MAGEL2

Chr 15AD

MAGE family member L2

NCBI Gene: 54551ENSG00000254585UniProt: 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. 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-BMAL1 heterodimer. Significantly promotes the cytoplasmic accumulation of CLOCK (By similarity)

Primary Disease Associations & Inheritance

Schaaf-Yang syndromeMIM #615547
AD
600
ClinVar variants
24
Pathogenic / LP
0.98
pLI score· haploinsufficient
1
Active trials
Clinical Summary— MAGEL2
🧬
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.
📋
ClinVar Variants
24 Pathogenic / Likely Pathogenic· 480 VUS of 600 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.56Z-score
OE missense 1.08 (1.00–1.18)
399 obs / 368.6 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.10 (0.04–0.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.08 (1.00–1.18)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.17
0≤1.21.6
LoF obs/exp: 2 / 20.2Missense obs/exp: 399 / 368.6Syn Z: -1.72

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic15
VUS480
Likely Benign79
Benign3
Conflicting14
9
Pathogenic
15
Likely Pathogenic
480
VUS
79
Likely Benign
3
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
8
0
9
Likely Pathogenic
11
1
3
0
15
VUS
2
378
37
63
480
Likely Benign
0
12
1
66
79
Benign
0
1
0
2
3
Conflicting
—14
Total1439249131600

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.

Gene2Phenotype Curations

MAGEL2-related Schaaf-Yang syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
MAGE-LIKE 2; MAGEL2
MIM #605283 · *

Schaaf-Yang syndrome

MIM #615547

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — MAGEL2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita.
Laquerriere A et al.·J Med Genet
2022
MAGEL2 (patho-)physiology and Schaaf-Yang syndrome.
Schubert T et al.·Dev Med Child Neurol
2025Review
MAGEL2-related disorders: A study and case series.
Patak J et al.·Clin Genet
2019Case report
Mutations in MAGEL2 and L1CAM Are Associated With Congenital Hypopituitarism and Arthrogryposis.
Gregory LC et al.·J Clin Endocrinol Metab
2019
Crisponi/cold-induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts.
Buers I et al.·Clin Genet
2020Review
Magel2 Modulates Bone Remodeling and Mass in Prader-Willi Syndrome by Affecting Oleoyl Serine Levels and Activity.
Baraghithy S et al.·J Bone Miner Res
2019Functional
Variant reclassification over time decreases the level of diagnostic uncertainty in monogenic obesity: Experience from two centres.
Morandi A et al.·Pediatr Obes
2024
Chitayat-Hall and Schaaf-Yang syndromes:a common aetiology: expanding the phenotype of MAGEL2-related disorders.
Jobling R et al.·J Med Genet
2018
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
The adult phenotype of Schaaf-Yang syndrome.
Marbach F et al.·Orphanet J Rare Dis
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation

External Resources

Links to major genomics databases and tools