AP4M1

Chr 7AR

adaptor related protein complex 4 subunit mu 1

Also known as: CPSQ3, MU-4, MU-ARP2, SPG50

NCBI Gene: 9179 ENSG00000221838 UniProt: O00189 OMIM: 602296

This protein is a subunit of the AP-4 complex that recognizes and sorts cargo proteins with tyrosine-based motifs from the trans-Golgi network to the endosomal-lysosomal system. Mutations cause spastic paraplegia 50, an autosomal recessive disorder. The pathogenic mechanism involves disrupted intracellular protein trafficking between these membrane compartments.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a subunit of the heterotetrameric AP-4 complex. The encoded protein belongs to the adaptor complexes medium subunits family. This AP-4 complex is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Spastic paraplegia 50, autosomal recessiveMIM #612936

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · AP-4 deficiency syndrome · AR · ClinGen 2021
Definitive · hereditary spastic paraplegia 50 · AR · Ambry Genetics
Supportive · AP4-related intellectual disability and spastic paraplegia · AR · Orphanet

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.31

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — AP4M1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.31LOEUF

pLI 0.000

Z-score 0.26

OE 0.95 (0.69–1.31)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.21Z-score

OE missense 1.21 (1.10–1.33)

311 obs / 256.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.95 (0.69–1.31)

0≤0.351.4

Missense OE?1.21 (1.10–1.33)

0≤0.61.4

Synonymous OE?1.39

0≤1.21.6

LoF obs/exp: 26 / 27.5Missense obs/exp: 311 / 256.4Syn Z: -3.23

Background carrier burden — how many people carry a rare variant somewhere in AP4M1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 75

705 rare PASS variants

Rare truncating (LoF)

1 in 780

147 rare PASS variants

Rare synonymous (reference)

1 in 150

310 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for AP4M1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 96	1 in 780
South Asian	~43k	1 in 79	1 in 460
Remaining (unassigned)	~30k	1 in 66	1 in 910
European (Finnish)	~27k	1 in 440	1 in 2,600
Admixed American	~22k	1 in 71	1 in 830
African / African American	~21k	1 in 73	1 in 700
East Asian	~20k	1 in 73	1 in 900
Ashkenazi Jewish	~13k	1 in 650	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 70	1 in 360

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 15 coding exons well covered in gnomAD exomes and genomes.? see exons ↓