_loss	1.0000
4:184009155:CAG:C	acceptor_loss	1.0000
4:184009157:G:A	acceptor_loss	1.0000
4:184009157:GGT:G	acceptor_gain	1.0000
4:184017237:C:G	donor_gain	1.0000
4:183927772:T:A	acceptor_gain	0.9900
4:183927773:G:A	acceptor_gain	0.9900
4:183990122:GATGC:G	donor_gain	0.9900
4:184001319:CTGCA:C	acceptor_loss	0.9900
4:184001320:TGCA:T	acceptor_loss	0.9900
4:184001321:GCA:G	acceptor_loss	0.9900
4:184001322:CA:C	acceptor_loss	0.9900
4:184001323:A:AG	acceptor_gain	0.9900
4:184001324:G:GA	acceptor_loss	0.9900
4:184001324:G:GG	acceptor_gain	0.9900
4:184001324:GGT:G	acceptor_gain	0.9900
4:184009156:A:AG	acceptor_gain	0.9900
4:184009156:AG:A	acceptor_gain	0.9900
4:184009156:AGGT:A	acceptor_gain	0.9900
4:184009157:G:GT	acceptor_gain	0.9900
4:184009157:GG:G	acceptor_gain	0.9900
4:184009157:GGTG:G	acceptor_gain	0.9900
4:184009157:GGTGT:G	acceptor_gain	0.9900
4:184017087:A:AG	acceptor_gain	0.9900
4:184017088:G:GG	acceptor_gain	0.9900
4:183988407:GAATG:G	donor_gain	0.9800
4:183990003:A:AG	acceptor_gain	0.9800
4:183990004:G:GG	acceptor_gain	0.9800
4:183990004:GTCAC:G	acceptor_gain	0.9800
4:183990136:TTTA:T	donor_gain	0.9800

AlphaMissense

6123 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:184001369:T:C	F71L	1.000
4:184001371:T:A	F71L	1.000
4:184001371:T:G	F71L	1.000
4:184001448:T:C	L97P	1.000
4:184001460:T:C	L101P	1.000
4:184009721:T:A	W295R	1.000
4:184009721:T:C	W295R	1.000
4:184009723:G:C	W295C	1.000
4:184009723:G:T	W295C	1.000
4:184009788:G:C	R317P	1.000
4:184011389:A:C	S851R	1.000
4:184011391:C:A	S851R	1.000
4:184011391:C:G	S851R	1.000
4:184011401:G:C	D855H	1.000
4:184011402:A:T	D855V	1.000
4:184011404:A:C	S856R	1.000
4:184011406:T:A	S856R	1.000
4:184011406:T:G	S856R	1.000
4:184011407:G:A	G857R	1.000
4:184011407:G:C	G857R	1.000
4:184011408:G:A	G857E	1.000
4:184011410:T:C	F858L	1.000
4:184011411:T:C	F858S	1.000
4:184011411:T:G	F858C	1.000
4:184011412:C:A	F858L	1.000
4:184011412:C:G	F858L	1.000
4:184011415:C:A	N859K	1.000
4:184011415:C:G	N859K	1.000
4:184001370:T:C	F71S	0.999
4:184001391:T:A	L78H	0.999

dbSNP variants (sampled 300 via entrez): RS1000013315 (4:183989630 A>G), RS1000024934 (4:183892121 C>T), RS1000029618 (4:183813461 T>C), RS1000039148 (4:183916712 C>T), RS1000047739 (4:183859879 AT>A), RS1000055244 (4:183873461 A>AG), RS10000613 (4:183977638 G>A,C,T), RS1000071711 (4:184015549 C>T), RS1000072407 (4:183934643 T>C), RS1000073757 (4:183929242 A>G), RS1000074896 (4:183873158 G>T), RS1000077228 (4:183818836 C>T), RS1000085804 (4:183858443 T>G), RS1000112323 (4:183814652 C>T), RS10001133 (4:183958472 T>C)

Disease associations

OMIM: gene MIM:617359 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001859_57	Thiazide-induced adverse metabolic effects in hypertensive patients	8.000000e-06
GCST003542_88	Night sleep phenotypes	8.000000e-06
GCST003806_5	Response to bupropion and depression	6.000000e-07
GCST005359_11	Disease progression in age-related macular degeneration	9.000000e-06
GCST005580_179	Intraocular pressure	2.000000e-08
GCST006976_45	Macular thickness	1.000000e-14
GCST007741_29	Iris color (b* coordinate)	7.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0008336	disease progression measurement
EFO:0004695	intraocular pressure measurement
EFO:0009764	eye colour measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, increases expression	2
sodium arsenite	affects methylation, increases expression	2
Nickel	decreases expression	2
Valproic Acid	decreases expression, decreases methylation, increases expression	2
Aflatoxin B1	increases methylation, decreases expression	2
sulforaphane	decreases expression	1
benzo(e)pyrene	increases methylation	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
beta-methylcholine	affects expression	1
15-acetyldeoxynivalenol	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	increases reaction, affects binding	1
ICG 001	increases expression	1
abrine	decreases expression	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaldehyde	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects expression, increases reaction	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Methapyrilene	increases methylation	1

Clinical trials (associated diseases)

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