PINX1

Summary

PINX1 (PIN2 (TERF1) interacting telomerase inhibitor 1, HGNC:30046) is a protein-coding gene on chromosome 8p23.1, encoding PIN2/TERF1-interacting telomerase inhibitor 1 (Q96BK5). Microtubule-binding protein essential for faithful chromosome segregation.

Enables telomerase RNA binding activity and telomerase inhibitor activity. Involved in several processes, including negative regulation of macromolecule metabolic process; positive regulation of protein localization to nucleolus; and protein localization to organelle. Acts upstream of or within telomere maintenance via telomerase. Located in several cellular components, including chromosomal region; nuclear lumen; and spindle. Implicated in hepatocellular carcinoma.

Source: NCBI Gene 54984 — RefSeq curated summary.

At a glance

• GWAS associations: 56
• Clinical variants (ClinVar): 98 total — 1 pathogenic
• MANE Select transcript: NM_017884

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30046
Approved symbol	PINX1
Name	PIN2 (TERF1) interacting telomerase inhibitor 1
Location	8p23.1
Locus type	gene with protein product
Status	Approved
Aliases	LPTL, LPTS, FLJ20565, MGC8850, Gno1, Pxr1
Ensembl gene	ENSG00000254093
Ensembl biotype	protein_coding
OMIM	606505
Entrez	54984

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000314787, ENST00000517607, ENST00000519088, ENST00000520018, ENST00000523559, ENST00000524026, ENST00000524061, ENST00000524114, ENST00000895852

RefSeq mRNA: 2 — MANE Select: NM_017884 NM_001284356, NM_017884

CCDS: CCDS47801, CCDS64825

Canonical transcript exons

ENST00000314787 — 7 exons

Exon	Start	End
ENSE00000979596	10820193	10820269
ENSE00001776764	10764961	10765916
ENSE00003477551	10831665	10831743
ENSE00003541210	10826152	10826244
ENSE00003564936	10834666	10834775
ENSE00003572717	10832892	10832984
ENSE00003843568	10839738	10839875

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 88.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.6866 / max 132.9588, expressed in 1800 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91815	8.6275	1765
91814	5.5280	1722
91813	0.5311	227

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	88.73	silver quality
oocyte	CL:0000023	86.97	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.74	gold quality
calcaneal tendon	UBERON:0003701	84.86	gold quality
cardiac muscle of right atrium	UBERON:0003379	84.76	gold quality
left ventricle myocardium	UBERON:0006566	84.70	gold quality
parotid gland	UBERON:0001831	84.13	gold quality
secondary oocyte	CL:0000655	83.93	gold quality
gastrocnemius	UBERON:0001388	83.67	gold quality
upper arm skin	UBERON:0004263	83.58	silver quality
vena cava	UBERON:0004087	83.11	gold quality
muscle of leg	UBERON:0001383	83.01	gold quality
cartilage tissue	UBERON:0002418	82.86	gold quality
islet of Langerhans	UBERON:0000006	82.77	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.71	gold quality
skin of abdomen	UBERON:0001416	82.57	gold quality
skin of leg	UBERON:0001511	82.55	gold quality
tendon	UBERON:0000043	82.41	gold quality
gingival epithelium	UBERON:0001949	82.35	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.17	gold quality
tibial nerve	UBERON:0001323	82.11	gold quality
tendon of biceps brachii	UBERON:0008188	82.00	gold quality
lower esophagus mucosa	UBERON:0035834	81.87	gold quality
lymph node	UBERON:0000029	81.86	gold quality
zone of skin	UBERON:0000014	81.48	gold quality
cortical plate	UBERON:0005343	81.45	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	81.38	gold quality
muscle tissue	UBERON:0002385	81.27	gold quality
esophagus mucosa	UBERON:0002469	81.21	gold quality
ganglionic eminence	UBERON:0004023	81.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

28 targeting PINX1, 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-8485	100.00	77.57	4731
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-501-5P	98.77	68.88	1328
HSA-MIR-500A-5P	98.76	69.13	1241
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-216B-3P	98.55	67.19	1223
HSA-MIR-6864-5P	98.38	66.59	1079
HSA-MIR-3929	98.32	65.58	1026
HSA-MIR-599	98.32	66.99	1037
HSA-MIR-5088-5P	97.97	64.28	487
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-924	97.78	66.21	681
HSA-MIR-1972	97.67	67.38	1172
HSA-MIR-6781-3P	97.44	66.85	970
HSA-MIR-3152-5P	96.98	66.88	819
HSA-MIR-627-5P	95.51	66.80	509

Literature-anchored findings (GeneRIF, showing 40)

• role in rRNA and small nucleolar RNA maturation, not in telomere elongation inhibition (PMID:12107183)
• Over-expression of LPTS-L can induce hepatoma cells into crisis due to the reduction of telomerase activity. (PMID:12439923)
• Data show that liver-related putative tumor suppressor gene (LPTS) mutations occur in hepatocellular carcinoma but are infrequent and of little effect on the telomerase inhibitory function of the protein. (PMID:12508358)
• molecular cloning of the 5’-flanking region and determination of the transcription initiation site and four DNase I hypersensitive sites (PMID:14984932)
• in vitro PinX1 binds directly to the hTERT protein subunit, primarily to the hTR-binding domain, as well as to the hTR subunit (PMID:15381700)
• LOH of PINX1 locus associated with reduced expression of PINX1 in gastric cancer (PMID:15637589)
• PINX1 may play major role in gastric cancer development and regulate it through different pathways and expression is a sign of cancer development. (PMID:18784941)
• Results reveal a novel positive role for PinX1 in telomerase/telomere regulations and suggest that the constitutive expression of PinX1 attributes to telomere maintenance by telomerase and tumorigenicity in cancer cells. (PMID:19117989)
• Results show that hPinX1 regulates the nucleolar accumulation and telomeric association of TRF1. (PMID:19265708)
• PinX1 is recruited to chromosome periphery by Nucleolin and a complex of PinX1 and Nucleolin is essential for faithful chromosome congression. (PMID:19393617)
• The results indicate that PinX1 plays an important role in faithful chromosome segregation in mitosis. (PMID:19553660)
• loss of PinX1 is an adverse independent molecular marker for epithelial ovarian carcinoma patients. (PMID:20367640)
• Suppression of telomerase activity mediated by PinX1 is involved in the Mad1/c-Myc pathway. (PMID:20544396)
• Polo-like kinase 1 (Plk1) is a novel interacting protein of PinX1 and may negatively regulate the stability of PinX1 by mitotic phosphorylation. (PMID:20573420)
• these results suggest that the C-terminal fragment of LPTS/PinX1 (LPTS/PinX1(290-328)) contains a telomerase inhibitory domain that is required for the inhibition of telomere elongation and the induction of cell crisis. (PMID:20620128)
• the telomerase inhibitor PinX1 is recruited to telomeres by TRF1 and provides a critical link between TRF1 and telomerase inhibition to prevent telomere elongation and help maintain telomere homeostasis. (PMID:21119197)
• PinX1 may play important roles in NPC proliferation, migration and apoptosis and has application potential in tumor-targeted gene therapy (PMID:22316341)
• one function of PinX1 is to stabilize TRF1 during mitosis, perhaps to promote transition into M phase of the cell cycle. (PMID:22331467)
• Silencing of PinX1 significantly reduced the localization of telomerase to telomere during mid-late S phase, suggesting the involvement of PinX1 in the cell cycle-dependent trafficking of hTERT to telomere. (PMID:22749911)
• Data are consistent with the earlier data that showed that PINX1 somatic mutation was rare in hepatocellular carcinomas, medulloblatomas, gastric carcinomas, and colorectal carcinomas. (PMID:22882268)
• Suggest that PinX1 could serve as a novel predictor for response to chemoradiotherapy in esophageal squamous cell carcinoma. (PMID:23341363)
• Overexpression of PinX1 blocked Eca109 cell proliferation and induced cell apoptosis by downregulating telomerase activity. (PMID:23912465)
• Down-regulation of PinX1 play an important role in the tumorigenesis and development of urothelial carcinoma of the bladder. (PMID:24268029)
• Data indicate that HPV16 E6 suppresses the expression of PinX1 via inhibiting p53 transcriptional activity, resulting in the enhancement of telomerase activity. (PMID:24412852)
• these findings suggested that PinX1 may maintain telomere integrity by regulating TRF1 stability and that hTERT may act as both a positive and a negative regulator of TRF1 homeostasis in a PinX1-dependent manner. (PMID:24415760)
• These results confirmed the role of PinX1 as a major tumor suppressor gene in breast cancer cell lines. (PMID:24672800)
• The results suggest that activation of Prp43p by Gno1p/PINX1 within early pre-ribosomal particles is crucial for their subsequent maturation. (PMID:24823796)
• Data confirmed that levels of PinX1 and caspase 3, 8 and 9 expression were closely linked to the poor prognosis of colorectal cancer. (PMID:24839934)
• the expression of PinX1 in CSCC patients is likely a predictor of the response to paclitaxel chemotherapy. (PMID:25045845)
• PinX1 inhibits cell proliferation, migration and invasion in glioma cells. (PMID:25698538)
• Two novel markers, rs7840785 (PINX1) and rs7844465 (ZHX2), are significantly associated with carotid intima-media thickness. (PMID:25746325)
• PinX1 expression was an independent negative prognostic factor for breast cancer patients. (PMID:25888829)
• PinX1 negatively regulated ccRCC metastasis and the expression of MMP-2 and NF-kappaB-p65 (PMID:26033551)
• Data show a novel molecular mechanism for PINX1 as an attenuator of estrogen receptor activity in breast cancer cell lines, furthering its role as a tumor suppressor gene in breast cancer. (PMID:26187699)
• The stability of PinX1 is maintained in nucleolus in the presence of TERT. (PMID:26194824)
• PinX1 protein expression is decreased in colorectal cancer patients and predicts a poor prognosis. (PMID:26211574)
• High PinX1 expression significantly correlated with a worse 5-year overall and disease-specific survival in gliomas. (PMID:26261583)
• PINX1 Polymorphisms are associated with Hepatocellular Carcinoma in Thai Patients with Chronic Hepatitis B Virus Infection. (PMID:27221889)
• The cost-effective expression of PinX1 could constitute a novel molecular predictor/marker for NSCLC management. (PMID:28372542)
• Low expression of PinX1 is associated with malignant behavior in basal-like breast cancer. (PMID:28586040)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pinx1	ENSDARG00000023532
mus_musculus	Pinx1	ENSMUSG00000021958
rattus_norvegicus	Pinx1	ENSRNOG00000012012
drosophila_melanogaster	CG11180	FBGN0034528
caenorhabditis_elegans		WBGENE00011966

Paralogs (1): GPATCH4 (ENSG00000160818)

Protein

Protein identifiers

PIN2/TERF1-interacting telomerase inhibitor 1 — Q96BK5 (reviewed: Q96BK5)

Alternative names: Liver-related putative tumor suppressor, Pin2-interacting protein X1, Protein 67-11-3, TRF1-interacting protein 1

All UniProt accessions (4): E5RGR1, E5RJG9, Q96BK5, H0YBF0

UniProt curated annotations — full annotation on UniProt →

Function. Microtubule-binding protein essential for faithful chromosome segregation. Mediates TRF1 and TERT accumulation in nucleolus and enhances TRF1 binding to telomeres. Inhibits telomerase activity. May inhibit cell proliferation and act as tumor suppressor.

Subunit / interactions. Interacts with MCRS1, TERT, TERF1, NCL/nucleolin, and the telomerase RNA.

Subcellular location. Nucleus. Nucleolus. Chromosome. Telomere. Centromere. Kinetochore.

Tissue specificity. Ubiquitous; expressed at low levels. Not detectable in a number of hepatocarcinoma cell lines.

Post-translational modifications. Cleaved by enterovirus protease 3C to promote apoptosis.

Domain organisation. The TID (telomerase inhibiting domain) domain is sufficient to bind TERT and inhibit its activity. The TBM domain mediates interaction with TERF1.

Similarity. Belongs to the PINX1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96BK5-1	1	yes
Q96BK5-2	2, PINY1

RefSeq proteins (2): NP_001271285, NP_060354* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000467	G_patch_dom	Domain
IPR050656	PINX1	Family

Pfam: PF01585

UniProt features (28 total): sequence variant 5, sequence conflict 5, region of interest 4, mutagenesis site 3, compositionally biased region 3, modified residue 2, splice variant 2, chain 1, domain 1, site 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96BK5-F1	65.13	0.12

Functional residue map

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

Catalytic / active sites (1): 50–51 ((microbial infection) cleavage by enterovirus 71 protease 3c)

Post-translational modifications (2): 270, 273

Mutagenesis-validated functional residues (3):

Position	Phenotype
50	abolishes cleavage by enterovirus 71.
291	abolishes interaction with terf1.
293	does not affect interaction with terf1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 171 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_TELOMERE_MAINTENANCE_VIA_TELOMERASE, PID_TELOMERASE_PATHWAY, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_CHROMOSOME_LOCALIZATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING, GOBP_TELOMERE_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_CELL_CYCLE_G2_M_PHASE_TRANSITION, GOBP_REGULATION_OF_TELOMERE_MAINTENANCE

GO Biological Process (11): telomere maintenance via telomerase (GO:0007004), mitotic metaphase chromosome alignment (GO:0007080), negative regulation of cell population proliferation (GO:0008285), negative regulation of G2/M transition of mitotic cell cycle (GO:0010972), negative regulation of protein ubiquitination (GO:0031397), regulation of protein stability (GO:0031647), negative regulation of telomere maintenance via telomerase (GO:0032211), protein localization to chromosome, telomeric region (GO:0070198), protein localization to nucleolus (GO:1902570), negative regulation of telomere maintenance via telomere lengthening (GO:1904357), positive regulation of protein localization to nucleolus (GO:1904751)

GO Molecular Function (5): telomerase inhibitor activity (GO:0010521), protein-containing complex binding (GO:0044877), telomerase RNA binding (GO:0070034), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (10): nuclear chromosome (GO:0000228), kinetochore (GO:0000776), chromosome, telomeric region (GO:0000781), nucleoplasm (GO:0005654), nucleolus (GO:0005730), mitochondrion (GO:0005739), spindle (GO:0005819), chromosome, centromeric region (GO:0000775), nucleus (GO:0005634), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membraneless organelle	4
binding	3
nuclear lumen	3
telomerase activity	2
telomere maintenance via telomere lengthening	2
chromosomal region	2
intracellular membrane-bounded organelle	2
RNA-templated DNA biosynthetic process	1
telomere-telomerase complex assembly	1
mitotic sister chromatid segregation	1
mitotic cell cycle	1
metaphase chromosome alignment	1
mitotic cell cycle process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
G2/M transition of mitotic cell cycle	1
regulation of G2/M transition of mitotic cell cycle	1
negative regulation of mitotic cell cycle phase transition	1
negative regulation of cell cycle G2/M phase transition	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
regulation of biological quality	1
telomere maintenance via telomerase	1
regulation of telomere maintenance via telomerase	1
negative regulation of telomere maintenance via telomere lengthening	1
negative regulation of DNA biosynthetic process	1
protein localization to chromosome	1
protein localization to nucleus	1
negative regulation of telomere maintenance	1
regulation of telomere maintenance via telomere lengthening	1
positive regulation of protein localization to nucleus	1
protein localization to nucleolus	1
regulation of protein localization to nucleolus	1
enzyme inhibitor activity	1
RNA binding	1
nucleus	1
chromosome	1
condensed chromosome, centromeric region	1

Protein interactions and networks

STRING

1088 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PINX1	TERF1	P54274	771
PINX1	POT1	Q9NUX5	647
PINX1	TINF2	Q9BSI4	475
PINX1	ACD	Q96AP0	430
PINX1	GAD1	Q99259	414
PINX1	TEP1	Q99973	350
PINX1	DHX15	O43143	333
PINX1	TERT	O14746	289
PINX1	TERF2	Q15554	279
PINX1	ZFYVE21	Q9BQ24	275
PINX1	ECT2L	Q008S8	266
PINX1	SERTAD1	Q9UHV2	266
PINX1	SINHCAF	Q9NP50	256
PINX1	NXPH4	O95158	251
PINX1	CIAO2B	Q9Y3D0	249

IntAct

233 interactions, top by confidence:

A	B	Type	Score
TERF1	PINX1	psi-mi:“MI:0915”(physical association)	0.880
EAF1	ELL2	psi-mi:“MI:0914”(association)	0.840
PINX1	NPM1	psi-mi:“MI:0915”(physical association)	0.810
PINX1	NPM1	psi-mi:“MI:0407”(direct interaction)	0.810
PINX1	NPM1	psi-mi:“MI:0403”(colocalization)	0.810
PINX1	NPM1	psi-mi:“MI:0914”(association)	0.810
PINX1	TERT	psi-mi:“MI:0914”(association)	0.680
PINX1	TERT	psi-mi:“MI:0915”(physical association)	0.680
AIDA	PINX1	psi-mi:“MI:0915”(physical association)	0.670
NPM1	TERT	psi-mi:“MI:0914”(association)	0.580
TERT	NPM1	psi-mi:“MI:0914”(association)	0.580
MFAP1	PINX1	psi-mi:“MI:0915”(physical association)	0.560
EIF1AD	PINX1	psi-mi:“MI:0915”(physical association)	0.560
TLK1	PINX1	psi-mi:“MI:0915”(physical association)	0.560
GYS1	PINX1	psi-mi:“MI:0915”(physical association)	0.560
PINX1	TLK1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (145): PINX1 (Affinity Capture-MS), PINX1 (Affinity Capture-MS), ALB (Affinity Capture-MS), FXR1 (Affinity Capture-MS), FAM98A (Affinity Capture-MS), PPP2R2D (Affinity Capture-MS), TERF1 (Affinity Capture-MS), PINX1 (Affinity Capture-Western), PINX1 (Affinity Capture-Western), DHX15 (Affinity Capture-Western), PINX1 (Reconstituted Complex), PINX1 (Reconstituted Complex), PINX1 (Proximity Label-MS), PINX1 (Proximity Label-MS), PINX1 (Affinity Capture-MS)

ESM2 similar proteins: A4L691, D3ZTQ1, O75151, O88271, P35689, Q07G43, Q08288, Q12872, Q14241, Q24K12, Q2KJE1, Q3KRF3, Q3TFK5, Q3USH5, Q4ADK4, Q4ADK7, Q4V842, Q566R3, Q5BJN8, Q5RET9, Q5T3I0, Q5U3K5, Q5ZJJ1, Q5ZK28, Q60FC2, Q63187, Q68FU8, Q6AYK5, Q6IQ49, Q6NRI5, Q6P859, Q6PFK1, Q75QI0, Q75UQ2, Q7T293, Q7TN31, Q7ZVC9, Q8CB77, Q8CIL4, Q8HXY9

Diamond homologs: A0JMV4, A4IGK4, A4L691, A5DSB5, B2GV05, P15771, P52756, P70501, P98175, Q0IIX9, Q17784, Q1RMU5, Q5ZII9, Q66J74, Q68FU8, Q6C233, Q6DDU9, Q7TN31, Q7TQC7, Q8CH02, Q8CH09, Q8IWZ8, Q8IX01, Q8N302, Q91YE7, Q94C11, Q96BK5, Q99KG3, Q9CZX5, Q9NW75, Q9UTK6, P78332, A4R0T9, A5DRH5, A5E4P1, A6R371, A6RIE1, A6ZUT6, A7EFS3, A7TG30

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PLK1	down-regulates	PINX1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 176 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
SARS-CoV-1 modulates host translation machinery	10	24.1×	2e-10
Eukaryotic Translation Initiation	9	21.7×	6e-09
Cap-dependent Translation Initiation	9	21.7×	6e-09
Peptide chain elongation	21	20.8×	2e-20
Viral mRNA Translation	21	20.8×	2e-20
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	21	20.6×	2e-20
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	22	20.2×	7e-21
Selenocysteine synthesis	21	19.7×	4e-20

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	21	24.1×	5e-21
maturation of SSU-rRNA	5	23.8×	2e-04
translation	26	16.6×	1e-21
ribosomal large subunit biogenesis	6	16.5×	2e-04
ribosomal small subunit biogenesis	11	15.6×	3e-08
mRNA transport	6	9.8×	3e-03
rRNA processing	10	8.8×	4e-05
mRNA splicing, via spliceosome	10	5.7×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	76
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
221719	GRCh37/hg19 8p23.1(chr8:8131816-12249050)x1	Pathogenic

SpliceAI

2706 predictions. Top by Δscore:

Variant	Effect	Δscore
8:10726662:CTTTC:C	acceptor_gain	1.0000
8:10726664:TTC:T	acceptor_gain	1.0000
8:10726665:TC:T	acceptor_gain	1.0000
8:10726666:CC:C	acceptor_gain	1.0000
8:10726672:C:CT	acceptor_gain	1.0000
8:10726674:C:CT	acceptor_gain	1.0000
8:10730190:A:AC	donor_gain	1.0000
8:10730191:C:CC	donor_gain	1.0000
8:10730191:CTCA:C	donor_gain	1.0000
8:10730194:A:AC	donor_gain	1.0000
8:10730194:AC:A	donor_gain	1.0000
8:10730195:C:CC	donor_gain	1.0000
8:10730195:CC:C	donor_gain	1.0000
8:10730195:CCCAG:C	donor_gain	1.0000
8:10765912:TCGCC:T	acceptor_gain	1.0000
8:10765913:CGCC:C	acceptor_gain	1.0000
8:10765913:CGCCC:C	acceptor_gain	1.0000
8:10765915:CC:C	acceptor_gain	1.0000
8:10765915:CCC:C	acceptor_loss	1.0000
8:10765916:CCTA:C	acceptor_gain	1.0000
8:10765917:C:CC	acceptor_gain	1.0000
8:10765917:CT:C	acceptor_loss	1.0000
8:10765919:A:C	acceptor_gain	1.0000
8:10765927:C:CT	acceptor_gain	1.0000
8:10826146:TCTTA:T	donor_loss	1.0000
8:10826147:CTTA:C	donor_loss	1.0000
8:10826147:CTTAC:C	donor_loss	1.0000
8:10826148:TTA:T	donor_loss	1.0000
8:10826149:TACC:T	donor_loss	1.0000
8:10826150:A:C	donor_loss	1.0000

AlphaMissense

2185 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:10834678:C:A	W39C	0.999
8:10834678:C:G	W39C	0.999
8:10834680:A:G	W39R	0.999
8:10834680:A:T	W39R	0.999
8:10826159:G:C	F129L	0.998
8:10826159:G:T	F129L	0.998
8:10826161:A:G	F129L	0.998
8:10834706:C:T	G30D	0.997
8:10831714:A:C	F84L	0.996
8:10831714:A:T	F84L	0.996
8:10831716:A:G	F84L	0.996
8:10834679:C:G	W39S	0.996
8:10834729:C:A	W22C	0.996
8:10834729:C:G	W22C	0.996
8:10834731:A:G	W22R	0.996
8:10834731:A:T	W22R	0.996
8:10831737:A:G	W77R	0.995
8:10831737:A:T	W77R	0.995
8:10832980:A:G	L45S	0.995
8:10834694:A:G	L34P	0.995
8:10826173:G:C	H125D	0.994
8:10832917:C:T	G66E	0.994
8:10820265:C:A	K133N	0.993
8:10820265:C:G	K133N	0.993
8:10826179:G:T	R123S	0.993
8:10832977:C:T	G46E	0.993
8:10834679:C:A	W39L	0.993
8:10831694:A:G	L91P	0.992
8:10831706:A:G	L87P	0.992
8:10831715:A:G	F84S	0.992

dbSNP variants (sampled 300 via entrez): RS1000011490 (8:10782613 G>A), RS1000017065 (8:10802608 T>G), RS1000037906 (8:10828180 T>C), RS1000055312 (8:10790417 C>A,T), RS1000077324 (8:10771257 G>T), RS1000080635 (8:10839159 G>A), RS1000100858 (8:10812946 T>A), RS1000134648 (8:10838910 C>G), RS1000143880 (8:10820490 T>C), RS1000219042 (8:10784422 T>A,G), RS1000252143 (8:10823221 G>A), RS1000259551 (8:10796939 A>G), RS1000307312 (8:10804658 G>A,C,T), RS1000331551 (8:10767334 A>G), RS1000359312 (8:10827125 G>A,T)

Disease associations

OMIM: gene MIM:606505 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): primary ovarian failure (MONDO:0005387), intellectual disability (MONDO:0001071)

Orphanet (2): NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

56 associations (top):

Study	Trait	p-value
GCST000758_12	Triglycerides	1.000000e-08
GCST000847_5	Retinal vascular caliber	4.000000e-07
GCST001231_7	Carotid intima media thickness	2.000000e-08
GCST002216_2	Triglycerides	3.000000e-11
GCST003103_2	Systemic lupus erythematosus	8.000000e-06
GCST003876_9	Gut microbiota (beta diversity)	5.000000e-08
GCST004237_8	Triglyceride levels	3.000000e-12
GCST004610_162	White blood cell count	2.000000e-13
GCST004627_42	Lymphocyte count	3.000000e-09
GCST006166_105	Diastolic blood pressure x alcohol consumption interaction (2df test)	2.000000e-14
GCST006166_70	Diastolic blood pressure x alcohol consumption interaction (2df test)	3.000000e-13
GCST006167_35	Mean arterial pressure x alcohol consumption interaction (2df test)	5.000000e-09
GCST006167_80	Mean arterial pressure x alcohol consumption interaction (2df test)	2.000000e-07
GCST006190_10	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-06
GCST006190_79	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	4.000000e-10
GCST006192_54	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-16
GCST006192_81	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-13
GCST006193_43	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	2.000000e-08
GCST006193_81	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-12
GCST006195_33	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-15
GCST006195_72	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	4.000000e-19
GCST006434_105	Systolic blood pressure x alcohol consumption interaction (2df test)	4.000000e-23
GCST006434_88	Systolic blood pressure x alcohol consumption interaction (2df test)	3.000000e-22
GCST006613_15	Triglycerides	1.000000e-19
GCST006867_66	Type 2 diabetes	6.000000e-10
GCST007324_18	Adventurousness	2.000000e-09
GCST007325_19	General risk tolerance (MTAG)	3.000000e-08
GCST007436_10	Carotid intima media thickness	7.000000e-12
GCST007556_1	Autism spectrum disorder	1.000000e-08
GCST007709_176	General factor of neuroticism	1.000000e-09

EFO canonical traits (19, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004731	eye measurement
EFO:0007874	gut microbiome measurement
EFO:0004587	lymphocyte count
EFO:0004329	alcohol drinking
EFO:0006336	diastolic blood pressure
EFO:0006340	mean arterial pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0008579	risk-taking behaviour
EFO:0007660	neuroticism measurement
EFO:0009863	anxiety measurement
EFO:0009930	Calcium channel blocker use measurement
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007789	BMI-adjusted waist circumference
EFO:0004736	aspartate aminotransferase measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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
Valproic Acid	decreases methylation, increases expression, affects expression	4
Cadmium Chloride	decreases expression, increases expression	2
FR900359	decreases phosphorylation	1
bisphenol A	affects cotreatment, decreases methylation	1
IMOL S-140	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1
Hydrogen Peroxide	affects expression	1
Methyl Methanesulfonate	increases expression	1
Ribonucleotides	affects binding	1
Silicon Dioxide	increases expression	1
Tobacco Smoke Pollution	increases expression	1

Clinical trials (associated diseases)

272 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
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
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
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF