STAG3

Summary

STAG3 (STAG3 cohesin complex component, HGNC:11356) is a protein-coding gene on chromosome 7q22.1, encoding Cohesin subunit SA-3 (Q9UJ98). Meiosis specific component of cohesin complex. In precision oncology, STAG3 Underexpression is associated with resistance to Vemurafenib in Melanoma (CIViC Level D).

The protein encoded by this gene is expressed in the nucleus and is a subunit of the cohesin complex which regulates the cohesion of sister chromatids during cell division. A mutation in this gene is associated with premature ovarian failure. Alternate splicing results in multiple transcript variants encoding distinct isoforms. This gene has multiple pseudogenes.

Source: NCBI Gene 10734 — RefSeq curated summary.

At a glance

• Gene–disease (curated): premature ovarian failure 8 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 264 total — 11 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 18
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_001282717

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11356
Approved symbol	STAG3
Name	STAG3 cohesin complex component
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	SA3
Ensembl gene	ENSG00000066923
Ensembl biotype	protein_coding
OMIM	608489
Entrez	10734

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 12 protein_coding, 6 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000317296, ENST00000394018, ENST00000412190, ENST00000416412, ENST00000422690, ENST00000426455, ENST00000439782, ENST00000440830, ENST00000459699, ENST00000476057, ENST00000477469, ENST00000479359, ENST00000482546, ENST00000491498, ENST00000492674, ENST00000496157, ENST00000615138, ENST00000620100, ENST00000938222, ENST00000938223, ENST00000938224, ENST00000938225

RefSeq mRNA: 5 — MANE Select: NM_001282717 NM_001282716, NM_001282717, NM_001282718, NM_001375438, NM_012447

CCDS: CCDS34703, CCDS64730, CCDS75642

Canonical transcript exons

ENST00000615138 — 34 exons

Exon	Start	End
ENSE00002447250	100188453	100188529
ENSE00002515660	100188812	100189016
ENSE00003459341	100204021	100204122
ENSE00003473328	100200453	100200542
ENSE00003487563	100180493	100180672
ENSE00003487572	100200236	100200328
ENSE00003502204	100186200	100186296
ENSE00003504459	100211435	100211539
ENSE00003526533	100199262	100199367
ENSE00003536381	100199541	100199644
ENSE00003545047	100211011	100211185
ENSE00003549626	100189445	100189596
ENSE00003549959	100198087	100198166
ENSE00003550551	100213735	100213806
ENSE00003571175	100214007	100214381
ENSE00003578480	100198843	100198957
ENSE00003582733	100201786	100201866
ENSE00003583172	100202172	100202340
ENSE00003583240	100204627	100204775
ENSE00003595812	100195309	100195382
ENSE00003596509	100201090	100201160
ENSE00003599227	100205005	100205133
ENSE00003602324	100197156	100197279
ENSE00003613619	100202454	100202590
ENSE00003623491	100182090	100182192
ENSE00003627024	100198475	100198582
ENSE00003643277	100197778	100197876
ENSE00003645949	100200769	100200969
ENSE00003675174	100201949	100202041
ENSE00003676077	100205227	100205384
ENSE00003692400	100201264	100201351
ENSE00003693953	100211795	100211876
ENSE00003743363	100177918	100178005
ENSE00003786173	100182723	100182839

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 98.94.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4389 / max 243.1348, expressed in 298 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79937	0.8068	110
79941	0.2350	95
79943	0.2331	54
79940	0.0922	40
79936	0.0508	21
79938	0.0129	7
79939	0.0081	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.94	gold quality
right testis	UBERON:0004534	98.53	gold quality
left testis	UBERON:0004533	98.42	gold quality
secondary oocyte	CL:0000655	96.32	gold quality
testis	UBERON:0000473	95.63	gold quality
right uterine tube	UBERON:0001302	95.53	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.24	gold quality
cerebellar hemisphere	UBERON:0002245	94.71	gold quality
cerebellar cortex	UBERON:0002129	94.53	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.33	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.71	gold quality
gastrocnemius	UBERON:0001388	91.76	gold quality
body of pancreas	UBERON:0001150	91.25	gold quality
muscle of leg	UBERON:0001383	91.17	gold quality
cerebellum	UBERON:0002037	90.81	gold quality
adenohypophysis	UBERON:0002196	90.81	gold quality
cortical plate	UBERON:0005343	90.22	gold quality
spleen	UBERON:0002106	90.05	gold quality
right frontal lobe	UBERON:0002810	90.00	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.64	gold quality
spinal cord	UBERON:0002240	89.33	gold quality
left ovary	UBERON:0002119	89.21	gold quality
lymph node	UBERON:0000029	88.99	gold quality
sural nerve	UBERON:0015488	88.81	gold quality
pituitary gland	UBERON:0000007	88.73	gold quality
right ovary	UBERON:0002118	88.42	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.97	gold quality
tibial nerve	UBERON:0001323	87.97	gold quality
ganglionic eminence	UBERON:0004023	87.94	gold quality
anterior cingulate cortex	UBERON:0009835	87.37	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-8381	yes	1037.37
E-MTAB-6701	yes	98.43
E-HCAD-10	yes	23.65
E-ANND-3	yes	18.66
E-CURD-11	no	187.38
E-MTAB-6386	no	72.01
E-CURD-120	no	8.18
E-CURD-112	no	3.96

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F6, EZH2

miRNA regulators (miRDB)

25 targeting STAG3, 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-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4458	99.96	71.64	1650
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-5587-5P	99.07	68.58	838
HSA-MIR-3929	98.32	65.58	1026
HSA-MIR-6826-3P	98.19	66.32	1153
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-526B-5P	97.41	67.99	1074
HSA-MIR-6772-3P	97.04	65.89	784
HSA-MIR-3162-5P	95.67	67.53	794
HSA-MIR-5708	90.54	64.01	66

Literature-anchored findings (GeneRIF, showing 21)

• identified as one of five genes containing 11 somatic mutations in a panel that included 132 colorectal cancers, then demonstrated that down-regulation of such homologs resulted in chromosomal instability and chromatid cohesion defects in human cells (PMID:18299561)
• plays a role in regulation of transcription due to genetic imprinting, sister chromatid exchange, chromosome segregation and as an insulator element. (review) (PMID:18788457)
• we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer (PMID:20635389)
• We identified a homozygous 1-bp deletion inducing a frameshift mutation in STAG3 on chromosome 7. Female mice devoid of Stag3 are sterile. (PMID:24597867)
• STAG3 truncating variant as the cause of primary ovarian insufficiency has been found in two sisters in a consanguineous Lebanese family. (PMID:26059840)
• Loss of STAG2 or STAG3, which encode subunits of the cohesin complex, in melanoma cells results in resistance to BRAF inhibitors (BRAFi). Loss-of-function mutations in STAG2, as well as decreased expression of STAG2 or STAG3 proteins were found in several tumor samples from patients with acquired resistance to BRAFi and in BRAFi-resistant melanoma cell lines. (PMID:27500726)
• RT-PCR revealed that the mutation causes loss of wild-type donor splice-site which leads to aberrant splicing of STAG3 mRNA and consecutive formation of STAG3 alternative transcript (p.Leu490Thrfs*10) . This is the first report of splice-site mutation of STAG3 gene causes POI in 2 Han Chinese patients. (PMID:28393351)
• c.677C > G associated with primary ovarian insufficiency (PMID:28802712)
• Rec8-Stag3 cohesin is shown to be susceptible to Wapl-dependent ring opening and sororin-mediated protection. (PMID:29724914)
• The association of stromal antigen 3 (STAG3) sequence variations with spermatogenic impairment in the male Korean population. (PMID:31115363)
• For the first time, study reports biallelic variants in STAG3, in one sporadic patient, and a homozygous RNF212 variant, in the two brothers, as the genetic cause of non-obstructive azoospermia. Meiotic studies allowed the detection of the functional consequences of the mutations and provided information on the role of STAG3 and RNF212 in human male meiosis. (PMID:31125047)
• This is the first report of STAG3 mutations in a Caucasian family with primary ovarian insufficiency. (PMID:31363903)
• Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest. (PMID:31682730)
• STAG3 homozygous missense variant causes primary ovarian insufficiency and male non-obstructive azoospermia. (PMID:32634216)
• The meiosis-specific cohesin component stromal antigen 3 promotes cell migration and chemotherapeutic resistance in colorectal cancer. (PMID:33039558)
• Analysis of STAG3 variants in Chinese non-obstructive azoospermia patients with germ cell maturation arrest. (PMID:33980954)
• Biallelic loss of function variants in STAG3 result in primary ovarian insufficiency. (PMID:34497033)
• A Long Contiguous Stretch of Homozygosity Disclosed a Novel STAG3 Biallelic Pathogenic Variant Causing Primary Ovarian Insufficiency: A Case Report and Review of the Literature. (PMID:34828315)
• New STAG3 gene variant as a cause of premature ovarian insufficiency", trans “Nueva variante del gen STAG3 causante de insuficiencia ovarica prematura (PMID:35503298)
• The upregulation of stromal antigen 3 expression suppresses the phenotypic hallmarks of hepatocellular carcinoma through the Smad3-CDK4/CDK6-cyclin D1 and CXCR4/RhoA pathways. (PMID:35941537)
• METTL3/IGF2BP2 axis affects the progression of colorectal cancer by regulating m6A modification of STAG3. (PMID:37828232)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	stag3	ENSDARG00000104388
mus_musculus	Stag3	ENSMUSG00000036928
rattus_norvegicus	Stag3	ENSRNOG00000001360
drosophila_melanogaster	SA2	FBGN0043865
caenorhabditis_elegans		WBGENE00004738

Paralogs (2): STAG2 (ENSG00000101972), STAG1 (ENSG00000118007)

Protein

Protein identifiers

Cohesin subunit SA-3 — Q9UJ98 (reviewed: Q9UJ98)

Alternative names: SCC3 homolog 3, Stromal antigen 3, Stromalin-3

All UniProt accessions (6): Q9UJ98, C9J3T3, C9JTG4, C9JYW5, D6W5U7, H7C0H6

UniProt curated annotations — full annotation on UniProt →

Function. Meiosis specific component of cohesin complex. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The meiosis-specific cohesin complex probably replaces mitosis specific cohesin complex when it dissociates from chromatin during prophase I.

Subunit / interactions. Component of the meiosis-specific cohesin complex, which also contains the SMC1 (SMC1A or SMC1B) and SMC3 heterodimer. Such complex likely contains RAD21, or the meiosis-specific related protein REC8. Interacts with CCDC79/TERB1; recruiting cohesin to telomeres to develop structural rigidity.

Subcellular location. Nucleus. Chromosome. Centromere.

Tissue specificity. Testis specific.

Post-translational modifications. Phosphorylated.

Disease relevance. Premature ovarian failure 8 (POF8) [MIM:615723] An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. The disease is caused by variants affecting the gene represented in this entry. A homozygous deletion in STAG3 predicted to result in frameshift and premature truncation, has been shown to be the cause of premature ovarian failure in a large consanguineous family. Spermatogenic failure 61 (SPGF61) [MIM:619672] An autosomal recessive male infertility disorder characterized by non-obstructive azoospermia, due to complete meiotic arrest at the primary spermatocyte stage. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SCC3 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UJ98-1	1	yes
Q9UJ98-2	2
Q9UJ98-3	3

RefSeq proteins (5): NP_001269645, NP_001269646, NP_001269647, NP_001362367, NP_036579 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013721	STAG	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR020839	SCD	Domain
IPR039662	Cohesin_Scc3/SA	Family
IPR056396	HEAT_SCC3-SA	Domain

Pfam: PF08514, PF21581, PF24571

UniProt features (36 total): sequence conflict 12, compositionally biased region 9, sequence variant 5, region of interest 4, splice variant 3, chain 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UJ98-F1	78.46	0.59

Functional residue map

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

Post-translational modifications (1): 1203

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1221632	Meiotic synapsis
R-HSA-1474165	Reproduction
R-HSA-1500620	Meiosis
R-HSA-1640170	Cell Cycle

MSigDB gene sets: 205 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, MODULE_169, REACTOME_MEIOTIC_SYNAPSIS, GGGTGGRR_PAX4_03, GOBP_SYNAPTONEMAL_COMPLEX_ORGANIZATION, GOBP_ORGANELLE_FISSION, KIM_RESPONSE_TO_TSA_AND_DECITABINE_UP, HUTTMANN_B_CLL_POOR_SURVIVAL_DN, MODULE_171, GOBP_SISTER_CHROMATID_COHESION, GOBP_CHROMOSOME_ORGANIZATION_INVOLVED_IN_MEIOTIC_CELL_CYCLE, GOBP_HOMOLOGOUS_CHROMOSOME_SEGREGATION, GOBP_MEIOTIC_CELL_CYCLE_PROCESS, CTGYNNCTYTAA_UNKNOWN

GO Biological Process (8): sister chromatid cohesion (GO:0007062), synaptonemal complex assembly (GO:0007130), establishment of meiotic sister chromatid cohesion (GO:0034089), chromosome segregation (GO:0007059), homologous chromosome pairing at meiosis (GO:0007129), protein localization to chromosome (GO:0034502), cell division (GO:0051301), meiotic cell cycle (GO:0051321)

GO Molecular Function (1): chromatin binding (GO:0003682)

GO Cellular Component (14): chromosome, centromeric region (GO:0000775), chromatin (GO:0000785), synaptonemal complex (GO:0000795), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), meiotic cohesin complex (GO:0030893), condensed nuclear chromosome (GO:0000794), lateral element (GO:0000800), transverse filament (GO:0000802), male germ cell nucleus (GO:0001673), chromosome (GO:0005694), cohesin complex (GO:0008278)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Meiosis	1
Reproduction	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell cycle process	2
chromosome organization involved in meiotic cell cycle	2
chromosome	2
nuclear lumen	2
intracellular membraneless organelle	2
synaptonemal complex	2
chromosome organization	1
homologous chromosome pairing at meiosis	1
cellular component assembly	1
synaptonemal complex organization	1
establishment of sister chromatid cohesion	1
meiotic sister chromatid cohesion	1
homologous chromosome segregation	1
protein localization to organelle	1
cellular process	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
binding	1
chromosomal region	1
synaptonemal structure	1
intracellular membrane-bounded organelle	1
cohesin complex	1
nuclear chromosome	1
condensed chromosome	1
nucleus	1
germ cell nucleus	1
protein-containing complex	1

Protein interactions and networks

STRING

1210 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STAG3	SMC1B	Q8NDV3	998
STAG3	REC8	O95072	998
STAG3	RAD21L1	Q9H4I0	997
STAG3	SMC3	Q9UQE7	996
STAG3	SMC1A	Q14683	991
STAG3	RAD21	O60216	988
STAG3	SYCP3	Q8IZU3	834
STAG3	SYCE1	Q8N0S2	828
STAG3	HORMAD1	Q86X24	751
STAG3	PDS5A	Q29RF7	733
STAG3	SPO11	Q9Y5K1	717
STAG3	SYCP2	Q9BX26	716
STAG3	SYCE2	Q6PIF2	710
STAG3	SYCP1	Q15431	698
STAG3	HORMAD2	Q8N7B1	691

IntAct

3 interactions, top by confidence:

A	B	Type	Score
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
yopM	STAG3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): STAG3 (Affinity Capture-MS), STAG3 (Affinity Capture-MS), STAG3 (Affinity Capture-MS), STAG3 (Affinity Capture-MS), STAG3 (Affinity Capture-MS), STAG3 (Affinity Capture-MS), STAG3 (Affinity Capture-MS), STAG3 (Affinity Capture-MS), STAG3 (Affinity Capture-MS), STAG3 (Affinity Capture-MS), STAG3 (Affinity Capture-MS), SMC1A (Affinity Capture-Western), SMC3 (Affinity Capture-Western), STAG3 (Negative Genetic), STAG3 (Negative Genetic)

ESM2 similar proteins: A0A1D5PJB7, A0A1L8HX76, A6QR40, O08764, O60294, O95382, P10938, P70218, P97452, Q12851, Q14137, Q15334, Q16586, Q28686, Q32P44, Q3TJ91, Q499N3, Q499U2, Q4KLI9, Q561R2, Q562C2, Q5RBH8, Q5RCX2, Q61161, Q6AY79, Q6F5E8, Q6P1M3, Q6V7V2, Q7SZE3, Q7TMC8, Q80Y17, Q8BYZ7, Q8C3I8, Q8C6B2, Q8CHW4, Q8K4K5, Q8MKF0, Q8N0W3, Q8VC03, Q91WI7

Diamond homologs: O35638, O70576, P0CL83, P0CL84, P0CL85, Q19555, Q8N3U4, Q8TBR4, Q8WVM7, Q99M76, Q9D3E6, Q9DGN0, Q9DGN1, Q9UJ98, O13816, O82265

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
STAG3	“form complex”	“RAD21L Cohesin complex”	binding

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	13
Uncertain significance	142
Likely benign	29
Benign	31

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
126427	NM_001282717.2(STAG3):c.562del (p.Gln188fs)	Pathogenic
1328922	NM_001282717.2(STAG3):c.291dup (p.Asn98fs)	Pathogenic
1328923	NM_001282717.2(STAG3):c.1950C>A (p.Tyr650Ter)	Pathogenic
1328924	NM_001282717.2(STAG3):c.1936dup (p.Ala646fs)	Pathogenic
1328925	NM_001282717.2(STAG3):c.2394+1G>A	Pathogenic
1328929	NM_001282717.2(STAG3):c.3381_3384del (p.Glu1128fs)	Pathogenic
224903	NM_001282717.2(STAG3):c.1947_1948dup (p.Tyr650fs)	Pathogenic
4293889	NM_001282717.2(STAG3):c.2821C>T (p.Gln941Ter)	Pathogenic
430588	NM_001282717.2(STAG3):c.1573+5G>A	Pathogenic
4813861	NM_001282717.2(STAG3):c.2773del (p.Ser925fs)	Pathogenic
929755	NM_001282717.2(STAG3):c.1069C>T (p.Arg357Ter)	Pathogenic
1048096	NM_001282717.2(STAG3):c.1953_1955del (p.Leu652del)	Likely pathogenic
1325148	NM_001282717.2(STAG3):c.3106C>T (p.Gln1036Ter)	Likely pathogenic
1709457	NM_001282717.2(STAG3):c.3369_3381del (p.Glu1124fs)	Likely pathogenic
1802231	NM_001282717.2(STAG3):c.2221-1_2225delinsAC	Likely pathogenic
2632675	NM_001282717.2(STAG3):c.709del (p.Leu237fs)	Likely pathogenic
3062323	NM_001282717.2(STAG3):c.3550G>T (p.Glu1184Ter)	Likely pathogenic
374000	NM_001282717.2(STAG3):c.2776C>T (p.Arg926Ter)	Likely pathogenic
4278477	NM_001282717.2(STAG3):c.2291del (p.Asp764fs)	Likely pathogenic
451295	NM_001282717.2(STAG3):c.337-2A>C	Likely pathogenic
451296	NM_001282717.2(STAG3):c.1065+1G>C	Likely pathogenic
617739	NM_001282717.2(STAG3):c.1262T>G (p.Leu421Arg)	Likely pathogenic
617740	NM_001282717.2(STAG3):c.1312C>T (p.Arg438Ter)	Likely pathogenic
869148	NM_001282717.2(STAG3):c.1571del (p.Gln524fs)	Likely pathogenic

SpliceAI

6099 predictions. Top by Δscore:

Variant	Effect	Δscore
7:100182088:A:AG	acceptor_gain	1.0000
7:100182089:G:GG	acceptor_gain	1.0000
7:100182089:GGA:G	acceptor_gain	1.0000
7:100182089:GGAAT:G	acceptor_gain	1.0000
7:100182188:CACCG:C	donor_gain	1.0000
7:100182189:ACCG:A	donor_gain	1.0000
7:100182190:CCG:C	donor_gain	1.0000
7:100182190:CCGGT:C	donor_loss	1.0000
7:100182191:CG:C	donor_gain	1.0000
7:100182192:GG:G	donor_gain	1.0000
7:100182193:G:GA	donor_loss	1.0000
7:100182193:G:GG	donor_gain	1.0000
7:100182696:T:G	acceptor_gain	1.0000
7:100182713:T:G	acceptor_gain	1.0000
7:100182714:A:AG	acceptor_gain	1.0000
7:100182715:C:G	acceptor_gain	1.0000
7:100182716:A:AG	acceptor_gain	1.0000
7:100182717:T:G	acceptor_gain	1.0000
7:100182719:TTA:T	acceptor_loss	1.0000
7:100182720:TAGG:T	acceptor_loss	1.0000
7:100182721:AGGT:A	acceptor_gain	1.0000
7:100182722:G:GA	acceptor_loss	1.0000
7:100182722:GGTG:G	acceptor_gain	1.0000
7:100182838:AGG:A	donor_loss	1.0000
7:100182839:GG:G	donor_loss	1.0000
7:100182840:G:GA	donor_loss	1.0000
7:100186198:A:AG	acceptor_gain	1.0000
7:100186199:G:GC	acceptor_gain	1.0000
7:100186199:GTCT:G	acceptor_gain	1.0000
7:100186292:TAAAG:T	donor_loss	1.0000

AlphaMissense

8073 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:100197262:T:A	W350R	1.000
7:100197262:T:C	W350R	1.000
7:100197871:T:C	F387L	1.000
7:100197873:C:A	F387L	1.000
7:100197873:C:G	F387L	1.000
7:100197250:A:G	K346E	0.999
7:100197252:A:C	K346N	0.999
7:100197252:A:T	K346N	0.999
7:100197260:G:A	G349D	0.999
7:100197264:G:C	W350C	0.999
7:100197264:G:T	W350C	0.999
7:100189004:A:C	S235R	0.998
7:100189006:C:A	S235R	0.998
7:100189006:C:G	S235R	0.998
7:100197157:G:C	D315H	0.998
7:100197175:C:A	R321S	0.998
7:100197205:T:A	W331R	0.998
7:100197205:T:C	W331R	0.998
7:100197251:A:T	K346I	0.998
7:100197253:T:C	Y347H	0.998
7:100197263:G:C	W350S	0.998
7:100197269:T:C	L352P	0.998
7:100197275:A:T	D354V	0.998
7:100197812:T:C	L367P	0.998
7:100197859:T:C	F383L	0.998
7:100197860:T:C	F383S	0.998
7:100197861:C:A	F383L	0.998
7:100197861:C:G	F383L	0.998
7:100197872:T:C	F387S	0.998
7:100204111:A:C	S931R	0.998

dbSNP variants (sampled 300 via entrez): RS1000133510 (7:100178744 A>G), RS1000184339 (7:100183306 A>T), RS1000195303 (7:100176809 G>A,C,T), RS1000241826 (7:100211678 G>A), RS1000411143 (7:100215461 C>A,T), RS1000465183 (7:100215760 G>A), RS1000485949 (7:100179075 G>A), RS1000608811 (7:100219275 A>C,T), RS1000632331 (7:100219475 A>G,T), RS1000744582 (7:100214349 T>C), RS1000801490 (7:100214598 G>A), RS1000832308 (7:100196303 C>T), RS1000847043 (7:100212852 C>A,T), RS1000919604 (7:100181936 C>T), RS1001058578 (7:100206150 G>A)

Disease associations

OMIM: gene MIM:608489 | disease phenotypes: MIM:615723, MIM:619672, MIM:610532

GenCC curated gene-disease

Disease	Classification	Inheritance
premature ovarian failure 8	Strong	Autosomal recessive
spermatogenic failure 61	Strong	Autosomal recessive

Mondo (7): premature menopause (MONDO:0001119), premature ovarian failure 8 (MONDO:0014321), spermatogenic failure 61 (MONDO:0030507), ovarian disorder (MONDO:0005558), female infertility (MONDO:0021124), hypomyelinating leukodystrophy 5 (MONDO:0012514), primary ovarian failure (MONDO:0005387)

Orphanet (2): Hypomyelination-congenital cataract syndrome (Orphanet:85163), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000027	Azoospermia
HP:0000118	Phenotypic abnormality
HP:0000786	Primary amenorrhea
HP:0000837	Increased circulating gonadotropin level
HP:0003251	Male infertility
HP:0008209	Premature ovarian insufficiency
HP:0008214	Decreased serum estradiol
HP:0008232	Elevated circulating follicle stimulating hormone level
HP:0008669	Abnormal spermatogenesis
HP:0008734	Decreased testicular size
HP:0010464	Streak ovary
HP:0011462	Young adult onset
HP:0011961	Non-obstructive azoospermia
HP:0011962	Obstructive azoospermia
HP:0011969	Elevated circulating luteinizing hormone level
HP:0031039	Spermatocyte maturation arrest
HP:0100615	Ovarian neoplasm

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002882_6	Ticagrelor levels in individuals with acute coronary syndromes treated with ticagrelor	9.000000e-10
GCST007320_92	Alzheimer’s disease or family history of Alzheimer’s disease	3.000000e-08
GCST010002_259	Refractive error	3.000000e-16
GCST010702_48	Subcortical volume (MOSTest)	6.000000e-10
GCST010703_289	Brain morphology (MOSTest)	6.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007007	ticagrelor measurement
EFO:0009268	family history of Alzheimer’s disease
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D007247	Infertility, Female	C12.050.351.500.498; C12.100.250.498; C12.100.750.350
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D010049	Ovarian Diseases	C12.050.351.500.056.630; C12.100.250.056.630; C19.391.630
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C567166	Leukodystrophy, Hypomyelinating, 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
STAG3 Underexpression	Vemurafenib	Melanoma	Resistance	CIViC D	EID1660

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases mutagenesis	3
Air Pollutants	increases abundance, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Particulate Matter	increases expression, increases abundance	2
bisphenol A	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
Atrazine	increases expression	1
Cisplatin	increases expression	1
Dexamethasone	decreases expression, affects cotreatment	1
Indomethacin	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Valproic Acid	affects cotreatment, decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases expression	1
Asbestos, Serpentine	decreases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT01577472	PHASE4	COMPLETED	Efficacy Study Comparing the Effect of Clomiphencitrate to an Antagonist Protocol
NCT01791751	PHASE4	COMPLETED	Impact of Clomiphene Citrate Administration During the Early Luteal Phase on Endocrine Profile in IVF Cycles
NCT02070198	PHASE4	UNKNOWN	Long Acting FSH Plus Antagonist Versus Daily FSH Plus Antagonist Versus Short Agonist Protocol in Poor Responders Undergoing IVF
NCT02328924	PHASE4	COMPLETED	There is a Value of Luteinizing Hormone Predictive of in Vitro Fertilization Treatment Outcome in Antagonist Protocols?
NCT03057574	PHASE4	UNKNOWN	Gonapure® in Multifollicular Stimulation in Egyptian Women Undergoing IVF/ICSI
NCT05197374	PHASE4	COMPLETED	Effect of Estradiol Pretreatment on Antagonist ICSI Cycles
NCT05281341	PHASE4	COMPLETED	Effect of GH Administration in Poor Responders Undergoing Intracytoplasmic Sperm Injection (ICSI)
NCT05286554	PHASE4	COMPLETED	Addition of Gonadotropin Releasing Hormone Agonist to Luteal Phase Support
NCT05608590	PHASE4	UNKNOWN	What is the Best Moment for Performing an HSG in Women With a Unfulfilled Childwish
NCT05753098	PHASE4	COMPLETED	Effect of Sildenafil Citrate Compared to Estrogen as Adjuvant Therapy for Unexplained Infertility
NCT06434233	PHASE4	RECRUITING	Opioid Use After Laparoscopic Salpingectomy
NCT06684951	PHASE4	COMPLETED	Effects of Intrauterine Flushing With Human Chorionic Gonadotropin on ICSI Outcome
NCT06921395	PHASE4	RECRUITING	Phase IV Study to Evaluate the Efficacy and Safety of Fang Le Shu Compared to Guo Na Fen for Controlled Ovarian Stimulation in Infertile Women Undergoing in Vitro Fertilization-embryo Transfer (IVF-ET).
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT01462890	PHASE3	COMPLETED	Evaluation of Optimal Treatment Duration of Bevacizumab Combination With Standard Chemotherapy in Patients With Ovarian Cancer
NCT01850030	PHASE3	COMPLETED	A Multicenter Study Comparing the Efficacy, Safety and Tolerability of Oral Dydrogesterone 30 mg Daily Versus Intravaginal Micronized Progesterone Capsules 600 mg Daily for Luteal Support in In-Vitro Fertilization
NCT02175498	PHASE3	COMPLETED	Effectiveness of Homeopathic Treatment in Female Infertility
NCT02491437	PHASE3	COMPLETED	A Study Comparing the Efficacy, Safety and Tolerability of Oral Dydrogesterone 30 mg Daily Versus Crinone 8% Intravaginal Progesterone Gel 90 mg Daily for Luteal Support in In-Vitro Fertilization (LOTUS II)
NCT03429621	PHASE3	COMPLETED	Effect of Simethicone on Reducing Bowel Interference During Tubal Resection
NCT03542331	PHASE3	UNKNOWN	Endometrial Effects of Lipiodol
NCT03767569	PHASE3	UNKNOWN	Myo-inositol as Pretreatment in Hyperandrogenic PCOS Patients
NCT03862586	PHASE3	COMPLETED	NAC Effect on Hox Genes Expressions in RIF
NCT05266924	PHASE3	UNKNOWN	Recombinant Follicle-stimulating Hormone in Treatment for Infertility
NCT05460858	PHASE3	UNKNOWN	NAC Effect on Infertile Women With Endometrioma
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT00050414	PHASE2	COMPLETED	A Study of Trabectedin in Patients With Advanced Ovarian Cancer
NCT01310647	PHASE2	COMPLETED	Antral Follicle Priming Prior to ICSI (Intracytoplasmic Sperm Injection) in Previously Diagnosed Low Responders
NCT01460979	PHASE2	COMPLETED	Efficacy,Tolerability,Safety of Temsirolimus in Women With Platinum-refractory Ovarian Carcinoma or Advanced Endometrial Carcinoma
NCT03562897	PHASE2	COMPLETED	Evaluation of Ocoxin-Viusid® in Advanced or Metastatic Ovarian Epithelial Cancer