AP4M1

Chr 7

adaptor related protein complex 4 subunit mu 1

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

NCBI Gene: 9179ENSG00000221838UniProt: O00189

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]

Primary Disease Associations & Inheritance

UniProtSpastic paraplegia 50, autosomal recessive
279
ClinVar variants
22
Pathogenic / LP
0.00
pLI score
4
Active trials
Clinical Summary— AP4M1
🧬
Gene-Disease Validity (ClinGen)
AP-4 deficiency syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
22 Pathogenic / Likely Pathogenic· 145 VUS of 279 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
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?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.
-1.21Z-score
OE missense 1.21 (1.10–1.33)
311 obs / 256.4 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.0.95 (0.69–1.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.21 (1.10–1.33)
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.1.39
0≤1.21.6
LoF obs/exp: 26 / 27.5Missense obs/exp: 311 / 256.4Syn Z: -3.23

ClinVar Variant Classifications

279 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
Likely Pathogenic8
VUS145
Likely Benign109
Benign2
Conflicting1
14
Pathogenic
8
Likely Pathogenic
145
VUS
109
Likely Benign
2
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
9
0
14
Likely Pathogenic
6
0
2
0
8
VUS
2
133
8
2
145
Likely Benign
2
1
46
60
109
Benign
0
0
1
1
2
Conflicting
—1
Total151346663279

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

View in ClinVar →

Protein Context — Lollipop Plot

AP4M1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

AP4M1-related cerebral palsy spastic quadriplegic

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — AP4M1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies.
Chen X et al.·J Clin Invest
2023
Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.
Ebrahimi-Fakhari D et al.·Brain
2020
AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.
Dowling JJ et al.·Nat Med
2024Clinical trial
Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes.
Novikova G et al.·Nat Commun
2021
Putative founder effect of Arg338* AP4M1 (SPG50) variant causing severe intellectual disability, epilepsy and spastic paraplegia: Report of three families.
Becker A et al.·Clin Genet
2023
Identification of novel homozygous variants in FOXE3 and AP4M1 underlying congenital syndromic anophthalmia and microphthalmia.
Akbar W et al.·J Gene Med
2024
A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency.
Jameel M et al.·BMC Med Genet
2014Case report
Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia.
Bettencourt C et al.·Orphanet J Rare Dis
2017Case report
Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features.
Tüysüz B et al.·Am J Med Genet A
2014Case report
HACE1, GLRX5, and ELP2 gene variant cause spastic paraplegies.
Sager G et al.·Acta Neurol Belg
2022
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
Spastic Paraplegia Type 50

Administration of MELPIDA to Determine the Safety and Efficacy for Patients With Spastic Paraplegia Type 50

ACTIVE NOT RECRUITING
NCT06069687Phase PHASE1The Hospital for Sick ChildrenStarted 2022-03-11
MELPIDA
Spasticity, MuscleMicrocephalyIntellectual Deficiency

Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)

RECRUITING
NCT05518188Phase PHASE1, PHASE2Elpida Therapeutics SPCStarted 2023-02-15
MELPIDA
HSPHereditary Spastic ParaplegiaHereditary Spastic Paraparesis

Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)

NOT YET RECRUITING
NCT06948019Phase PHASE1, PHASE2BlackfinBio LtdStarted 2025-08
BFB-101 (AAV9-CBh-AP4B1)
Hereditary Spastic Paraplegia Type 50

Phase 3 Efficacy Study With Concurrent Control of IT MELPIDA in SPG50.Concurrent Controls.

RECRUITING
NCT06692712Phase PHASE3Elpida Therapeutics SPCStarted 2026-02-01
MELPIDA

External Resources

Links to major genomics databases and tools