AP4B1

Chr 1AR

adaptor related protein complex 4 subunit beta 1

Also known as: BETA-4, CPSQ5, SPG47

NCBI Gene: 10717ENSG00000134262UniProt: Q9Y6B7

This gene encodes a subunit of a heterotetrameric adapter-like complex 4 that is involved in targeting proteins from the trans-Golgi network to the endosomal-lysosomal system. Mutations in this gene are associated with cerebral palsy spastic quadriplegic type 5 (CPSQ5) disorder. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

Primary Disease Associations & Inheritance

Spastic paraplegia 47, autosomal recessiveMIM #614066
AR
486
ClinVar variants
70
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— AP4B1
🧬
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
70 Pathogenic / Likely Pathogenic· 250 VUS of 486 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
0.83LOEUF
pLI 0.000
Z-score 2.37
OE 0.57 (0.40–0.83)
Tolerant

Typical tolerance to LoF variation

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.
0.13Z-score
OE missense 0.98 (0.90–1.07)
398 obs / 405.4 exp
Tolerant

Mild missense constraint

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.0.57 (0.40–0.83)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.90–1.07)
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.1.01
0≤1.21.6
LoF obs/exp: 20 / 35.1Missense obs/exp: 398 / 405.4Syn Z: -0.06

ClinVar Variant Classifications

486 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44
Likely Pathogenic26
VUS250
Likely Benign138
Benign12
Conflicting16
44
Pathogenic
26
Likely Pathogenic
250
VUS
138
Likely Benign
12
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
20
0
24
0
44
Likely Pathogenic
13
3
10
0
26
VUS
3
229
16
2
250
Likely Benign
0
7
52
79
138
Benign
0
2
10
0
12
Conflicting
—16
Total3624111281486

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

View in ClinVar →

Protein Context — Lollipop Plot

AP4B1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

AP4B1-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 Relationships

1 OMIM entry

OMIM

Spastic paraplegia 47, autosomal recessive

MIM #614066

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — AP4B1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.
Ebrahimi-Fakhari D et al.·Brain
2020
Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47.
Wiseman JP et al.·EMBO Mol Med
2024
AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range.
Salayev K et al.·Eur J Med Genet
2022
Clinical and genetic characterization of AP4B1-associated SPG47.
Ebrahimi-Fakhari D et al.·Am J Med Genet A
2018
Clinical and genetic characterization of patients segregating variants in KPTN, MINPP1, NGLY1, AP4B1, and SON underlying neurodevelopmental disorders: Genetic and phenotypic expansion.
Ullah A et al.·Int J Dev Neurosci
2022Cohort
[AP4-assocated hereditary spastic paraplegias].
Rudenskaya GE et al.·Zh Nevrol Psikhiatr Im S S Korsakova
2021
Hereditary spastic paraplegia associated with a novel homozygous intronic noncanonical splice site variant in the AP4B1 gene.
Gómez-González C et al.·Ann Hum Genet
2022Case report
An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome.
Abdollahpour H et al.·Eur J Hum Genet
2015
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
Identification and analyses of exonic and copy number variants in spastic paraplegia.
Shafique A et al.·Sci Rep
2024
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
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)

External Resources

Links to major genomics databases and tools