APLN

Summary

APLN (apelin, HGNC:16665) is a protein-coding gene on chromosome Xq26.1, encoding Apelin (Q9ULZ1). Peptide hormone that functions as endogenous ligand for the G-protein-coupled apelin receptor (APLNR/APJ), that plays a role in cadiovascular homeostasis.

This gene encodes a peptide that functions as an endogenous ligand for the G-protein coupled apelin receptor. The encoded preproprotein is proteolytically processed into biologically active C-terminal peptide fragments. These peptide fragments activate different tissue specific signaling pathways that regulate diverse biological functions including fluid homeostasis, cardiovascular function and insulin secretion. This protein also functions as a coreceptor for the human immunodeficiency virus 1.

Source: NCBI Gene 8862 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 31 total — 2 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_017413

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16665
Approved symbol	APLN
Name	apelin
Location	Xq26.1
Locus type	gene with protein product
Status	Approved
Aliases	apelin, XNPEP2
Ensembl gene	ENSG00000171388
Ensembl biotype	protein_coding
OMIM	300297
Entrez	8862

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000429967, ENST00000865540

RefSeq mRNA: 1 — MANE Select: NM_017413 NM_017413

CCDS: CCDS48165

Canonical transcript exons

ENST00000429967 — 3 exons

Exon	Start	End
ENSE00001679471	129645259	129647917
ENSE00002277138	129654564	129654956
ENSE00003536029	129648621	129648792

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 89.88.

FANTOM5 (CAGE): breadth broad, TPM avg 15.2110 / max 1705.5151, expressed in 788 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200438	15.1598	787
200437	0.0512	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	89.88	gold quality
spinal cord	UBERON:0002240	89.66	gold quality
left ventricle myocardium	UBERON:0006566	88.93	gold quality
kidney epithelium	UBERON:0004819	88.40	gold quality
vena cava	UBERON:0004087	87.87	silver quality
substantia nigra	UBERON:0002038	87.12	gold quality
subthalamic nucleus	UBERON:0001906	86.96	gold quality
midbrain	UBERON:0001891	86.69	gold quality
cardiac muscle of right atrium	UBERON:0003379	86.23	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.85	gold quality
hypothalamus	UBERON:0001898	85.24	gold quality
pancreatic ductal cell	CL:0002079	85.04	silver quality
upper arm skin	UBERON:0004263	84.88	gold quality
lateral nuclear group of thalamus	UBERON:0002736	84.53	silver quality
dorsal plus ventral thalamus	UBERON:0001897	84.51	gold quality
amygdala	UBERON:0001876	83.86	gold quality
inferior vagus X ganglion	UBERON:0005363	83.31	gold quality
lateral globus pallidus	UBERON:0002476	82.99	silver quality
ventral tegmental area	UBERON:0002691	82.98	gold quality
substantia nigra pars compacta	UBERON:0001965	82.82	gold quality
medulla oblongata	UBERON:0001896	82.78	gold quality
pericardium	UBERON:0002407	82.42	silver quality
pons	UBERON:0000988	82.20	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.95	gold quality
substantia nigra pars reticulata	UBERON:0001966	81.50	silver quality
temporal lobe	UBERON:0001871	81.28	gold quality
Ammon’s horn	UBERON:0001954	81.18	gold quality
globus pallidus	UBERON:0001875	81.13	silver quality
saphenous vein	UBERON:0007318	80.98	gold quality
superior vestibular nucleus	UBERON:0007227	80.82	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.77

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
FGF2	Repression
FGFR1	Repression

Upstream regulators (CollecTRI, top): FOXC1, HIF1A, KLF5, PPARGC1A, RARA, SP1, STAT3, USF1

miRNA regulators (miRDB)

169 targeting APLN, 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-340-5P	100.00	72.50	4437
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057

Literature-anchored findings (GeneRIF, showing 40)

• Differential expression of apelin in patients with chronic heart failure. (PMID:12914775)
• Plasma level of apelin increased in patients with left ventricular dysfunction; apelin is localized primarily in the endothelium of the coronary arteries and is found at a higher concentration in cardiac tissue after mechanical offloading (PMID:12963638)
• reported the presence of APJ receptor-like immunoreactivity on cardiomyocytes, vascular smooth muscle cells and endothelial cells and the presence of apelin-like immunoreactivity in secretory vesicles of vascular endothelial cells (PMID:15664671)
• Insulin and obesity up-regulate apelin in adipocytes. (PMID:15677759)
• Apelin counteracts the effects of AVP in the maintenance of body fluid homeostasis. (PMID:16115460)
• Human osteoblasts express apelin and APJ and apelin enhances human osteoblast proliferation, but has no effect on osteoblast differentiation, and APJ/PI3 kinase/Akt pathway is involved in the proliferation response. (PMID:16563531)
• Apelin might be a candidate to understand potential links between obesity and associated disorders such as inflammation and insulin resistance. (PMID:16723381)
• The transcriptional regulation of human and rat apelin is reported. (PMID:17060400)
• apelin and APJ are expressed in preeclamptic placentas and may have a role in development of preeclampsia (PMID:17128405)
• potential link with pathogenesis of glucose resistance and type 2 diabetes. (PMID:17177135)
• Apelin and APJ expression is highly upregulated in microvascular proliferations of brain tumors such as malignant gliomas. (PMID:17412318)
• Immunohistochemistry was performed to investigate the expression and localization of apelin in normal human breast tissue and breast carcinoma. (PMID:17823846)
• The apelin-APJ pathway may thus provide a mechanism for systemic endothelial monitoring of tissue perfusion and adaptive regulation of cardiovascular function. (PMID:17906101)
• there is a relationship between plasma osmolality, plasma apelin and plasma AVP in various states of hydration (PMID:18272843)
• In conclusion, the ERK1/2, but not p38 MAPK pathway is activated by apelin-13 through coupling of human APJ to Gi2-protein, which contributes to cellular responses. (PMID:18401529)
• Dysregulation of apelin might be involved in the mechanism of establishment of overt diabetes mellitus as well as associated atherosclerotic complications. (PMID:18484561)
• Serum Apelin level changes in patients with severe sepsis and septic shock, which may provide clues in diagnosis and prognosis. (PMID:18505110)
• Hypoxia-inducible factor-1alpha knockdown abolishes hypoxia-induced apelin expression. (PMID:18617693)
• Both apelin isoforms caused reproducible vasodilation in forearm resistance vessels (p < 0.0001). (PMID:18772060)
• Human patients with liver cirrhosis show a marked increase in apelin levels. (PMID:18816630)
• LDL-cholesterol lowering increases plasma apelin in isolated hypercholesterolemia. (PMID:18845302)
• Reduced apelin levels are observed in a homogenous population of stable angina subjects; the plasma apelin level is negatively correlated with the degree of coronary stenosis. (PMID:19015606)
• Assessment of the association between apelin and coronary artery disease among kidney allograft recipients. (PMID:19100414)
• Nuclear magnetic resonance and circular dichroism spectroscopy results are presented for a variety of apelin peptides at both physiological and low temperatures allowing determination of the bioactive structure of apelin. (PMID:19123778)
• genetic variation within apelin and AGTRL1 likely contributes to essential hypertension, BMI and the onset age of hypertension (PMID:19307984)
• Plasma dimethylarginine and apelin levels are similar in type 2 diabetic paatients with and without diabetic retinopthy. (PMID:19344973)
• Hypoxia induces the expression of apelin gene. Overexpression of apelin clearly accelerates in vivo tumour growth, due to an increased number of vessels irrigating these tumours. Review. (PMID:19527631)
• APLN SNP rs2235306 was associated with fasting plasma glucose levels in males. It suggests that APLN genetic variants may contribute to clinical features related to glucose metabolism in Chinese population. (PMID:19567136)
• Data show that in cardiac tissue, the apelin peptides are among the most potent endogenous positive inotropic agents yet reported. (PMID:19597036)
• Untreated obstructive sleep apnea was associated with elevated plasma apelin levels, altered apelin secretory dynamics in response to oral glucose and lack of an apparent circadian variability. (PMID:19643928)
• Blood apelin level changes with lifestyle changes and in patients with type 2 diabetes. (PMID:19766342)
• Apelin is a recently identified peptide which plays an important role in cardiovascular function and in water metabolism–REVIEW (PMID:19804703)
• No association between circulating apelin levels and gestational diabetes (PMID:19926159)
• Plasma apelin levels are lower in newly diagnosed and untreated type 2 diabetic subjects than in healthy control subjects. (PMID:19940213)
• plasma apelin levels are not altered in nondiabetic and normotensive male subjects with nonalcoholic fatty liver disease (PMID:20045153)
• While apelin/APJ myocardial expression decreases, apelin plasma levels increase in left ventricular hypertrophy (PMID:20055692)
• Aortic valve stenosis is characterized by an up-regulation of the apelin-APJ signaling pathway. (PMID:20099713)
• The apelin/APJ system may be involved in retinal neovascularization during the development of proliferative diabetic retinopathy. (PMID:20220056)
• Our study indicates that genetic variation of APLN and ACE2 may influence BP response to potassium intake. (PMID:20224560)
• apelin concentrations decreased as a result of fat tissue depletion in patients with anorexia nervosa (PMID:20382684)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	apln	ENSDARG00000053279
mus_musculus	Apln	ENSMUSG00000037010
rattus_norvegicus	Apln	ENSRNOG00000003984

Protein

Protein identifiers

Apelin — Q9ULZ1 (reviewed: Q9ULZ1)

Alternative names: APJ endogenous ligand

All UniProt accessions (1): Q9ULZ1

UniProt curated annotations — full annotation on UniProt →

Function. Peptide hormone that functions as endogenous ligand for the G-protein-coupled apelin receptor (APLNR/APJ), that plays a role in cadiovascular homeostasis. Functions as a balanced agonist activating both G(i) protein pathway and beta-arrestin pathway of APLNR. Downstream G proteins activation, apelin can inhibit cAMP production and activate key intracellular effectors such as ERKs. On the other hand, APLNR activation induces beta-arrestin recruitment to the membrane leading to desensitization and internalization of the receptor. Apelin blunts cardiac hypertrophic induction from APLNR on response to pathological stimuli, but also induces myocardial hypertrophy under normal conditions. Apelin-36 dissociates more hardly than (pyroglu)apelin-13 from APLNR. Involved in the regulation of cardiac precursor cell movements during gastrulation and heart morphogenesis. Has an inhibitory effect on cytokine production in response to T-cell receptor/CD3 cross-linking; the oral intake of apelin in the colostrum and the milk might therefore modulate immune responses in neonates. Plays a role in early coronary blood vessels formation. Mediates myocardial contractility in an ERK1/2-dependent manner. May also have a role in the central control of body fluid homeostasis by influencing vasopressin release and drinking behavior. (Microbial infection) Endogenous ligand for the apelin receptor (APLNR), an alternative coreceptor with CD4 for HIV-1 infection. Inhibits HIV-1 entry in cells coexpressing CD4 and APLNR. Apelin-36 has a greater inhibitory activity on HIV infection than other synthetic apelin derivatives.

Subcellular location. Secreted. Extracellular space.

Tissue specificity. Expressed in the brain with highest levels in the frontal cortex, thalamus, hypothalamus and midbrain. Secreted by the mammary gland into the colostrum and the milk.

Post-translational modifications. Several active peptides may be produced by proteolytic processing of the peptide precursor.

Similarity. Belongs to the apelin family.

RefSeq proteins (1): NP_059109* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026155	Apelin	Family

Pfam: PF15360

UniProt features (11 total): peptide 4, site 2, signal peptide 1, propeptide 1, strand 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8XZH	ELECTRON MICROSCOPY	2.6
8XZJ	ELECTRON MICROSCOPY	3
8XQF	ELECTRON MICROSCOPY	3.13
8XZG	ELECTRON MICROSCOPY	3.2
8XQE	ELECTRON MICROSCOPY	3.48

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULZ1-F1	67.45	0.17

Antibody-complex structures (SAbDab): 4 — 8XQE, 8XQF, 8XZH, 8XZJ

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 (2): 75 (important for the balance between g(i) and beta-arrestin pathways induced by apelin-13-aplnr system); 77 (important for the balance between g(i) and beta-arrestin pathways induced by apelin-13-aplnr system)

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-418594	G alpha (i) signalling events
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 227 (showing top): GOBP_G_PROTEIN_COUPLED_RECEPTOR_INTERNALIZATION, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_BEHAVIOR, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_CORONARY_VASCULATURE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, CMYB_01, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS, GOBP_MUSCLE_CELL_PROLIFERATION, CAGCTG_AP4_Q5

GO Biological Process (32): angiogenesis (GO:0001525), regulation of the force of heart contraction (GO:0002026), negative regulation of systemic arterial blood pressure (GO:0003085), immune response (GO:0006955), signal transduction (GO:0007165), gastrulation (GO:0007369), lactation (GO:0007595), positive regulation of heart rate (GO:0010460), negative regulation of gene expression (GO:0010629), positive regulation of heat generation (GO:0031652), negative regulation of fibroblast growth factor receptor signaling pathway (GO:0040037), positive regulation of phosphorylation (GO:0042327), drinking behavior (GO:0042756), negative regulation of blood pressure (GO:0045776), positive regulation of heart contraction (GO:0045823), negative regulation of vasoconstriction (GO:0045906), positive regulation of corticotropin secretion (GO:0051461), positive regulation of corticotropin-releasing hormone secretion (GO:0051466), apelin receptor signaling pathway (GO:0060183), coronary vasculature development (GO:0060976), positive regulation of miRNA transcription (GO:1902895), positive regulation of G protein-coupled receptor internalization (GO:1904022), negative regulation of vascular associated smooth muscle cell proliferation (GO:1904706), positive regulation of vascular endothelial cell proliferation (GO:1905564), G protein-coupled receptor internalization (GO:0002031), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), feeding behavior (GO:0007631), positive regulation of cell population proliferation (GO:0008284), positive regulation of cardiac muscle hypertrophy (GO:0010613), regulation of body fluid levels (GO:0050878), negative regulation of cardiac muscle hypertrophy in response to stress (GO:1903243), positive regulation of cardiac muscle hypertrophy in response to stress (GO:1903244)

GO Molecular Function (4): signaling receptor binding (GO:0005102), hormone activity (GO:0005179), apelin receptor binding (GO:0031704), identical protein binding (GO:0042802)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by GPCR	2
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1
Signal Transduction	1
GPCR ligand binding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of heart contraction	2
positive regulation of multicellular organismal process	2
positive regulation of peptide hormone secretion	2
protein binding	2
cellular anatomical structure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
regulation of biological quality	1
regulation of systemic arterial blood pressure	1
negative regulation of blood pressure	1
immune system process	1
response to stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ectoderm formation	1
endoderm formation	1
mesoderm formation	1
embryonic morphogenesis	1
body fluid secretion	1
mammary gland development	1
milk ejection reflex	1
regulation of heart rate	1
positive regulation of heart contraction	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
heat generation	1
regulation of heat generation	1
fibroblast growth factor receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of fibroblast growth factor receptor signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
phosphorylation	1
regulation of phosphorylation	1
positive regulation of phosphate metabolic process	1
feeding behavior	1
regulation of blood pressure	1

Protein interactions and networks

STRING

1202 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APLN	APLNR	P35414	999
APLN	APELA	P0DMC3	859
APLN	ACE2	Q9BYF1	785
APLN	RARRES2	Q99969	760
APLN	INS	P01308	739
APLN	NAMPT	P43490	723
APLN	KNG1	P01042	720
APLN	RETN	Q9HD89	715
APLN	SERPINA12	Q8IW75	712
APLN	GHRL	Q9UBU3	708
APLN	REN	P00797	705
APLN	ADIPOQ	Q15848	699
APLN	RETNLB	Q9BQ08	697
APLN	ITLN1	Q8WWA0	697
APLN	NTS	P30990	689

IntAct

3 interactions, top by confidence:

A	B	Type	Score
MDFI	APLN	psi-mi:“MI:0915”(physical association)	0.490

BioGRID (8): APLN (Two-hybrid), APLN (Two-hybrid), RBPMS (Two-hybrid), APLN (Two-hybrid), APLN (Two-hybrid), APLN (Two-hybrid), MDFI (Two-hybrid), APLN (Reconstituted Complex)

ESM2 similar proteins: A0A679PF76, A5LHG2, D2HJ50, D5J9S0, F5CPE8, P01172, P01286, P02822, P07480, P09681, P09916, P0DJK0, P0DJK1, P0DW25, P10683, P11242, P13207, P16043, P17640, P20800, P22389, P22466, P23943, P33745, P45644, P47212, P48143, P48756, P51694, P58844, P79799, P83228, Q06145, Q1RMJ9, Q5NRP8, Q5NRQ0, Q60549, Q62949, Q6DJ00, Q765Z5

Diamond homologs: Q4TTN8, Q9R0R3, Q9R0R4, Q9TUI9, Q9ULZ1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ACE2	“up-regulates activity”	APLN	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	17
Likely benign	1
Benign	5

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3245284	NC_000023.10:g.(?128674417)(128975921_?)del	Pathogenic
442724	GRCh37/hg19 Xp22.33-q28(chrX:168547-151304063)x1	Pathogenic
625854	GRCh37/hg19 Xq25-28(chrX:122757437-155208244)x1	Likely pathogenic

SpliceAI

354 predictions. Top by Δscore:

Variant	Effect	Δscore
X:129648690:C:A	donor_gain	0.9900
X:129648712:T:TA	donor_gain	0.9900
X:129648716:TG:T	donor_gain	0.9900
X:129648791:CC:C	acceptor_gain	0.9900
X:129648792:CC:C	acceptor_gain	0.9900
X:129654559:CTCA:C	donor_loss	0.9900
X:129654560:TCA:T	donor_loss	0.9900
X:129654561:CAC:C	donor_loss	0.9900
X:129648789:GACCC:G	acceptor_loss	0.9700
X:129648792:CCTGC:C	acceptor_loss	0.9700
X:129648793:C:G	acceptor_loss	0.9700
X:129648794:T:A	acceptor_loss	0.9700
X:129654558:ACTC:A	donor_loss	0.9700
X:129654557:CACT:C	donor_loss	0.9600
X:129654563:CCT:C	donor_gain	0.9600
X:129648642:C:A	donor_gain	0.9500
X:129651457:C:CC	acceptor_gain	0.9400
X:129652087:C:A	donor_gain	0.9400
X:129654562:A:AC	donor_gain	0.9400
X:129654562:ACCT:A	donor_gain	0.9400
X:129654563:C:CC	donor_gain	0.9400
X:129654563:CCTC:C	donor_gain	0.9400
X:129648795:G:C	acceptor_loss	0.9300
X:129648793:C:CC	acceptor_gain	0.9200
X:129648729:TG:T	donor_gain	0.9000
X:129648789:GACC:G	acceptor_gain	0.8900
X:129648715:TTG:T	donor_gain	0.8700
X:129650510:C:A	donor_gain	0.8600
X:129651456:A:AC	acceptor_gain	0.8600
X:129648616:AGTAC:A	donor_loss	0.8500

AlphaMissense

481 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:129648629:G:C	F77L	0.995
X:129648629:G:T	F77L	0.995
X:129648631:A:G	F77L	0.995
X:129648644:C:A	K72N	0.989
X:129648644:C:G	K72N	0.989
X:129648630:A:C	F77C	0.987
X:129648630:A:G	F77S	0.982
X:129648636:A:G	M75T	0.982
X:129648631:A:T	F77I	0.978
X:129648645:T:A	K72M	0.977
X:129648635:C:A	M75I	0.976
X:129648635:C:G	M75I	0.976
X:129648635:C:T	M75I	0.976
X:129648658:G:T	R68S	0.969
X:129648631:A:C	F77V	0.965
X:129648654:A:T	L69H	0.965
X:129648670:G:T	R64S	0.964
X:129648645:T:G	K72T	0.962
X:129648646:T:C	K72E	0.962
X:129648651:G:A	S70F	0.962
X:129648633:G:T	P76H	0.959
X:129648647:A:C	H71Q	0.956
X:129648647:A:T	H71Q	0.956
X:129648649:G:C	H71D	0.956
X:129648643:C:G	G73R	0.955
X:129648643:C:T	G73R	0.955
X:129654591:A:G	W14R	0.949
X:129654591:A:T	W14R	0.949
X:129648651:G:T	S70Y	0.947
X:129648646:T:G	K72Q	0.943

dbSNP variants (sampled 300 via entrez): RS1000142682 (X:129648152 T>A), RS1001112198 (X:129650518 C>T), RS1001143158 (X:129650029 T>G), RS1001302729 (X:129647225 G>A), RS1002128204 (X:129644813 C>T), RS1002192292 (X:129652832 T>C,G), RS1002264532 (X:129652359 T>A), RS1002797504 (X:129648265 C>T), RS1003049253 (X:129655066 C>A,T), RS1003150261 (X:129654728 T>A), RS1003192018 (X:129655040 G>A,T), RS1003266114 (X:129654651 G>A,T), RS1005472872 (X:129644854 T>C), RS1005560763 (X:129649969 G>C), RS1005640167 (X:129646127 C>T)

Disease associations

OMIM: gene MIM:300297 | disease phenotypes: MIM:309000, MIM:300799

GenCC curated gene-disease

Mondo (4): oculocerebrorenal syndrome (MONDO:0010645), syndromic X-linked intellectual disability Raymond type (MONDO:0010427), intellectual disability (MONDO:0001071), premature menopause (MONDO:0001119)

Orphanet (2): Oculocerebrorenal syndrome of Lowe (Orphanet:534), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
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
D009800	Oculocerebrorenal Syndrome	C10.228.140.163.100.640; C12.050.351.968.419.815.720; C12.200.777.419.815.720; C12.950.419.815.720; C16.131.077.662; C16.320.322.750; C16.320.565.151.600; C16.320.565.189.640; C16.320.709; C16.320.831.750; C18.452.132.100.640; C18.452.648.151.600; C18.452.648.189.640

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases reaction, increases expression, decreases expression, increases secretion, affects reaction	3
Estradiol	affects cotreatment, decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
sotorasib	affects cotreatment, decreases expression	1
methylmercuric chloride	increases expression	1
oxybenzone	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	increases expression, increases secretion	1
tetrachlorodian	increases expression, increases secretion	1
cobalt oxide	increases expression	1
entinostat	decreases expression	1
2-chloro-5-nitrobenzanilide	decreases reaction, increases expression	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Catechin	affects cotreatment, increases expression	1
Dexamethasone	decreases expression	1
Methotrexate	decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Oxygen	increases expression	1
Paraquat	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Polystyrenes	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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
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
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT07410455	PHASE2	NOT_YET_RECRUITING	An Open-label, Phase 2 Pilot Study on the Efficacy and Safety of Piclidenoson in Patients With Lowe Syndrome
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
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
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)
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
NCT00359515	Not specified	COMPLETED	Genetic Analysis of Oculocerebrorenal Syndrome of Lowe
NCT01314560	Not specified	COMPLETED	Study of the Pathophysiological Mechanisms Involved in Bleeding Events
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02780297	Not specified	RECRUITING	Prospective Research Rare Kidney Stones (ProRKS)
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome