MAGEL2

protein-coding

MAGE family member L2, the group of MAGE family

Gene summary

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. [provided by RefSeq, Oct 2010]

Previous symbols:

NDNL1

MANE transcript

NM_019066.5

Inheritance

ClinVar variants

P:118U:975B:346

Top phenotype

Schaaf-Yang syndrome (Prader-Willi-like syndrome)

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr15:23,643,549-23,647,867

External References & Databases

Ensembl (ENSG00000254585)

Transcript & Mutation Effects

hg38 • Region Span ~4.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Schaaf-Yang syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014243

Submitter: Labcorp Genetics (formerly Invitae)

Schaaf-Yang syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014243

Submitter: G2P

Schaaf-Yang syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014243

Submitter: Illumina

Schaaf-Yang syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014243

Submitter: ClinGen

*MAGEL2* is a single exon gene located on the maternally imprinted (paternally expressed) locus on chromosome 15q11–q13. *MAGEL2* was first reported in relation to autosomal dominant Schaaf-Yang syndrome in 2013 (Schaaf et al., PMID: 24076603). Schaaf-Yang syndrome is a rare neurodevelopmental disorder that shares multiple clinical features with Prader-Willi syndrome. It usually manifests at birth with muscular hypotonia in all and distal joint contractures in a majority of affected individuals. Gastrointestinal/feeding problems are particularly pronounced in infancy and childhood, but can transition to hyperphagia and obesity in adulthood. All affected individuals show developmental delay, resulting in intellectual disability of variable degree. Other findings may include short stature, seizures, eye anomalies, and hypogonadism. Some patients were originally referred as Chitayat-Hall syndrome but as the molecular mechanism is the same (null variant on the paternal allele), these disease entities were lumped together. Thirteen variants (nonsense and frameshift) that have been reported in 16 probands in five publications (PMIDs: 24076603, 26365340, 27195816, 28281571, 33076953) are included in this curation. Many more patients are reported in the literature, especially with the recurrent variants c.1996dupC and c.1996delC (reviewed in PMID: 30302899), but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be truncating variation on the paternal allele. This gene-disease association is also supported by experimental evidence, including two mouse models (PMIDs: 17893678, 20876615). In summary, there is definitive evidence supporting the relationship between *MAGEL2* and autosomal dominant Schaaf-Yang syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 1, 2021 (SOP Version 8). As of August 2026, this record underwent administrative updates to update scoring to be consistent with SOP Version 12. No new evidence was added, and the classification remains the same.

Schaaf-Yang syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014243

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Schaaf-Yang syndrome (Prader-Willi-like syndrome)AD

Manifestation: Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Neurologic

Intervention: Endocrine

Rationale: The condition has been described as including neonatal hyperinsulinemia hypoglycemia, and awareness may allow prompt management

Refs: 24076603; 25473036; 26365340; 27195816; 28281571

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAGEL2 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 1087

MAGEL2-related disorderTotal: 486

Inborn genetic diseasesTotal: 312

Schaaf-Yang syndromeTotal: 176

not specifiedTotal: 107

Prader-Willi syndromeTotal: 22

Intellectual disabilityTotal: 6

Neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019066.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			84 clinvar	208 clinvar	6 clinvar	298
missense	2 clinvar	1 clinvar	876 clinvar	125 clinvar	7 clinvar	1011
nonsense	20 clinvar	27 clinvar	5 clinvar			52
start loss		1 clinvar	1 clinvar			2
frameshift	26 clinvar	41 clinvar	9 clinvar			76
splice donor/acceptor (+/-2bp)						0
Total	48	70	975	333	13	1439

Highest pathogenic variant AF is 0.00001549108

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019066.5	RefSeq	NP_061939.3	1	MANE Select
ENST00000650528.1	Ensembl	ENSP00000497810.1	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Circadian rythm related genes
Prader-Willi and Angelman Syndrome

Biological Process

Arp2/3 complex-mediated actin nucleation
retrograde transport, endosome to Golgi
regulation of circadian rhythm
negative regulation of transcription, DNA-templated
rhythmic process

Molecular Function

ubiquitin-protein transferase activity
protein binding

Cellular Component

nucleus
endosome
early endosome
cytosol
retromer complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000532292
Coding exons: 1
Length: 2485
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.563	399	369	1.08	0.0000209	4145
Missense (PolyPhen)		76	73.131	1.0392		861
Synonymous	-1.72	185	158	1.17	0.00000941	1352
Loss of Function	3.75	2	20.2	0.0992	0.00000112	209

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (PubMed:23452853). Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-ARNTL/BMAL1 heterodimer. Significantly promotes the cytoplasmic accumulation of CLOCK (By similarity). {ECO:0000250|UniProtKB:Q9QZ04, ECO:0000269|PubMed:20864041, ECO:0000269|PubMed:23452853}.;

Essentials

Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium