MAGEL2

Summary

MAGEL2 (MAGE family member L2, HGNC:6814) is a protein-coding gene on chromosome 15q11.2, encoding MAGE-like protein 2 (Q9UJ55). Probably enhances ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases, possibly through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex.

Prader-Willi syndrome (PWS) is caused by the loss of expression of imprinted genes in chromosome 15q11-q13 region. Affected individuals exhibit neonatal hypotonia, developmental delay, and childhood-onset obesity. Necdin (NDN), a gene involved in the terminal differentiation of neurons, localizes to this region of the genome and has been implicated as one of the genes responsible for the etiology of PWS. This gene is structurally similar to NDN, is also localized to the PWS chromosomal region, and is paternally imprinted, suggesting a possible role for it in PWS.

Source: NCBI Gene 54551 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Schaaf-Yang syndrome (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 1,367 total — 44 pathogenic, 44 likely-pathogenic
• Phenotypes (HPO): 194
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_019066

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6814
Approved symbol	MAGEL2
Name	MAGE family member L2
Location	15q11.2
Locus type	gene with protein product
Status	Approved
Aliases	nM15
Ensembl gene	ENSG00000254585
Ensembl biotype	protein_coding
OMIM	605283
Entrez	54551

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000650528

RefSeq mRNA: 1 — MANE Select: NM_019066 NM_019066

CCDS: CCDS73700

Canonical transcript exons

ENST00000650528 — 1 exons

Exon	Start	End
ENSE00003833977	23643549	23647867

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 86.27.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3036 / max 48.5664, expressed in 354 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
148995	1.1343	346
148996	0.1693	109

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	86.27	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.88	gold quality
hypothalamus	UBERON:0001898	77.82	gold quality
Brodmann (1909) area 23	UBERON:0013554	75.92	silver quality
endothelial cell	CL:0000115	75.77	silver quality
middle temporal gyrus	UBERON:0002771	75.26	silver quality
tibia	UBERON:0000979	75.18	silver quality
pituitary gland	UBERON:0000007	73.83	gold quality
adenohypophysis	UBERON:0002196	72.59	gold quality
islet of Langerhans	UBERON:0000006	72.31	gold quality
nucleus accumbens	UBERON:0001882	72.14	gold quality
postcentral gyrus	UBERON:0002581	70.64	silver quality
primary visual cortex	UBERON:0002436	70.02	gold quality
superior frontal gyrus	UBERON:0002661	69.50	gold quality
prefrontal cortex	UBERON:0000451	69.01	gold quality
ventricular zone	UBERON:0003053	68.90	gold quality
entorhinal cortex	UBERON:0002728	68.47	silver quality
cortical plate	UBERON:0005343	68.19	gold quality
ganglionic eminence	UBERON:0004023	67.91	gold quality
parietal lobe	UBERON:0001872	67.50	silver quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	67.15	silver quality
Brodmann (1909) area 46	UBERON:0006483	66.90	silver quality
frontal cortex	UBERON:0001870	66.50	gold quality
neocortex	UBERON:0001950	66.24	gold quality
cartilage tissue	UBERON:0002418	66.07	silver quality
forebrain	UBERON:0001890	65.86	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	65.82	gold quality
cerebral cortex	UBERON:0000956	65.52	gold quality
occipital lobe	UBERON:0002021	65.35	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	408.67
E-ANND-3	no	1.29

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting MAGEL2, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-96-5P	99.95	72.80	2140
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-548L	99.06	70.90	2560
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-4733-3P	98.35	65.20	994
HSA-MIR-4773	98.35	67.30	1710

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 18)

• MAGEL2 gene is imprinted, with preferential expression from the paternal allele. (PMID:10556298)
• Results suggest that MAGEL2 may not play a role in the pathophysiology of schizophrenia and mood disorders in the Japanese population. (PMID:20467835)
• These findings provide a cellular and molecular function for MAGE-L2-TRIM27 in retrograde transport, including an unappreciated role of K63-linked ubiquitination and identification of an activating signal of the WASH regulatory complex. (PMID:23452853)
• MAGEL2 is a new gene causing complex autism spectrum disorder and MAGEL2 loss of function can contribute to several aspects of the Prader-Willi syndrome phenotype. (PMID:24076603)
• A similar progressive loss of leptin sensitivity caused by loss of MAGEL2 in children with Prader-Willi syndrome could explain the delayed onset of increased appetite and weight gain in this complex disorder. (PMID:25926624)
• Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis. (PMID:26365340)
• This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families (PMID:27195816)
• Genes encoding MAGEL2 partners, either in the retrograde transport or in the ubiquitination-deubiquitination complexes, are promising candidates as Opitz trigonocephaly C syndrome -causing genes. (PMID:28281571)
• the single-nucleotide polymorphism rs850807, which is putatively functional and linked with MAGEL2 and NDN Genetic variation in rs850807 was strongly and exclusively associated with the ideas of reference subscale of the schizophrenia spectrum, which is best typified as paranoia (PMID:29343559)
• We report on first two unrelated patients of Polish descent with Schaaf-Yang syndrome caused by de-novo intragenic mutations in the MAGEL2 gene, identified by next-generation sequencing (PMID:29389715)
• hitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2-related disorders is expanded to include growth hormone deficiency as an important and treatable complication. (PMID:29599419)
• a mutation, c.1996delC on the maternal imprinted gene MAGEL2 that was carried by the affected fetus and husband, leading to Schaaf-Yang syndrome. (PMID:31114935)
• MAGEL2-related disorders: A study and case series. (PMID:31397880)
• We report MAGEL2 and L1CAM mutations in four pedigrees with variable Congenital hypopituitarism and arthrogryposis. Human embryonic expression analysis revealed MAGEL2 transcripts in the developing hypothalamus and ventral diencephalon at Carnegie stages (CSs) 19, 20, and 23 and in the Rathke pouch at CS20 and CS23. L1CAM was expressed in the developing hypothalamus, ventral diencephalon, and hindbrain (CS19, CS20, CS23). (PMID:31504653)
• Loss of MAGEL2 in Prader-Willi syndrome leads to decreased secretory granule and neuropeptide production. (PMID:32879135)
• Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2. (PMID:36243518)
• Magel2 truncation alters select behavioral and physiological outcomes in a rat model of Schaaf-Yang syndrome. (PMID:36637363)
• Truncated variants of MAGEL2 are involved in the etiologies of the Schaaf-Yang and Prader-Willi syndromes. (PMID:38908375)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndnl2	ENSDARG00000058212
mus_musculus	Magel2	ENSMUSG00000056972
rattus_norvegicus	Magel2	ENSRNOG00000010158
drosophila_melanogaster	MAGE	FBGN0037481

Paralogs (37): MAGEC2 (ENSG00000046774), TRO (ENSG00000067445), MAGEB2 (ENSG00000099399), MAGED2 (ENSG00000102316), MAGEB4 (ENSG00000120289), MAGEA9 (ENSG00000123584), MAGEA10 (ENSG00000124260), MAGEA4 (ENSG00000147381), MAGED4 (ENSG00000154545), MAGEC1 (ENSG00000155495), MAGEA8 (ENSG00000156009), MAGEC3 (ENSG00000165509), MAGEB6 (ENSG00000176746), MAGEB18 (ENSG00000176774), MAGEF1 (ENSG00000177383), MAGEB10 (ENSG00000177689), MAGED1 (ENSG00000179222), NDN (ENSG00000182636), MAGEB17 (ENSG00000182798), MAGEA2B (ENSG00000183305), NSMCE3 (ENSG00000185115), MAGEA11 (ENSG00000185247), MAGEE2 (ENSG00000186675), MAGED4B (ENSG00000187243), MAGEH1 (ENSG00000187601), MAGEB5 (ENSG00000188408), MAGEB16 (ENSG00000189023), MAGEA6 (ENSG00000197172), MAGEA1 (ENSG00000198681), MAGEB3 (ENSG00000198798), MAGEE1 (ENSG00000198934), MAGEA12 (ENSG00000213401), MAGEB1 (ENSG00000214107), MAGEA3 (ENSG00000221867), MAGEB6B (ENSG00000232030), MAGEA9B (ENSG00000267978), MAGEA2 (ENSG00000268606)

Protein

Protein identifiers

MAGE-like protein 2 — Q9UJ55 (reviewed: Q9UJ55)

Alternative names: Necdin-like protein 1, Protein nM15

All UniProt accessions (1): Q9UJ55

UniProt curated annotations — full annotation on UniProt →

Function. Probably enhances ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases, possibly through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex. Acts as a regulator of retrograde transport via its interaction with VPS35. Recruited to retromer-containing endosomes and promotes the formation of ‘Lys-63’-linked polyubiquitin chains at ‘Lys-220’ of WASHC1 together with TRIM27, leading to promote endosomal F-actin assembly. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer. Significantly promotes the cytoplasmic accumulation of CLOCK.

Subunit / interactions. Part of a complex consisting of MAGEL2, TRIM27 and USP7; directly interacts with USP7. Interacts with TRIM27. Interacts with VPS35; leading to recruitment at retromer-containing endosomes. Interacts with BMAL1 and PER2.

Subcellular location. Early endosome. Cytoplasm. Nucleus.

Tissue specificity. Expressed in placenta, fetal and adult brain. Not detected in heart and small intestine, very low levels in fibroblasts. Not expressed in brain of a Prader-Willi patient.

Disease relevance. Schaaf-Yang syndrome (SHFYNG) [MIM:615547] A disease characterized by clinical features of Prader-Willi syndrome, including neonatal hypotonia with poor suck, feeding problems in infancy, obesity, developmental delay, short stature, and hypogonadism. Additionally, patients manifest autism spectrum disorder. Some patients have dysmorphic facial features. The disease is caused by variants affecting the gene represented in this entry. All mutations occurred on the paternal allele.

Miscellaneous. Imprinted, expressed from the paternal chromosome only.

RefSeq proteins (1): NP_061939* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002190	MHD_dom	Domain
IPR037445	MAGE	Family
IPR041898	MAGE_WH1	Homologous_superfamily
IPR041899	MAGE_WH2	Homologous_superfamily

Pfam: PF01454

UniProt features (28 total): compositionally biased region 15, region of interest 11, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UJ55-F1	44.28	0.09

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 481 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_REGULATION_OF_ACTIN_NUCLEATION, FISCHER_G1_S_CELL_CYCLE, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, chr15q11, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_REGULATION_OF_CIRCADIAN_RHYTHM, GOBP_POSITIVE_REGULATION_OF_ACTIN_NUCLEATION, GOBP_ACTIN_FILAMENT_ORGANIZATION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, GUO_HEX_TARGETS_UP, TGGNNNNNNKCCAR_UNKNOWN, GOBP_PROTEIN_K63_LINKED_UBIQUITINATION

GO Biological Process (8): negative regulation of transcription by RNA polymerase II (GO:0000122), Arp2/3 complex-mediated actin nucleation (GO:0034314), retrograde transport, endosome to Golgi (GO:0042147), regulation of circadian rhythm (GO:0042752), negative regulation of DNA-templated transcription (GO:0045892), rhythmic process (GO:0048511), positive regulation of actin nucleation (GO:0051127), protein K63-linked ubiquitination (GO:0070534)

GO Molecular Function (2): ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), endosome (GO:0005768), early endosome (GO:0005769), cytosol (GO:0005829), cytoplasm (GO:0005737), retromer complex (GO:0030904)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
actin nucleation	2
endomembrane system	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
intercellular transport	1
endosomal transport	1
cytosolic transport	1
circadian rhythm	1
regulation of biological process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
biological_process	1
regulation of actin nucleation	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
protein polyubiquitination	1
ubiquitin-like protein transferase activity	1
binding	1
intracellular membrane-bounded organelle	1
cytoplasmic vesicle	1
endosome	1
cytoplasm	1
intracellular anatomical structure	1
membrane protein complex	1

Protein interactions and networks

STRING

890 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAGEL2	NPAP1	Q9NZP6	955
MAGEL2	TRIM27	P14373	950
MAGEL2	MKRN3	Q13064	942
MAGEL2	SNRPN	P14648	922
MAGEL2	USP7	Q93009	905
MAGEL2	ATP10A	O60312	853
MAGEL2	OXT	P01178	785
MAGEL2	CSAG1	Q6PB30	726
MAGEL2	UBE3A	P78355	716
MAGEL2	NPAS4	Q8IUM7	652
MAGEL2	OCA2	Q04671	637
MAGEL2	TUBGCP5	Q96RT8	625
MAGEL2	SNURF	Q9Y675	603
MAGEL2	NIPA1	Q7RTP0	596
MAGEL2	GNRH1	P01148	588

IntAct

18 interactions, top by confidence:

A	B	Type	Score
USP7	TRIM27	psi-mi:“MI:0915”(physical association)	0.810
USP7	MAGEL2	psi-mi:“MI:0915”(physical association)	0.660
MAGEL2	USP7	psi-mi:“MI:0915”(physical association)	0.660
MAGEL2	USP7	psi-mi:“MI:0407”(direct interaction)	0.660
TRIM27	MAGEL2	psi-mi:“MI:0915”(physical association)	0.640
MAGEL2	TRIM27	psi-mi:“MI:0914”(association)	0.640
MAGEL2	TRIM27	psi-mi:“MI:0915”(physical association)	0.640
MAGEL2	SUFU	psi-mi:“MI:0915”(physical association)	0.560
FHL2	MAGEL2	psi-mi:“MI:0915”(physical association)	0.560
AP2B1	MAGEL2	psi-mi:“MI:0407”(direct interaction)	0.440
FYN	MYCBP2	psi-mi:“MI:0914”(association)	0.350
SUFU	MAGEL2	psi-mi:“MI:0915”(physical association)	0.000
FHL2	MAGEL2	psi-mi:“MI:0915”(physical association)	0.000

ESM2 similar proteins: A0A1B0GUW6, A1EGX6, A4FU49, A6NJ88, A6QP92, E9PAV3, E9Q0C6, F1QU13, O94854, P18583, P24587, P27546, P27816, P36225, P43597, P70670, Q08DY0, Q2T9N0, Q32L62, Q4R729, Q4V7A4, Q5H9T9, Q5M7W5, Q5SWP3, Q5XHX6, Q5XPK0, Q659K0, Q68DN1, Q68FX6, Q69ZZ9, Q6AZ54, Q6P6B1, Q6ZRG5, Q70KF4, Q710D7, Q810T2, Q8K4E0, Q8N3K9, Q8TCU4, Q8WWL7

Diamond homologs: A0A0J9YX57, A1A5P9, A2A368, A2A9R3, A6NCF6, A6QLI5, A8MXT2, O15479, O15480, O15481, O60732, P25233, P43355, P43356, P43357, P43358, P43360, P43361, P43362, P43363, P43364, P43365, P43366, Q12816, Q4R998, Q5PPP4, Q5RFC2, Q6AY37, Q6ITT4, Q6PCZ4, Q8BQR7, Q8N7X4, Q8TD90, Q8TD91, Q96JG8, Q96LZ2, Q96M61, Q96MG7, Q99608, Q9BE18

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
MAGEL2	“up-regulates activity”	TRIM27	binding
MAGEL2	“up-regulates activity”	WASHC1	binding
CLOCK	“down-regulates activity”	MAGEL2	binding
ARNTL	“down-regulates activity”	MAGEL2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1367 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	44
Uncertain significance	918
Likely benign	209
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065480	NM_019066.5(MAGEL2):c.277C>T (p.Pro93Ser)	Pathogenic
1071043	NM_019066.5(MAGEL2):c.1850G>A (p.Trp617Ter)	Pathogenic
1071044	NM_019066.5(MAGEL2):c.2153C>A (p.Ser718Ter)	Pathogenic
1073104	NM_019066.5(MAGEL2):c.1990_1991insT (p.Pro664fs)	Pathogenic
1076479	NM_019066.5(MAGEL2):c.3044dup (p.Pro1016fs)	Pathogenic
1184134	NM_019066.5(MAGEL2):c.1837C>T (p.Gln613Ter)	Pathogenic
1320254	NM_019066.5(MAGEL2):c.2216del (p.Ser738_Ser739insTer)	Pathogenic
1685934	NM_019066.5(MAGEL2):c.2894G>A (p.Trp965Ter)	Pathogenic
1685935	NM_019066.5(MAGEL2):c.2099dup (p.Val701fs)	Pathogenic
190122	NM_019066.5(MAGEL2):c.1996dup (p.Gln666fs)	Pathogenic
224132	NM_019066.5(MAGEL2):c.3208G>T (p.Glu1070Ter)	Pathogenic
2429984	NM_019066.5(MAGEL2):c.2036del (p.Thr679fs)	Pathogenic
2499594	NM_019066.5(MAGEL2):c.2895G>A (p.Trp965Ter)	Pathogenic
2574225	NM_019066.5(MAGEL2):c.2821dup (p.Arg941fs)	Pathogenic
280384	NM_019066.5(MAGEL2):c.2163C>A (p.Cys721Ter)	Pathogenic
280815	NM_019066.5(MAGEL2):c.2070dup (p.Ala691fs)	Pathogenic
3336906	NM_019066.5(MAGEL2):c.2191dup (p.Ser731fs)	Pathogenic
3777152	NM_019066.5(MAGEL2):c.3050T>A (p.Leu1017Ter)	Pathogenic
3903167	NM_019066.5(MAGEL2):c.2059C>T (p.Gln687Ter)	Pathogenic
403667	NM_019066.5(MAGEL2):c.2958del (p.Ser987fs)	Pathogenic
440463	NM_019066.5(MAGEL2):c.1996del (p.Gln666fs)	Pathogenic
440464	NM_019066.5(MAGEL2):c.2118del (p.Leu708fs)	Pathogenic
440466	NM_019066.5(MAGEL2):c.1621C>T (p.Gln541Ter)	Pathogenic
4819080	NM_019066.5(MAGEL2):c.1861_1862del (p.Lys621fs)	Pathogenic
504272	NM_019066.5(MAGEL2):c.1927dup (p.Val643fs)	Pathogenic
520706	NM_019066.5(MAGEL2):c.3122del (p.Val1041fs)	Pathogenic
545929	NM_019066.5(MAGEL2):c.2982_2983del (p.Glu995fs)	Pathogenic
548682	NM_019066.5(MAGEL2):c.1761G>A (p.Trp587Ter)	Pathogenic
548683	NM_019066.5(MAGEL2):c.1762C>T (p.Gln588Ter)	Pathogenic
620452	NM_019066.5(MAGEL2):c.2874G>A (p.Trp958Ter)	Pathogenic

SpliceAI

60 predictions. Top by Δscore:

Variant	Effect	Δscore
15:23647728:A:AC	donor_gain	0.9500
15:23647729:C:CC	donor_gain	0.9500
15:23647733:G:C	donor_gain	0.9400
15:23647729:CTTAG:C	donor_gain	0.9100
15:23644328:ACTTG:A	acceptor_gain	0.7900
15:23644327:AACTT:A	acceptor_gain	0.7700
15:23647724:T:A	donor_gain	0.6400
15:23647068:C:T	acceptor_gain	0.5800
15:23647732:A:AC	donor_gain	0.5700
15:23647730:T:C	donor_gain	0.5500
15:23647732:AG:A	donor_gain	0.5100
15:23646028:G:GT	acceptor_gain	0.4900
15:23647128:C:CT	acceptor_gain	0.4900
15:23644329:C:A	acceptor_gain	0.4700
15:23647713:G:C	donor_gain	0.4600
15:23647158:C:CT	acceptor_gain	0.4300
15:23647128:C:T	acceptor_gain	0.4200
15:23646032:A:AT	acceptor_gain	0.4100
15:23647732:AGCTG:A	donor_gain	0.4000
15:23647745:C:A	donor_gain	0.4000
15:23647068:C:CT	acceptor_gain	0.3900
15:23647158:C:T	acceptor_gain	0.3500
15:23647060:G:T	acceptor_gain	0.3400
15:23647098:C:CT	acceptor_gain	0.3400
15:23647098:C:T	acceptor_gain	0.3300
15:23647129:G:T	acceptor_gain	0.3300
15:23646889:CCTGG:C	donor_gain	0.3200
15:23645065:T:TA	donor_gain	0.3100
15:23647069:G:T	acceptor_gain	0.3100
15:23647159:G:T	acceptor_gain	0.3000

AlphaMissense

7992 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:23644193:A:G	W1184R	0.998
15:23644193:A:T	W1184R	0.998
15:23644389:G:C	S1118R	0.997
15:23644389:G:T	S1118R	0.997
15:23644391:T:G	S1118R	0.997
15:23644513:A:G	L1077S	0.996
15:23644550:C:G	A1065P	0.995
15:23644190:C:G	G1185R	0.994
15:23644191:C:A	W1184C	0.994
15:23644191:C:G	W1184C	0.994
15:23644537:A:G	L1069P	0.994
15:23644109:A:G	W1212R	0.993
15:23644109:A:T	W1212R	0.993
15:23644549:G:T	A1065D	0.993
15:23644651:A:G	L1031P	0.992
15:23644653:G:C	F1030L	0.992
15:23644653:G:T	F1030L	0.992
15:23644655:A:G	F1030L	0.992
15:23644663:A:G	L1027S	0.992
15:23645079:C:A	K888N	0.992
15:23645079:C:G	K888N	0.992
15:23644243:A:G	L1167P	0.991
15:23644363:A:T	V1127D	0.991
15:23644524:A:C	F1073L	0.991
15:23644524:A:T	F1073L	0.991
15:23644526:A:G	F1073L	0.991
15:23644161:C:A	K1194N	0.990
15:23644161:C:G	K1194N	0.990
15:23644273:A:T	I1157N	0.990
15:23644336:A:G	L1136P	0.990

dbSNP variants (sampled 300 via entrez): RS1000301707 (15:23647740 C>A), RS1000866624 (15:23646738 A>C,G), RS1001431597 (15:23646521 G>A,T), RS1002045692 (15:23647279 G>A,C), RS1002437939 (15:23647767 T>C), RS1002642056 (15:23645903 C>G,T), RS1002939036 (15:23646361 G>A,T), RS1003865970 (15:23648160 C>A), RS1004039085 (15:23644629 C>A,T), RS1004846255 (15:23648790 C>T), RS1005048340 (15:23643391 T>C), RS1005302537 (15:23649082 G>T), RS1005417145 (15:23646772 T>TG), RS1005878551 (15:23645719 G>A,T), RS1005922937 (15:23645877 G>A,T)

Disease associations

OMIM: gene MIM:605283 | disease phenotypes: MIM:208080, MIM:615547, MIM:176270, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
Schaaf-Yang syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Schaaf-Yang syndrome	Definitive	AD

Mondo (8): Schaaf-Yang syndrome (MONDO:0014243), Prader-Willi syndrome (MONDO:0008300), neurodevelopmental disorder (MONDO:0700092), Prader-Willi-like syndrome (MONDO:0018354), intellectual disability (MONDO:0001071), genetic developmental and epileptic encephalopathy (MONDO:0100062), autism spectrum disorder (MONDO:0005258), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042)

Orphanet (6): Schaaf-Yang syndrome (Orphanet:398069), Prader-Willi syndrome (Orphanet:739), Prader-Willi-like syndrome (Orphanet:398073), Multiple congenital anomalies/dysmorphic syndrome (Orphanet:68341), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

194 total (30 of 194 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000135	Hypogonadism
HP:0000175	Cleft palate
HP:0000194	Open mouth
HP:0000217	Xerostomia
HP:0000219	Thin upper lip vermilion
HP:0000268	Dolichocephaly
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000288	Abnormality of the philtrum
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000446	Narrow nasal bridge
HP:0000476	Cystic hygroma
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000504	Abnormality of vision
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000565	Esotropia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002541_101	Menarche (age at onset)	5.000000e-11
GCST005648_30	Serum metabolite concentrations in chronic kidney disease	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D011218	Prader-Willi Syndrome	C10.597.606.360.690; C16.131.077.730; C16.131.260.700; C16.320.180.700; C16.320.447.500; C18.654.726.750.500.740
C535385	Arthrogryposis, distal, with hypopituitarism, mental retardation, and facial anomalies (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression, increases methylation	3
bisphenol A	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Catechin	affects cotreatment, increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Silicon Dioxide	increases expression	1
Thimerosal	decreases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E3V4	ESi134-A	Induced pluripotent stem cell	Female
CVCL_E7TE	SYS FiPS66-mR6F-1	Induced pluripotent stem cell	Male
CVCL_E7TF	SYS FiPS68-mR6F-3	Induced pluripotent stem cell	Female
CVCL_E7TH	SYS FiPS132-mR6F-4	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01298180	PHASE4	COMPLETED	Is There a Sensibility Increased in the Growth Hormone at Child With Prader-Willi Syndrome?
NCT01542242	PHASE4	TERMINATED	Liraglutide Use in Prader-Willi Syndrome
NCT03031626	PHASE4	COMPLETED	Oxygen Versus Medical Air for Treatment of CSA in Prader Will Syndrome
NCT03616509	PHASE4	COMPLETED	GH in Adults With PWS, Effect on Hypotonia Evaluated by Functional MRI, Relationship With Strength and Body Composition
NCT04066088	PHASE4	WITHDRAWN	Dose Clinical Trial of Guanfacine Extended Release for the Reduction of Aggression and Self-injuries Behavior Associated With Prader-Willi Syndrome
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT06901245	PHASE4	RECRUITING	Tirzepatide in PWS, HO and GNSO
NCT00175305	PHASE3	TERMINATED	Prader-Willi Syndrome and Appetite
NCT00444964	PHASE3	COMPLETED	Growth Hormone Use in Adults With Prader-Willi Syndrome
NCT00603109	PHASE3	TERMINATED	Effect of Rimonabant on Weight Gain and Body Composition in Adults With Prader Willi Syndrome
NCT02179151	PHASE3	TERMINATED	Double-Blind, Placebo Controlled, Phase 3 Trial of ZGN-440 (Beloranib) in Obese Subjects With Prader-Willi Syndrome
NCT02204163	PHASE3	COMPLETED	Study to Assess the Efficacy and Safety of Eutropin in Prader-Willi Syndrome
NCT02810483	PHASE3	TERMINATED	Study of the Efficacy of Topiramate in Patients With Prader Willi Syndrome Over 8 Weeks
NCT03440814	PHASE3	COMPLETED	A Study of Diazoxide Choline in Patients With Prader-Willi Syndrome
NCT03554031	PHASE3	UNKNOWN	A Study to Evaluate the Efficacy and Safety of Recombinant Human Growth Hormone Injection in Patients With Prader-Willi Syndrome
NCT03649477	PHASE3	COMPLETED	Phase 3 Study of Intranasal Carbetocin (LV-101) in Patients With Prader-Willi Syndrome
NCT03714373	PHASE3	COMPLETED	Open-Label Extension Study of DCCR in PWS Followed by Double-Blind, Placebo-Controlled, Randomized Withdrawal Period
NCT04086810	PHASE3	WITHDRAWN	An Open-Label Study of DCCR Tablet in Patients With PWS
NCT04283578	PHASE3	COMPLETED	Oxytocin Treatment in Neonates and Infants With Prader-Willi Syndrome
NCT04697381	PHASE3	COMPLETED	Study of the Efficacy and Safety of Somatropin in Japanese Participants With PWS
NCT05032326	PHASE3	UNKNOWN	Long-term Interventional Follow-up Study of Children With Prader-Willi Syndrome Included in the OTBB3 Clinical Trial
NCT05387798	PHASE3	WITHDRAWN	A Phase 3 Extension Study of RAD011 (Cannabidiol Oral Solution) in Patients With Prader-Willi Syndrome
NCT05701774	PHASE3	ACTIVE_NOT_RECRUITING	Open-Label Extension Study of DCCR in Patients With Prader-Willi Syndrome
NCT06144645	PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Evaluation of Non-Invasive Vagus Nerve Stimulation for Temper Outbursts in People With PWS
NCT06366464	PHASE3	RECRUITING	A Study of Pitolisant in Patients With Prader-Willi Syndrome
NCT06828861	PHASE3	SUSPENDED	ARD-101 for Treatment of PWS: The Hunger Elimination or Reduction Objective Trial
NCT07197034	PHASE3	SUSPENDED	The Hunger Elimination or Reduction Objective (HERO ) Open -Label Extension (OLE) Trial
NCT07219485	PHASE3	ENROLLING_BY_INVITATION	A Study of Pitolisant in Participants With Prader-Willi Syndrome
NCT01038570	PHASE2	COMPLETED	Comparative Study Between Prader-Willi Patients Who Take Oxytocin Versus Placebo
NCT01818921	PHASE2	COMPLETED	An Efficacy, Safety, and Pharmacokinetics Study of Beloranib in Obese Subjects With Prader-Willi Syndrome
NCT02311673	PHASE2	COMPLETED	Phase 2 Trial to Evaluate Safety and Efficacy of Setmelanotide (RM-493) in Obese Participants With Prader-Willi Syndrome
NCT02629991	PHASE2	COMPLETED	Oxytocin vs. Placebo for the Treatment Hyperphagia in Children and Adolescents With Prader-Willi Syndrome
NCT02844933	PHASE2	TERMINATED	Cannabidiol Oral Solution for the Treatment of Patients With Prader-Willi Syndrome
NCT02893618	PHASE2	UNKNOWN	A 5 Treatment Period Pharmacokinetic Study Evaluating Dose Proportionality and Food Effects of Diazoxide Choline Controlled-Release Tablet (DCCR)
NCT03197662	PHASE2	COMPLETED	Intranasal Oxytocin vs. Placebo for the Treatment of Hyperphagia in Prader-Willi Syndrome
NCT03274856	PHASE2	COMPLETED	A Study of GLWL-01 in Patients With Prader-Willi Syndrome
NCT03458416	PHASE2	TERMINATED	A Study to Assess the Long-Term Safety of Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Participants With Prader-Willi Syndrome
NCT03831425	PHASE2	WITHDRAWN	Mitochondrial Complex I Dysfunction in PWS
NCT03848481	PHASE2	TERMINATED	CBDV vs Placebo in Children and Adults up to Age 30 With Prader-Willi Syndrome (PWS)
NCT04257929	PHASE2	COMPLETED	A Phase 2 Study to Evaluate the Safety and Efficacy of Pitolisant in Patients With Prader-Willi Syndrome, Followed by an Open Label Extension