MAG

Chr 19AR

myelin associated glycoprotein

Also known as: GMA, S-MAG, SIGLEC-4A, SIGLEC4, SIGLEC4A, SPG75

NCBI Gene: 4099 ENSG00000105695 UniProt: P20916 OMIM: 159460

The myelin-associated glycoprotein (MAG) is an adhesion molecule that mediates interactions between myelinating cells and neurons, maintains normal axon myelination, and protects motor neurons against apoptosis. Mutations cause spastic paraplegia 75, an autosomal recessive disorder affecting the corticospinal tracts. The gene is highly constrained against loss-of-function variants (LOEUF 0.424), indicating that MAG function is essential for normal neurological development and maintenance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a type I membrane protein and member of the immunoglobulin superfamily. It is thought to be involved in the process of myelination. It is a lectin that binds to sialylated glycoconjugates and mediates certain myelin-neuron cell-cell interactions. Three alternatively spliced transcripts encoding different isoforms have been described for this gene. [provided by RefSeq, Nov 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.421 OMIM phenotype

Clinical Summary— MAG

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Gene-Disease Validity (ClinGen)

complex hereditary spastic paraplegia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.21) despite low pLI — interpret in context.

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ClinVar Variants

16 unique Pathogenic / Likely Pathogenic· 179 VUS of 372 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 →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.42LOEUF

pLI 0.492

Z-score 3.84

OE 0.21 (0.12–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.13Z-score

OE missense 0.84 (0.77–0.92)

348 obs / 412.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.21 (0.12–0.42)

0≤0.351.4

Missense OE?0.84 (0.77–0.92)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 6 / 27.9Missense obs/exp: 348 / 412.9Syn Z: 0.18

This gene — mechanism propensity

0.6455th %ile

GOF

0.6638th %ile

LOF

0.3746th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF69% of P/LP variants are LoF · LOEUF 0.42

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

372 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic8

VUS179

Likely Benign147

Benign21

Conflicting6

Pathogenic

Likely Pathogenic

179

VUS

147

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	3	0	0	8
Likely Pathogenic	6	1	1	0	8
VUS	1	172	5	1	179
Likely Benign	0	7	33	107	147
Benign	0	3	10	8	21
Conflicting	—				6
Total	12	186	49	116	369

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap MAG — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →