MAGEL2

Chr 15AD

MAGE family member L2

Also known as: NDNL1, PWLS, SHFYNG, nM15

NCBI Gene: 54551ENSG00000254585UniProt: Q9UJ55OMIM: 605283

MAGEL2 encodes a protein that functions in early endosomes and is paternally imprinted within the Prader-Willi syndrome chromosomal region at 15q11-q13. Mutations cause Schaaf-Yang syndrome, which follows an autosomal dominant inheritance pattern. The protein is highly intolerant to loss-of-function mutations, suggesting haploinsufficiency as the likely pathogenic mechanism.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.311 OMIM phenotype
Clinical Summary— MAGEL2
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Gene-Disease Validity (ClinGen)
Schaaf-Yang syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
40 unique Pathogenic / Likely Pathogenic· 382 VUS of 500 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — MAGEL2
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.31LOEUF
pLI 0.975
Z-score 3.75
OE 0.10 (0.04–0.31)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
-0.56Z-score
OE missense 1.08 (1.00–1.18)
399 obs / 368.6 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.10 (0.04–0.31)
0≤0.351.4
Missense OE1.08 (1.00–1.18)
0≤0.61.4
Synonymous OE1.17
0≤1.21.6
LoF obs/exp: 2 / 20.2Missense obs/exp: 399 / 368.6Syn Z: -1.72
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveMAGEL2-related Schaaf-Yang syndromeLOFAD
DN
0.4190th %ile
GOF
0.3193th %ile
LOF
0.58top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF48% of P/LP variants are LoF · LOEUF 0.31
DN1 literature citation

Literature Evidence

DNThe concept that a deletion of the entire gene could have milder effects than a truncating mutation is intriguing. Because MAGEL2 is a one-exon gene, one could speculate that truncating mutations may result in a truncated protein, which then could have a dominant-negative effect.PMID:27195816

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic18
VUS382
Likely Benign58
Benign1
Conflicting19
22
Pathogenic
18
Likely Pathogenic
382
VUS
58
Likely Benign
1
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
0
18
0
22
Likely Pathogenic
15
1
2
0
18
VUS
7
310
8
57
382
Likely Benign
0
14
0
44
58
Benign
0
0
0
1
1
Conflicting
—19
Total2632528102500

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

MAGEL2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Hormonal Imbalances in Prader-Willi and Schaaf-Yang Syndromes Imply the Evolution of Specific Regulation of Hypothalamic Neuroendocrine Function in Mammals
Hoyos Sanchez MC et al.·Int J Mol Sci
2023
Preimplantation Genetic Testing (PGT) and Prenatal Diagnosis of Schaaf-Yang Syndrome: A Report of Three Families and a Research on Genotype-Phenotype Correlations
Xu N et al.·J Clin Med
2023
MAGEL2 (patho)physiology and Schaaf-Yang syndrome.
·Dev Med Child Neurol
2024
Sex differences in MAGEL2 gene promoter methylation in high functioning autism - trends from a pilot study using nanopore Cas9 targeted long read sequencing
Wieting J et al.·BMC Med Genomics
2024
Cell-specific secretory granule sorting mechanisms: the role of MAGEL2 and retromer in hypothalamic regulated secretion
Štepihar D et al.·Front Cell Dev Biol
2023Functional
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Long-read sequencing enables trio-assisted phasing of de novo variants in the imprinted gene MAGEL2.
Laver TW et al.·J Med Genet
2026
Identification of a De Novo MAGEL2 Pathogenic Variant in Schaaf-Yang Syndrome and the Importance of Paternal Allele Confirmation.
Hong YJ et al.·J Clin Lab Anal
2026Open Access
Magel2 in hypothalamic POMC neurons influences the impact of stress on anxiety-like behavior and spatial learning associated with a food reward in male mice.
Lee S et al.·Front Neural Circuits
2025Open Access
A Case of Prader-Willi Syndrome With a Deletion Including MAGEL2 , NDN , and MKRN3 , but Excluding SNRPN and SNORD116.
Buecking J et al.·Am J Med Genet A
2025
Somatostatin-expressing interneurons of prefrontal cortex modulate social deficits in the Magel2 mouse model of autism.
Wang X et al.·Mol Autism
2025Open AccessFunctional
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients