MDGA2

Chr 14AR

MAM domain containing glycosylphosphatidylinositol anchor 2

Also known as: DEE122, MAMDC1, c14_5286

NCBI Gene: 161357 ENSG00000139915 UniProt: Q7Z553 OMIM: 611128

MDGA2 encodes a protein predicted to regulate synapse organization and motor neuron differentiation, with involvement in cell-cell interactions at GABAergic and glutamatergic synapses. Mutations cause neurodevelopmental disorders with intellectual disability and motor dysfunction. The gene shows autosomal recessive inheritance and is highly constrained against loss-of-function variants, indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to be involved in regulation of synapse organization and spinal cord motor neuron differentiation. Predicted to act upstream of or within several processes, including motor behavior; negative regulation of neuron apoptotic process; and neuron migration. Predicted to be located in extracellular region and plasma membrane. Predicted to be active in GABA-ergic synapse; glutamatergic synapse; and postsynaptic density membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.241 OMIM phenotype

Clinical Summary— MDGA2

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 35 VUS of 59 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 0.999

Z-score 5.14

OE 0.10 (0.05–0.24)

Highly constrained

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

Missense Constraint?

1.68Z-score

OE missense 0.76 (0.69–0.84)

306 obs / 400.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.05–0.24)

0≤0.351.4

Missense OE?0.76 (0.69–0.84)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 4 / 38.3Missense obs/exp: 306 / 400.4Syn Z: 0.83

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateMDGA2-related developmental and epileptic encephalopathy with abnormal cranial MRILOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.3991th %ile

GOF

0.4678th %ile

LOF

0.66top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

59 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic1

VUS35

Likely Benign2

Benign3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	0	1	0	7
Likely Pathogenic	1	0	0	0	1
VUS	2	31	0	2	35
Likely Benign	0	1	0	1	2
Benign	0	2	0	1	3
Total	9	34	1	4	48

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap MDGA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →