AP2M1

Chr 3AD

adaptor related protein complex 2 subunit mu 1

Also known as: AP50, CLAPM1, MRD60, mu2

NCBI Gene: 1173 ENSG00000161203 UniProt: Q96CW1 OMIM: 601024

The AP2M1 protein is a component of the adaptor protein complex 2 (AP-2) that functions in clathrin-mediated endocytosis, cargo selection, and synaptic vesicle recycling. Mutations cause autosomal dominant intellectual developmental disorder with seizures. This represents a neurodevelopmental condition affecting cognitive function and seizure control through disruption of cellular membrane trafficking processes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a subunit of the heterotetrameric coat assembly protein complex 2 (AP2), which belongs to the adaptor complexes medium subunits family. The encoded protein is required for the activity of a vacuolar ATPase, which is responsible for proton pumping occurring in the acidification of endosomes and lysosomes. The encoded protein may also play an important role in regulating the intracellular trafficking and function of CTLA-4 protein. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.191 OMIM phenotype

Clinical Summary— AP2M1

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 107 VUS of 322 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.19LOEUF

pLI 0.999

Z-score 4.45

OE 0.04 (0.01–0.19)

Highly constrained

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

Missense Constraint?

4.88Z-score

OE missense 0.17 (0.13–0.21)

46 obs / 273.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.19)

0≤0.351.4

Missense OE?0.17 (0.13–0.21)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 1 / 25.0Missense obs/exp: 46 / 273.0Syn Z: 1.34

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongAP2M1-related developmental and epileptic encephalopathyOTHERAD

This gene — mechanism propensity

0.3196th %ile

GOF

0.2994th %ile

LOF

0.79top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.19

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

322 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS107

Likely Benign171

Benign23

Conflicting3

Pathogenic

Likely Pathogenic

107

VUS

171

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	1	0	0	1
VUS	7	83	16	1	107
Likely Benign	0	6	83	82	171
Benign	0	3	14	6	23
Conflicting	—				3
Total	7	94	113	89	306

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap AP2M1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →