PMEPA1

Summary

PMEPA1 (prostate transmembrane protein, androgen induced 1, HGNC:14107) is a protein-coding gene on chromosome 20q13.31, encoding Protein TMEPAI (Q969W9). Functions as a negative regulator of TGF-beta signaling and thereby probably plays a role in cell proliferation, differentiation, apoptosis, motility, extracellular matrix production and immunosuppression. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a transmembrane protein that contains a Smad interacting motif (SIM). Expression of this gene is induced by androgens and transforming growth factor beta, and the encoded protein suppresses the androgen receptor and transforming growth factor beta signaling pathways though interactions with Smad proteins. Overexpression of this gene may play a role in multiple types of cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 56937 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 49
• Clinical variants (ClinVar): 749 total — 20 pathogenic, 33 likely-pathogenic
• Phenotypes (HPO): 52
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_020182

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14107
Approved symbol	PMEPA1
Name	prostate transmembrane protein, androgen induced 1
Location	20q13.31
Locus type	gene with protein product
Status	Approved
Aliases	STAG1
Ensembl gene	ENSG00000124225
Ensembl biotype	protein_coding
OMIM	606564
Entrez	56937

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000265626, ENST00000341744, ENST00000347215, ENST00000395814, ENST00000395816, ENST00000395819, ENST00000414037, ENST00000472841

RefSeq mRNA: 5 — MANE Select: NM_020182 NM_001255976, NM_020182, NM_199169, NM_199170, NM_199171

CCDS: CCDS13462, CCDS13463, CCDS13464

Canonical transcript exons

ENST00000341744 — 4 exons

Exon	Start	End
ENSE00000845770	57653033	57653086
ENSE00001704955	57709474	57710015
ENSE00003678044	57659543	57659697
ENSE00003841712	57648396	57652598

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 97.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.9252 / max 721.2767, expressed in 1521 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188134	15.3647	1355
188133	4.2953	1016
188136	1.8677	683
188135	0.7745	335
188131	0.7554	336
188130	0.3190	180
188132	0.2955	171
188137	0.2036	78
188128	0.0249	6
188138	0.0246	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
visceral pleura	UBERON:0002401	97.45	gold quality
ascending aorta	UBERON:0001496	96.62	gold quality
thoracic aorta	UBERON:0001515	96.60	gold quality
descending thoracic aorta	UBERON:0002345	96.53	gold quality
aorta	UBERON:0000947	96.47	gold quality
popliteal artery	UBERON:0002250	96.40	gold quality
tibial artery	UBERON:0007610	96.39	gold quality
tibia	UBERON:0000979	96.31	gold quality
tendon of biceps brachii	UBERON:0008188	96.16	gold quality
artery	UBERON:0001637	95.88	gold quality
endocervix	UBERON:0000458	95.38	gold quality
urethra	UBERON:0000057	95.28	gold quality
prostate gland	UBERON:0002367	95.15	gold quality
lateral globus pallidus	UBERON:0002476	95.12	gold quality
right coronary artery	UBERON:0001625	94.90	gold quality
globus pallidus	UBERON:0001875	94.51	gold quality
parietal pleura	UBERON:0002400	94.51	gold quality
vena cava	UBERON:0004087	94.42	gold quality
medial globus pallidus	UBERON:0002477	94.41	gold quality
skin of hip	UBERON:0001554	94.28	gold quality
saphenous vein	UBERON:0007318	94.05	gold quality
islet of Langerhans	UBERON:0000006	94.04	gold quality
pericardium	UBERON:0002407	93.92	gold quality
synovial joint	UBERON:0002217	93.70	gold quality
putamen	UBERON:0001874	93.55	gold quality
pleura	UBERON:0000977	93.52	gold quality
inferior vagus X ganglion	UBERON:0005363	93.08	gold quality
layer of synovial tissue	UBERON:0007616	92.93	gold quality
coronary artery	UBERON:0001621	92.89	gold quality
mammalian vulva	UBERON:0000997	92.50	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-CURD-53	yes	2738.26
E-MTAB-8559	yes	1570.63
E-HCAD-31	yes	1089.64
E-GEOD-81547	yes	909.61
E-ENAD-27	yes	625.94
E-MTAB-10662	yes	564.21
E-MTAB-5061	yes	27.44
E-HCAD-11	yes	26.99
E-GEOD-135922	yes	24.47
E-MTAB-8410	yes	18.44
E-GEOD-83139	yes	12.84
E-ANND-3	yes	10.85
E-CURD-46	yes	10.19
E-MTAB-6386	no	577.47

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, NCOA3, SMAD7, SP1, TCF7L2, ZNF165

miRNA regulators (miRDB)

115 targeting PMEPA1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 38)

• Expression of PMEPA1 was well maintained both in colon cancer primary tumors and in colon cancer liver metastases. (PMID:12670906)
• PMEPA1 negatively regulates growth of androgen responsive or refractory prostate cancer cells, and these functions may be mediated through the interaction of PMEPA1 with the NEDD4 protein. (PMID:12907594)
• Differentially expressed genes were identified, including E-cadherin, IL-8 and STAG1/PMEPA1 in an androgen-independent prostate cancer PC3 subclone. (PMID:17318295)
• DNA methylation within the PMEPA1 promoter downstream sequences suggests that methylation of SP1 binding sites may also contribute to the repression of PMEPA1 gene (PMID:18174752)
• decreased PMEPA1 expression frequently noted in prostate cancers may lead to increased AR functions and strengthen the biological role of the NEDD4-binding protein PMEPA1 in prostate cancers (PMID:18703514)
• Results suggest that TMEPAI functions in breast cancer as a molecular switch that converts TGF-beta from a tumor suppressor to a tumor promoter. (PMID:20610632)
• The levels of TMEPAI in lung tumor tissues are very high. (PMID:23615405)
• TMEPAI promotes tumorigenic activities in lung cancer cells. (PMID:24438557)
• Downregulation of PMEPA1 may result in increased androgen receptor protein levels and function in cancer of the prostate cells, contributing to prostate tumorigenesis. (PMID:24694733)
• TMEPAI is translocated on the lysosome and late endosome, and that association with Nedd4 is required for the transport of TMEPAI to the lysosome. (PMID:24933703)
• EGF signaling collaboratively regulates TGF-beta-induced TMEPAI expression. (PMID:25482449)
• Data show that silencing of PMEPA1 protein facilitates the growth of prostate cancer cells and modulates androgen receptor (AR) through NEDD4 ubiquitin protein ligase and PTEN protein. (PMID:25883222)
• binding of SMAD2/3, the intracellular effectors of activin signaling, was significantly enriched at the Pmepa1 gene, which encodes a negative feedback regulator of TGF-beta signaling in cancer cells, and at the Kdm6b gene, which encodes an epigenetic regulator promoting transcriptional plasticity. (PMID:26215835)
• these data elaborated on the diverse activity among TCF/LEF family members with respect to the transcriptional regulation of the TMEPAI gene. (PMID:26590303)
• PMEPA1 was upregulated in breast cancer cell lines as well as in a set of clinical invasive breast ductal carcinomas. Interestingly, depletion of PMEPA1 decreased breast cancer stem cell (CSC)-enriched populations, while ectopic overexpression of PMEPA1 increased breast CSC-enriched populations. (PMID:26758191)
• Data show that over-expressed transmembrane prostate androgen-induced protein 1 (PMEPA1) can promote cell migration and maintain the mesenchymal-like morphology of breast cancer cells. (PMID:26927372)
• the present study suggest that the upregulation of miR19a3p expression levels contributes to tumor progression and that one of its underlying mechanisms involves inhibition of PMEPA1 expression. (PMID:27035427)
• study showed that the inhibition of autophagy induced by the depletion of TMEPAI is involved in regulation of Beclin-1. (PMID:27163528)
• Sp1 up-regulated TMEPAI protein expression, as well as Sp1 promoting TMEPAI-induced cell proliferation. (PMID:27625141)
• these findings indicated that PMEPA1 participates in TGF-beta- and hypoxia-regulated gene expression networks in solid tumors and thereby may contribute to tumor progression. (PMID:27697531)
• This study highlights that TMEPAI decreases c-Maf stability by recruiting the ubiquitin ligase NEDD4 to c-Maf for proteasomal degradation in myeloma cells. (PMID:29467225)
• describe recent progresses in the understanding of how the TMEPAI family physiologically contributes to cellular functions and diseases (PMID:29945215)
• JHY-A007-50 mediates the downregulation of TMEPAI expression. (PMID:30069967)
• observed that knockout (KO) of PMEPA1 in human breast cancer cell line MDA-MB-231 using a CRISPR-Cas9 system resulted in reduction of in vivo tumour growth and lung metastasis but not of in vitro monolayer growth capacity of these KO cell lines (PMID:30873542)
• Prostate transmembrane protein androgen induced 1 (PMEPA1) promotes colorectal cancer metastasis and epithelial-to-mesenchymal transition (EMT) in vivo and in vitro. (PMID:30887697)
• These data suggest that TMEPAI suppresses Wnt signaling by interfering with beta-catenin stability and nuclear translocation in a TGF-beta signaling-independent manner. (PMID:30890370)
• PMEPA1 isoform a drives progression of glioblastoma by promoting protein degradation of the Hippo pathway kinase LATS1. (PMID:31605013)
• PMEPA1/TMEPAI isoforms function via its PY and Smad-interaction motifs for tumorigenic activities of breast cancer cells. (PMID:32181976)
• PMEPA1 Gene Isoforms: A Potential Biomarker and Therapeutic Target in Prostate Cancer. (PMID:32842649)
• Diagnostic and therapeutic values of PMEPA1 and its correlation with tumor immunity in pan-cancer. (PMID:33831430)
• CSDE1 attenuates microRNA-mediated silencing of PMEPA1 in melanoma. (PMID:33833398)
• PMEPA1 Stimulates the Proliferation, Colony Formation of Pancreatic Cancer Cells via the MAPK Signaling Pathway. (PMID:33857498)
• PMEPA1 facilitates non-small cell lung cancer progression via activating the JNK signaling pathway. (PMID:33896822)
• Linc00941 regulates esophageal squamous cell carcinoma via functioning as a competing endogenous RNA for miR-877-3p to modulate PMEPA1 expression. (PMID:34254950)
• PMEPA1 Is a Prognostic Biomarker That Correlates With Cell Malignancy and the Tumor Microenvironment in Bladder Cancer. (PMID:34777336)
• PMEPA1 Serves as a Prognostic Biomarker and Correlates with Immune Infiltrates in Cervical Cancer. (PMID:35497877)
• Exploring the role of PMEPA1 in gastric cancer. (PMID:37683830)
• METTL16 suppressed the proliferation and cisplatin-chemoresistance of bladder cancer by degrading PMEPA1 mRNA in a m6A manner through autophagy pathway. (PMID:38385084)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pmepa1	ENSMUSG00000038400
rattus_norvegicus	Pmepa1	ENSRNOG00000050404
drosophila_melanogaster	CG5151	FBGN0036576

Paralogs (1): LDLRAD4 (ENSG00000168675)

Protein

Protein identifiers

Protein TMEPAI — Q969W9 (reviewed: Q969W9)

Alternative names: Prostate transmembrane protein androgen induced 1, Solid tumor-associated 1 protein, Transmembrane prostate androgen-induced protein

All UniProt accessions (4): A2A2F4, A2A2F5, Q969W9, Q5JY37

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a negative regulator of TGF-beta signaling and thereby probably plays a role in cell proliferation, differentiation, apoptosis, motility, extracellular matrix production and immunosuppression. In the canonical TGF-beta pathway, ZFYVE9/SARA recruits the intracellular signal transducer and transcriptional modulators SMAD2 and SMAD3 to the TGF-beta receptor. Phosphorylated by the receptor, SMAD2 and SMAD3 then form a heteromeric complex with SMAD4 that translocates to the nucleus to regulate transcription. Through interaction with SMAD2 and SMAD3, LDLRAD4 may compete with ZFYVE9 and SMAD4 and prevent propagation of the intracellular signal. Also involved in down-regulation of the androgen receptor (AR), enhancing ubiquitination and proteasome-mediated degradation of AR, probably by recruiting NEDD4.

Subunit / interactions. Interacts with NEDD4 (via PPxY motifs). Interacts with AR. Interacts with LDLRAD4. Interacts (via the SMAD interaction motif) with SMAD2 and SMAD3.

Subcellular location. Early endosome membrane. Golgi apparatus membrane.

Tissue specificity. Highest expression in prostate. Also expressed in ovary.

Domain organisation. The PPxY motifs mediate interaction with NEDD4. The SMAD interaction motif is required for interaction with SMAD2 and SMAD3 and the negative regulation of TGF-beta signaling.

Induction. Up-regulated by androgen and TGF-beta (at protein level).

Similarity. Belongs to the PMEPA1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q969W9-1	1, a	yes
Q969W9-2	2, b
Q969W9-3	3, c

RefSeq proteins (5): NP_001242905, NP_064567, NP_954638, NP_954639, NP_954640 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR043445	TMEPAI/LRAD4	Family

UniProt features (14 total): short sequence motif 3, topological domain 2, splice variant 2, mutagenesis site 2, chain 1, sequence variant 1, transmembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q969W9-F1	57.03	0.07

Functional residue map

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

Mutagenesis-validated functional residues (2):

Position	Phenotype
161	impairs interaction with nedd4. impairs polyubiquitination of ar; when associated with a-232.
232	impairs interaction with nedd4. impairs polyubiquitination of ar; when associated with a-232.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2173788	Downregulation of TGF-beta receptor signaling

MSigDB gene sets: 412 (showing top): E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, E2F_Q4_01, RRAGTTGT_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, E2F4DP1_01, REACTOME_MEIOTIC_SYNAPSIS, MORF_BRCA1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, TAL1ALPHAE47_01, GGGTGGRR_PAX4_03, AAAYRNCTG_UNKNOWN, GGCNKCCATNK_UNKNOWN, MORF_RAD51L3

GO Biological Process (4): negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), androgen receptor signaling pathway (GO:0030521), negative regulation of SMAD protein signal transduction (GO:0060392), negative regulation of signal transduction (GO:0009968)

GO Molecular Function (4): WW domain binding (GO:0050699), R-SMAD binding (GO:0070412), protein sequestering activity (GO:0140311), protein binding (GO:0005515)

GO Cellular Component (7): Golgi membrane (GO:0000139), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), early endosome membrane (GO:0031901), endosome (GO:0005768), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TGF-beta receptor signaling activates SMADs	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	2
bounding membrane of organelle	2
endomembrane system	2
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
nuclear receptor-mediated steroid hormone signaling pathway	1
regulation of SMAD protein signal transduction	1
SMAD protein signal transduction	1
negative regulation of intracellular signal transduction	1
signal transduction	1
regulation of signal transduction	1
negative regulation of cell communication	1
negative regulation of signaling	1
negative regulation of response to stimulus	1
protein domain specific binding	1
SMAD binding	1
protein binding	1
molecular sequestering activity	1
binding	1
Golgi apparatus	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
cellular anatomical structure	1
early endosome	1
endosome membrane	1
cytoplasmic vesicle	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2096 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PMEPA1	NEDD4	P46934	899
PMEPA1	SMAD2	Q15796	879
PMEPA1	AR	P10275	722
PMEPA1	SMAD3	P84022	601
PMEPA1	NKX3-1	Q99801	507
PMEPA1	TGFBR1	P36897	451
PMEPA1	TMPRSS2	O15393	449
PMEPA1	AIG1	Q9NVV5	448
PMEPA1	KLK3	P07288	446
PMEPA1	FKBP5	Q13451	443
PMEPA1	KLK2	P20151	420
PMEPA1	SKIL	P12756	417
PMEPA1	SMAD7	O15105	400
PMEPA1	KLKB1	P03952	396
PMEPA1	PLCD4	Q9BRC7	370

IntAct

19 interactions, top by confidence:

A	B	Type	Score
PMEPA1		psi-mi:“MI:0915”(physical association)	0.550
Dlg4	PMEPA1	psi-mi:“MI:0407”(direct interaction)	0.440
PMEPA1	PPIB	psi-mi:“MI:0915”(physical association)	0.400
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
PMEPA1	ACP2	psi-mi:“MI:0914”(association)	0.350
PMEPA1	PPP3CB	psi-mi:“MI:0914”(association)	0.350
PMEPA1	SCGB2A1	psi-mi:“MI:0914”(association)	0.350
ASIC4	CLGN	psi-mi:“MI:0914”(association)	0.350
CLGN	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SCARB2	SGCE	psi-mi:“MI:0914”(association)	0.350
SPINT2	SPAG9	psi-mi:“MI:0914”(association)	0.350
TMPRSS13	PROS1	psi-mi:“MI:0914”(association)	0.350
TNFRSF9	SCO1	psi-mi:“MI:0914”(association)	0.350
TYROBP	SCAMP2	psi-mi:“MI:0914”(association)	0.350
PMEPA1	UBQLN4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (78): PMEPA1 (Biochemical Activity), NEDD4 (Two-hybrid), HGS (Two-hybrid), STAM (Two-hybrid), HGS (Affinity Capture-Western), STAM (Affinity Capture-Western), HGS (Reconstituted Complex), STAM (Reconstituted Complex), DCTN6 (Two-hybrid), DCTN5 (Two-hybrid), DCTN6 (Reconstituted Complex), DCTN5 (Reconstituted Complex), PMEPA1 (Affinity Capture-RNA), PMEPA1 (Affinity Capture-Western), NEDD4 (Affinity Capture-Western)

ESM2 similar proteins: A2AR95, A4GWX9, A4IHY6, B9F4Q9, D2KUZ7, D3Z1Q2, O15165, O35181, P0C1G7, P0C6T3, P56975, Q0VA20, Q0VBF2, Q0VFM5, Q3B7T3, Q3UH99, Q3V0I2, Q4KL18, Q4KMG9, Q58DS4, Q5FWP4, Q5R8E0, Q5XG16, Q68FU0, Q6A098, Q6K0P5, Q6PAQ9, Q6UXU6, Q6ZSJ9, Q86YD5, Q8AVJ1, Q8BGE4, Q8BGW2, Q8BWJ4, Q8TB68, Q8WUU8, Q8WVE6, Q90VY2, Q92537, Q93YV5

Diamond homologs: D2KUZ7, O15165, Q8BWJ4, Q969W9, Q9D7R2, E9Q6D8, P13671, P61134, P61135, Q29RU4, Q811M5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ZNF165	“down-regulates quantity by repression”	PMEPA1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	33
Uncertain significance	336
Likely benign	239
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2124580	NM_005862.3(STAG1):c.2116del (p.Asp706fs)	Pathogenic
2572950	NM_005862.3(STAG1):c.3046C>T (p.Arg1016Ter)	Pathogenic
3027404	GRCh37/hg19 3q22.3(chr3:136219065-136365036)x1	Pathogenic
3323043	NM_005862.3(STAG1):c.1010G>A (p.Trp337Ter)	Pathogenic
3650660	NM_005862.3(STAG1):c.282dup (p.Lys95fs)	Pathogenic
3769899	NM_005862.3(STAG1):c.2911C>T (p.Arg971Ter)	Pathogenic
3772689	NM_005862.3(STAG1):c.395-2A>T	Pathogenic
3802102	NM_005862.3(STAG1):c.1339del (p.Ala447fs)	Pathogenic
4176067	NM_005862.3(STAG1):c.2964C>A (p.Tyr988Ter)	Pathogenic
437896	NC_000003.11:g.136254742_136427833del	Pathogenic
451354	NM_005862.3(STAG1):c.469G>A (p.Glu157Lys)	Pathogenic
4528293	NM_005862.3(STAG1):c.1141dup (p.Met381fs)	Pathogenic
4537876	NM_005862.3(STAG1):c.3616C>T (p.Arg1206Ter)	Pathogenic
4809952	NM_005862.3(STAG1):c.455_458del (p.Thr152fs)	Pathogenic
545081	NM_005862.3(STAG1):c.2241G>A (p.Trp747Ter)	Pathogenic
686586	GRCh37/hg19 3q22.3(chr3:136192663-136396078)x1	Pathogenic
689317	GRCh37/hg19 3q22.3(chr3:136193031-136305476)x1	Pathogenic
802013	NM_005862.3(STAG1):c.260del (p.Leu87fs)	Pathogenic
830788	NC_000003.12:g.(?136452033)(136477412_?)del	Pathogenic
995415	NM_005862.3(STAG1):c.391C>T (p.Arg131Ter)	Pathogenic
1013230	NM_005862.3(STAG1):c.997A>G (p.Lys333Glu)	Likely pathogenic
1064844	NM_005862.3(STAG1):c.132+5G>A	Likely pathogenic
1064852	NM_005862.3(STAG1):c.964_965insCT (p.Tyr322fs)	Likely pathogenic
1325144	NM_005862.3(STAG1):c.513del (p.Gln170_Trp171insTer)	Likely pathogenic
1333942	NM_005862.3(STAG1):c.625G>C (p.Gly209Arg)	Likely pathogenic
1700129	NM_005862.3(STAG1):c.947del (p.Gly316fs)	Likely pathogenic
1709088	NM_005862.3(STAG1):c.3691C>T (p.Arg1231Ter)	Likely pathogenic
1709726	NM_005862.3(STAG1):c.1716dup (p.Ile573fs)	Likely pathogenic
1711580	NM_005862.3(STAG1):c.3488A>G (p.Glu1163Gly)	Likely pathogenic
2036530	NM_005862.3(STAG1):c.1546+1G>T	Likely pathogenic

SpliceAI

1038 predictions. Top by Δscore:

Variant	Effect	Δscore
20:57659535:GCACT:G	donor_loss	1.0000
20:57659536:CACT:C	donor_loss	1.0000
20:57659537:ACTT:A	donor_loss	1.0000
20:57659538:CT:C	donor_loss	1.0000
20:57659539:TT:T	donor_loss	1.0000
20:57659540:TA:T	donor_loss	1.0000
20:57659541:A:AC	donor_gain	1.0000
20:57659541:ACT:A	donor_loss	1.0000
20:57659542:C:CT	donor_gain	1.0000
20:57659542:CT:C	donor_gain	1.0000
20:57659542:CTGA:C	donor_gain	1.0000
20:57659693:CTCCG:C	acceptor_gain	1.0000
20:57659694:TCCG:T	acceptor_gain	1.0000
20:57659695:CCG:C	acceptor_gain	1.0000
20:57659695:CCGC:C	acceptor_gain	1.0000
20:57659696:CG:C	acceptor_gain	1.0000
20:57659696:CGC:C	acceptor_gain	1.0000
20:57659697:GC:G	acceptor_loss	1.0000
20:57659698:C:CC	acceptor_gain	1.0000
20:57659698:CTGT:C	acceptor_loss	1.0000
20:57659699:T:A	acceptor_loss	1.0000
20:57659700:G:C	acceptor_gain	1.0000
20:57659700:G:GC	acceptor_gain	1.0000
20:57709472:A:AC	donor_gain	1.0000
20:57709473:C:CC	donor_gain	1.0000
20:57709473:CTGAT:C	donor_gain	1.0000
20:57652077:AT:A	donor_gain	0.9900
20:57652598:GCTGG:G	acceptor_loss	0.9900
20:57652599:C:CA	acceptor_loss	0.9900
20:57652831:C:CA	donor_gain	0.9900

AlphaMissense

1872 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:57652353:G:C	N188K	1.000
20:57652353:G:T	N188K	1.000
20:57652384:A:G	L178P	1.000
20:57652468:A:T	I150N	1.000
20:57652350:T:A	R189S	0.999
20:57652350:T:G	R189S	0.999
20:57652351:C:A	R189I	0.999
20:57652351:C:G	R189T	0.999
20:57652357:G:T	P187Q	0.999
20:57652360:G:T	P186H	0.999
20:57652384:A:T	L178Q	0.999
20:57652388:C:T	E177K	0.999
20:57652456:T:A	D154V	0.999
20:57652468:A:C	I150S	0.999
20:57652468:A:G	I150T	0.999
20:57659629:A:G	C60R	0.999
20:57652223:A:C	Y232D	0.998
20:57652223:A:G	Y232H	0.998
20:57652341:G:C	F192L	0.998
20:57652341:G:T	F192L	0.998
20:57652343:A:G	F192L	0.998
20:57652358:G:T	P187T	0.998
20:57652360:G:C	P186R	0.998
20:57652361:G:A	P186S	0.998
20:57652361:G:T	P186T	0.998
20:57652369:A:T	V183E	0.998
20:57652373:A:G	S182P	0.998
20:57652378:C:G	R180P	0.998
20:57652395:C:A	Q174H	0.998
20:57652395:C:G	Q174H	0.998

dbSNP variants (sampled 300 via entrez): RS1000008755 (20:57690721 T>C,G), RS1000030118 (20:57680187 G>A), RS1000083504 (20:57679989 C>A,T), RS1000144904 (20:57648106 G>A,C), RS1000167359 (20:57689878 A>G), RS1000223999 (20:57692441 G>A), RS1000236599 (20:57685697 G>A,T), RS1000277369 (20:57684654 G>A), RS1000327988 (20:57694989 G>A,C), RS1000354466 (20:57649558 C>T), RS1000417961 (20:57657986 T>C), RS1000437449 (20:57689621 C>A,T), RS1000459858 (20:57684921 C>T), RS1000485631 (20:57655503 T>TG), RS1000496942 (20:57655762 C>A)

Disease associations

OMIM: gene MIM:606564 | disease phenotypes: MIM:617635

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal dominant 47	Definitive	Autosomal dominant
hereditary disorder of connective tissue	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (6): intellectual disability, autosomal dominant 47 (MONDO:0030912), neurodevelopmental disorder (MONDO:0700092), coloboma (MONDO:0001476), hereditary disorder of connective tissue (MONDO:0023603), intellectual disability (MONDO:0001071), premature menopause (MONDO:0001119)

Orphanet (3): STAG1-related intellectual disability-facial dysmorphism-gastroesophageal reflux syndrome (Orphanet:502434), OBSOLETE: Ocular coloboma (Orphanet:194), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000050	Hypoplastic male external genitalia
HP:0000085	Horseshoe kidney
HP:0000154	Wide mouth
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000426	Prominent nasal bridge
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000527	Long eyelashes
HP:0000664	Synophrys
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000954	Single transverse palmar crease
HP:0000965	Cutis marmorata
HP:0001195	Single umbilical artery
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001319	Neonatal hypotonia
HP:0001377	Limited elbow extension
HP:0001382	Joint hypermobility
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age

GWAS associations

49 associations (top):

Study	Trait	p-value
GCST001738_1	Response to fenofibrate (adiponectin levels)	2.000000e-07
GCST001762_241	Obesity-related traits	7.000000e-06
GCST002539_50	Schizophrenia	7.000000e-11
GCST002647_93	Height	2.000000e-18
GCST002701_33	Verbal declarative memory	3.000000e-06
GCST002783_256	Body mass index	2.000000e-07
GCST002783_385	Body mass index	6.000000e-07
GCST002783_473	Body mass index	5.000000e-07
GCST003680_14	C-reactive protein levels or HDL-cholesterol levels (pleiotropy)	1.000000e-09
GCST004521_157	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004904_257	Body mass index	2.000000e-08
GCST004946_94	Schizophrenia	4.000000e-15
GCST005194_170	Coronary artery disease	8.000000e-12
GCST005195_107	Coronary artery disease	6.000000e-15
GCST005580_256	Intraocular pressure	2.000000e-10
GCST005580_259	Intraocular pressure	2.000000e-10
GCST005667_28	Central corneal thickness	9.000000e-10
GCST006611_16	HDL cholesterol	2.000000e-13
GCST006803_84	Schizophrenia	4.000000e-12
GCST007201_147	Schizophrenia	2.000000e-13
GCST007201_236	Schizophrenia	2.000000e-10
GCST007201_237	Schizophrenia	2.000000e-10
GCST007325_269	General risk tolerance (MTAG)	1.000000e-13
GCST008295_6	Number of decayed, missing and filled tooth surfaces or use of dentures	9.000000e-09
GCST008306_33	Dentures	1.000000e-07
GCST008512_8	Multisite chronic pain	9.000000e-09
GCST008595_40	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	6.000000e-10
GCST009414_10	Central corneal thickness	2.000000e-08
GCST009600_76	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	1.000000e-08
GCST010204_139	Low density lipoprotein cholesterol levels	4.000000e-11

EFO canonical traits (20, from GWAS)

EFO ID	Trait name
EFO:0003939	energy intake
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement
EFO:0004340	body mass index
EFO:0004458	C-reactive protein measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004695	intraocular pressure measurement
EFO:0005213	central corneal thickness
EFO:0008579	risk-taking behaviour
EFO:0010078	dentures
EFO:0010100	multisite chronic pain
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004615	apolipoprotein B measurement
EFO:0007863	illness severity status
EFO:0007789	BMI-adjusted waist circumference
EFO:0007985	platelet crit
EFO:0004533	alkaline phosphatase measurement
EFO:0004532	serum gamma-glutamyl transferase measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D003103	Coloboma	C11.250.110; C11.270.147; C16.131.384.282
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
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
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, decreases expression, decreases reaction, affects cotreatment	4
bisphenol A	affects cotreatment, affects methylation, decreases expression, decreases methylation, increases expression	3
Metribolone	affects expression, increases expression	3
Cyclosporine	decreases expression, increases expression	3
entinostat	increases expression, affects cotreatment	2
Resveratrol	decreases expression	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Vehicle Emissions	decreases methylation, increases abundance, increases expression	2
Benzo(a)pyrene	increases expression, increases methylation, affects methylation, decreases methylation	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Cocaine	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Dihydrotestosterone	increases expression	2
Valproic Acid	decreases expression, increases expression	2
Genistein	decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
GSK-J4	increases expression	1
bisphenol F	increases expression	1
chloroacetaldehyde	decreases expression	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
propylparaben	increases expression	1
lead acetate	increases expression	1
phentin acetate	decreases expression	1
beta-lapachone	increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice