AP4S1

Chr 14AR

adaptor related protein complex 4 subunit sigma 1

Also known as: AP47B, CLA20, CLAPS4, CPSQ6, SPG52

NCBI Gene: 11154 ENSG00000100478 UniProt: Q9Y587 OMIM: 607243

This protein is the small subunit of adaptor protein complex-4, which mediates vesicle formation and sorting of integral membrane proteins in the secretory and endocytic pathways at the Golgi apparatus and trans-Golgi network. Mutations cause spastic paraplegia 52 through an autosomal recessive inheritance pattern. The pathogenic mechanism appears to involve dominant-negative effects disrupting normal protein complex function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the adaptor complexes small subunit protein family. These proteins are components of the heterotetrameric adaptor protein complexes, which play important roles in the secretory and endocytic pathways by mediating vesicle formation and sorting of integral membrane proteins. The encoded protein is the small subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Mutations in this gene are associated with spastic quadriplegic cerebral palsy-6. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Dec 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.631 OMIM phenotype

Clinical Summary— AP4S1

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Gene-Disease Validity (ClinGen)

AP-4 deficiency syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

26 unique Pathogenic / Likely Pathogenic· 72 VUS of 192 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — AP4S1

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?

1.63LOEUF

pLI 0.000

Z-score 0.12

OE 0.96 (0.58–1.63)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.01Z-score

OE missense 1.00 (0.84–1.20)

85 obs / 84.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.96 (0.58–1.63)

0≤0.351.4

Missense OE?1.00 (0.84–1.20)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 9 / 9.4Missense obs/exp: 85 / 84.7Syn Z: -0.39

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongAP4S1-related cerebral palsy spastic quadriplegicLOFAR

This gene — mechanism propensity

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

0.7229th %ile

GOF

0.6442th %ile

LOF

0.2385th %ile

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.

ClinVar Variant Classifications

192 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic13

VUS72

Likely Benign54

Benign20

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	0	2	0	13
Likely Pathogenic	10	2	1	0	13
VUS	3	63	6	0	72
Likely Benign	0	3	30	21	54
Benign	0	1	19	0	20
Conflicting	—				4
Total	24	69	58	21	176

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap AP4S1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →