AP1S3

Summary

AP1S3 (adaptor related protein complex 1 subunit sigma 3, HGNC:18971) is a protein-coding gene on chromosome 2q36.1, encoding AP-1 complex subunit sigma-3 (Q96PC3). Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.

This gene encodes a member of the adaptor-related protein complex 1, sigma subunit genes. The encoded protein is a component of adaptor protein complex 1 (AP-1), one of the AP complexes involved in claathrin-mediated vesicular transport from the Golgi or endosomes. Disruption of the pathway for display of HIV-1 antigens, which prevents recognition of the virus by cytotoxic T cells, has been shown to involve the AP-1 complex (PMID: 15569716). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 130340 — RefSeq curated summary.

At a glance

• Gene–disease (curated): psoriasis 15, pustular, susceptibility to (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 49 total — 1 pathogenic
• Phenotypes (HPO): 30
• MANE Select transcript: NM_001039569

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18971
Approved symbol	AP1S3
Name	adaptor related protein complex 1 subunit sigma 3
Location	2q36.1
Locus type	gene with protein product
Status	Approved
Aliases	sigma1C
Ensembl gene	ENSG00000152056
Ensembl biotype	protein_coding
OMIM	615781
Entrez	130340

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 8 nonsense_mediated_decay, 7 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000334271, ENST00000396653, ENST00000396654, ENST00000409375, ENST00000415298, ENST00000443700, ENST00000444408, ENST00000446015, ENST00000699384, ENST00000699385, ENST00000699386, ENST00000699387, ENST00000699388, ENST00000699389, ENST00000699390, ENST00000699391, ENST00000699392, ENST00000699393, ENST00000903914

RefSeq mRNA: 1 — MANE Select: NM_001039569 NM_001039569

CCDS: CCDS42827

Canonical transcript exons

ENST00000396654 — 5 exons

Exon	Start	End
ENSE00001003125	223775901	223776009
ENSE00001525837	223837448	223837582
ENSE00001525839	223755326	223758750
ENSE00003976425	223777691	223777869
ENSE00003976434	223765213	223765350

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 81.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.3560 / max 553.3193, expressed in 1484 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34169	8.3634	1452
34167	0.7148	297
34171	0.6026	112
34174	0.2430	67
34168	0.1831	101
34172	0.1221	52
34175	0.0856	21
34173	0.0317	9
34170	0.0097	3

Top tissues by expression

138 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	81.01	gold quality
placenta	UBERON:0001987	78.01	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.98	gold quality
metanephros cortex	UBERON:0010533	77.09	gold quality
thyroid gland	UBERON:0002046	76.18	gold quality
left lobe of thyroid gland	UBERON:0001120	75.96	gold quality
kidney	UBERON:0002113	75.31	gold quality
duodenum	UBERON:0002114	75.19	gold quality
bone marrow cell	CL:0002092	75.13	gold quality
adult mammalian kidney	UBERON:0000082	75.02	gold quality
cortex of kidney	UBERON:0001225	74.90	gold quality
gall bladder	UBERON:0002110	74.59	gold quality
right lobe of thyroid gland	UBERON:0001119	74.06	gold quality
endometrium	UBERON:0001295	73.20	gold quality
lymph node	UBERON:0000029	72.29	gold quality
tonsil	UBERON:0002372	72.20	gold quality
esophagus mucosa	UBERON:0002469	72.01	gold quality
bone marrow	UBERON:0002371	71.84	gold quality
pancreas	UBERON:0001264	71.18	gold quality
vermiform appendix	UBERON:0001154	70.97	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	70.21	gold quality
primary visual cortex	UBERON:0002436	70.16	gold quality
superior frontal gyrus	UBERON:0002661	69.28	gold quality
rectum	UBERON:0001052	68.98	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.63	gold quality
lower esophagus mucosa	UBERON:0035834	68.44	gold quality
lung	UBERON:0002048	68.26	gold quality
cortical plate	UBERON:0005343	67.83	gold quality
upper lobe of left lung	UBERON:0008952	67.48	gold quality
small intestine	UBERON:0002108	67.35	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-38	yes	308.32
E-ANND-3	yes	10.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

161 targeting AP1S3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559

Literature-anchored findings (GeneRIF, showing 3)

• AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. (PMID:24791904)
• study demonstrated that AP1S3 interacts with hepatitis C virus E2 and protects it from proteasome-dependent degradation (PMID:27079945)
• Adaptor Protein Complex 1 Sigma 3 Is Highly Expressed in Glioma and Could Enhance Its Progression. (PMID:34367317)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap1s3b	ENSDARG00000027966
danio_rerio	ap1s3a	ENSDARG00000110439
mus_musculus	Ap1s3	ENSMUSG00000054702
rattus_norvegicus	Ap1s3	ENSRNOG00000049873
drosophila_melanogaster	AP-1sigma	FBGN0039132
caenorhabditis_elegans		WBGENE00000159

Paralogs (6): AP2S1 (ENSG00000042753), AP4S1 (ENSG00000100478), AP1S1 (ENSG00000106367), AP3S2 (ENSG00000157823), AP3S1 (ENSG00000177879), AP1S2 (ENSG00000182287)

Protein

Protein identifiers

AP-1 complex subunit sigma-3 — Q96PC3 (reviewed: Q96PC3)

Alternative names: Adaptor protein complex AP-1 subunit sigma-1C, Adaptor-related protein complex 1 subunit sigma-1C, Clathrin assembly protein complex 1 sigma-1C small chain, Golgi adaptor HA1/AP1 adaptin sigma-1C subunit, Sigma 1C subunit of AP-1 clathrin, Sigma-adaptin 1C, Sigma1C-adaptin

All UniProt accessions (10): A0A8V8TN69, A0A8V8TN74, A0A8V8TNP8, A0A8V8TPK7, A0A8V8TPZ3, B8ZZZ1, C9JZK4, Q96PC3, F8W8K9, G5E966

UniProt curated annotations — full annotation on UniProt →

Function. Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. Involved in TLR3 trafficking.

Subunit / interactions. Adaptor protein complex 1 (AP-1) is a heterotetramer composed of two large adaptins (gamma-type subunit AP1G1 and beta-type subunit AP1B1), a medium adaptin (mu-type subunit AP1M1 or AP1M2) and a small adaptin (sigma-type subunit AP1S1 or AP1S2 or AP1S3).

Subcellular location. Golgi apparatus. Cytoplasmic vesicle membrane. Membrane. Clathrin-coated pit.

Tissue specificity. Widely expressed.

Disease relevance. Psoriasis 15, pustular (PSORS15) [MIM:616106] A form of pustular psoriasis, a life-threatening disease defined by repeated flares of sudden onset consisting of diffuse erythematous skin eruption characterized by rapid coverage with pustules, high-grade fever, asthenia, marked leukocytosis, and elevated serum levels of C-reactive protein. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the adaptor complexes small subunit family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q96PC3-1	1	yes
Q96PC3-2	2
Q96PC3-4	4
Q96PC3-3	3

RefSeq proteins (1): NP_001034658* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000804	Clathrin_sm-chain_CS	Conserved_site
IPR011012	Longin-like_dom_sf	Homologous_superfamily
IPR016635	AP_complex_ssu	Family
IPR022775	AP_mu_sigma_su	Domain
IPR044733	AP1_sigma	Family

Pfam: PF01217

UniProt features (25 total): sequence variant 8, strand 7, helix 5, splice variant 4, chain 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
9DDT	X-RAY DIFFRACTION	1.68
7R4H	ELECTRON MICROSCOPY	2.34
6CM9	ELECTRON MICROSCOPY	3.73
6DFF	ELECTRON MICROSCOPY	3.9
6D83	ELECTRON MICROSCOPY	4.27
6D84	ELECTRON MICROSCOPY	6.72
6CRI	ELECTRON MICROSCOPY	6.8
4HMY	X-RAY DIFFRACTION	7
8D4E	ELECTRON MICROSCOPY	9.2
8D4C	ELECTRON MICROSCOPY	9.3
8D9W	ELECTRON MICROSCOPY	9.3
8D9V	ELECTRON MICROSCOPY	9.4
7UX3	ELECTRON MICROSCOPY	9.6
8D4D	ELECTRON MICROSCOPY	9.6
8D4F	ELECTRON MICROSCOPY	9.8
8D4G	ELECTRON MICROSCOPY	11.6
8D9R	ELECTRON MICROSCOPY	20
8D9S	ELECTRON MICROSCOPY	20
8D9T	ELECTRON MICROSCOPY	20
8D9U	ELECTRON MICROSCOPY	20

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96PC3-F1	93.61	0.86

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-164940	Nef mediated downregulation of MHC class I complex cell surface expression
R-HSA-2132295	MHC class II antigen presentation
R-HSA-432720	Lysosome Vesicle Biogenesis
R-HSA-432722	Golgi Associated Vesicle Biogenesis
R-HSA-1280218	Adaptive Immune System
R-HSA-162906	HIV Infection
R-HSA-162909	Host Interactions of HIV factors
R-HSA-1643685	Disease
R-HSA-164938	Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters
R-HSA-164952	The role of Nef in HIV-1 replication and disease pathogenesis
R-HSA-168256	Immune System
R-HSA-199991	Membrane Trafficking
R-HSA-199992	trans-Golgi Network Vesicle Budding
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5663205	Infectious disease
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 266 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_PROTEIN_TARGETING, GOBP_CELLULAR_PIGMENTATION, KEGG_LYSOSOME, REACTOME_THE_ROLE_OF_NEF_IN_HIV_1_REPLICATION_AND_DISEASE_PATHOGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_PIGMENTATION, REACTOME_NEF_MEDIATES_DOWN_MODULATION_OF_CELL_SURFACE_RECEPTORS_BY_RECRUITING_THEM_TO_CLATHRIN_ADAPTERS, REACTOME_HIV_INFECTION, GOCC_TRANS_GOLGI_NETWORK

GO Biological Process (6): protein targeting (GO:0006605), intracellular protein transport (GO:0006886), vesicle-mediated transport (GO:0016192), platelet dense granule organization (GO:0060155), melanosome assembly (GO:1903232), protein transport (GO:0015031)

GO Molecular Function (2): clathrin-cargo adaptor activity (GO:0035615), protein binding (GO:0005515)

GO Cellular Component (14): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), early endosome (GO:0005769), cytosol (GO:0005829), clathrin-coated pit (GO:0005905), AP-1 adaptor complex (GO:0030121), cytoplasmic vesicle membrane (GO:0030659), trans-Golgi network membrane (GO:0032588), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), endomembrane system (GO:0012505), membrane (GO:0016020), membrane coat (GO:0030117), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
trans-Golgi Network Vesicle Budding	2
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1
Adaptive Immune System	1
Immune System	1
Viral Infection Pathways	1
HIV Infection	1
The role of Nef in HIV-1 replication and disease pathogenesis	1
Host Interactions of HIV factors	1
Vesicle-mediated transport	1
Membrane Trafficking	1
Disease	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
cellular anatomical structure	4
establishment of protein localization	2
intracellular protein localization	2
transport	2
endomembrane system	2
protein transport	1
intracellular transport	1
cellular process	1
secretory granule organization	1
melanosome organization	1
organelle assembly	1
clathrin binding	1
cargo adaptor activity	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
lysosome	1
lytic vacuole membrane	1
endosome	1
membrane	1
clathrin coat of trans-Golgi network vesicle	1
clathrin adaptor complex	1
vesicle membrane	1
cytoplasmic vesicle	1
trans-Golgi network	1
organelle membrane	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
vacuole	1
plasma membrane	1
coated membrane	1
membrane protein complex	1
intracellular vesicle	1

Protein interactions and networks

STRING

690 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AP1S3	CARD14	Q9BXL6	773
AP1S3	IL36RN	Q9UBH0	726
AP1S3	AP1M1	Q9BXS5	685
AP1S3	AP1G1	O43747	610
AP1S3	IL1RL2	Q9HB29	581
AP1S3	AP1M2	Q9Y6Q5	471
AP1S3	CALU	O43852	467
AP1S3	AP1G2	O75843	438
AP1S3	UBQLN4	Q9NRR5	425
AP1S3	ACTN1	P12814	402
AP1S3	MAPT	P10636	389
AP1S3	FLNA	P21333	388
AP1S3	AP3B2	Q13367	388
AP1S3	P4HB	P07237	387
AP1S3	HSPA4	P34932	379

IntAct

21 interactions, top by confidence:

A	B	Type	Score
AP1B1	Ap1g1	psi-mi:“MI:0915”(physical association)	0.740
AAGAB	AP1S3	psi-mi:“MI:0915”(physical association)	0.670
AP1S3	AAGAB	psi-mi:“MI:0915”(physical association)	0.670
AAGAB	AP2A2	psi-mi:“MI:0914”(association)	0.670
Ap1g1	Ap1m1	psi-mi:“MI:0914”(association)	0.660
AP1S3	PRKAG1	psi-mi:“MI:0915”(physical association)	0.370
AP2M1	C1orf226	psi-mi:“MI:0914”(association)	0.350
AP2B1	SYNJ1	psi-mi:“MI:0914”(association)	0.350
AP1S3	AP1G1	psi-mi:“MI:0914”(association)	0.350
AP1M2	AP1G1	psi-mi:“MI:0914”(association)	0.350
FTL	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
COMT	AP1G1	psi-mi:“MI:0914”(association)	0.350
AP2M1	PER1	psi-mi:“MI:0914”(association)	0.350
VAMP4	Ap1g1	psi-mi:“MI:0914”(association)	0.350

BioGRID (35): AP1S3 (Two-hybrid), AP1S3 (Affinity Capture-MS), AP1S3 (Affinity Capture-MS), AP1S3 (Affinity Capture-MS), AP1S3 (Affinity Capture-MS), AP1S3 (Affinity Capture-MS), AP1S3 (Affinity Capture-MS), AP1S3 (Two-hybrid), AP1B1 (Affinity Capture-MS), AP1G1 (Affinity Capture-MS), AP1G2 (Affinity Capture-MS), AP1M1 (Affinity Capture-MS), AP1S3 (Affinity Capture-MS), NEDD8-MDP1 (Affinity Capture-MS), HEATR5B (Affinity Capture-MS)

ESM2 similar proteins: B0G185, O02173, O17901, O23685, O43041, O50016, O82201, P35181, P35604, P47064, P53290, P53680, P56377, P61923, P61924, P61966, P61967, P62743, P62744, Q00381, Q09905, Q17QC5, Q1JQ98, Q28IG8, Q3ZBB6, Q3ZBS3, Q4ICG5, Q4WS49, Q54H39, Q54NZ4, Q54WW3, Q553S2, Q557G3, Q59QC5, Q5BFF8, Q5R5F2, Q5R940, Q5ZKP4, Q75F71, Q7SAQ1

Diamond homologs: B0G185, O23685, O50016, O82201, P35181, P47064, P53680, P56377, P59780, P61966, P61967, P62743, P62744, Q00381, Q09905, Q17QC5, Q1JQ98, Q1JQA3, Q2YDH6, Q3ZBB6, Q3ZBS3, Q4ICG5, Q4WS49, Q54H39, Q54NZ4, Q54WW3, Q553S2, Q5BFF8, Q5R940, Q5RDP9, Q75F71, Q7SAQ1, Q7TN05, Q84WL9, Q8BSZ2, Q8LEZ8, Q8VZ37, Q92572, Q96PC3, Q9DB50

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	6	317.2×	3e-13
The role of Nef in HIV-1 replication and disease pathogenesis	6	317.2×	3e-13
Host Interactions of HIV factors	6	167.9×	1e-11
HIV Infection	6	59.5×	4e-09
MHC class II antigen presentation	6	44.6×	2e-08
Clathrin-mediated endocytosis	5	35.5×	1e-06
Membrane Trafficking	8	24.7×	3e-09
Vesicle-mediated transport	8	23.2×	4e-09

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle endocytosis	5	154.3×	1e-08
vesicle-mediated transport	6	41.3×	2e-07
intracellular protein transport	6	27.8×	1e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

49 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	18
Likely benign	11
Benign	9

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
58846	GRCh38/hg38 2q36.1(chr2:223597428-224061556)x1	Pathogenic

SpliceAI

1251 predictions. Top by Δscore:

Variant	Effect	Δscore
2:223765209:TGA:T	donor_loss	1.0000
2:223765210:GAC:G	donor_loss	1.0000
2:223765211:ACCT:A	donor_gain	1.0000
2:223765212:CCTC:C	donor_gain	1.0000
2:223765214:T:TA	donor_gain	1.0000
2:223772594:A:AC	donor_gain	1.0000
2:223772595:C:CC	donor_gain	1.0000
2:223775894:CACT:C	donor_loss	1.0000
2:223775895:ACTT:A	donor_loss	1.0000
2:223775896:CT:C	donor_loss	1.0000
2:223775897:T:TC	donor_loss	1.0000
2:223775898:T:TG	donor_loss	1.0000
2:223775899:A:AC	donor_gain	1.0000
2:223775899:ACAT:A	donor_loss	1.0000
2:223775900:C:CG	donor_gain	1.0000
2:223775900:CATTT:C	donor_gain	1.0000
2:223777687:ACAC:A	donor_gain	1.0000
2:223777688:CA:C	donor_gain	1.0000
2:223777688:CACC:C	donor_gain	1.0000
2:223777688:CACCT:C	donor_gain	1.0000
2:223777716:T:TA	donor_gain	1.0000
2:223777729:A:C	donor_gain	1.0000
2:223777737:T:TA	donor_gain	1.0000
2:223777788:T:TA	donor_gain	1.0000
2:223777865:TGTAT:T	acceptor_gain	1.0000
2:223777866:GTAT:G	acceptor_gain	1.0000
2:223777867:TAT:T	acceptor_gain	1.0000
2:223777867:TATCT:T	acceptor_loss	1.0000
2:223777868:AT:A	acceptor_gain	1.0000
2:223777869:TCTAG:T	acceptor_loss	1.0000

AlphaMissense

1033 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:223765340:A:G	L101P	1.000
2:223765327:A:C	F105L	0.999
2:223765327:A:T	F105L	0.999
2:223765329:A:G	F105L	0.999
2:223765337:T:A	D102V	0.999
2:223765337:T:G	D102A	0.999
2:223765340:A:T	L101Q	0.999
2:223765342:C:A	E100D	0.999
2:223765342:C:G	E100D	0.999
2:223765343:T:A	E100V	0.999
2:223765344:C:T	E100K	0.999
2:223765346:C:T	C99Y	0.999
2:223775907:A:C	F95L	0.999
2:223775907:A:T	F95L	0.999
2:223775909:A:G	F95L	0.999
2:223775920:A:G	L91P	0.999
2:223775923:A:G	L90P	0.999
2:223775935:C:G	R86P	0.999
2:223776000:A:C	S64R	0.999
2:223776000:A:T	S64R	0.999
2:223776002:T:G	S64R	0.999
2:223777818:A:G	W19R	0.999
2:223777818:A:T	W19R	0.999
2:223765280:C:A	G121V	0.998
2:223765301:A:G	L114P	0.998
2:223765329:A:T	F105I	0.998
2:223765331:A:T	I104N	0.998
2:223765336:A:C	D102E	0.998
2:223765336:A:T	D102E	0.998
2:223765337:T:C	D102G	0.998

dbSNP variants (sampled 300 via entrez): RS1000052665 (2:223813464 T>C), RS1000103773 (2:223776332 GT>G,GTT), RS1000142955 (2:223798861 C>T), RS1000167512 (2:223800222 A>C), RS1000195470 (2:223758038 T>C), RS1000233928 (2:223823387 A>T), RS1000259748 (2:223804651 G>A), RS1000260235 (2:223774771 T>C), RS1000282677 (2:223770155 C>T), RS1000375349 (2:223774972 G>A), RS1000390392 (2:223817531 C>A), RS1000484158 (2:223830351 C>A,T), RS1000516371 (2:223834899 C>G), RS1000547438 (2:223835217 G>C), RS1000552368 (2:223787336 G>A)

Disease associations

OMIM: gene MIM:615781 | disease phenotypes: MIM:616106

GenCC curated gene-disease

Disease	Classification	Inheritance
psoriasis 15, pustular, susceptibility to	Strong	Autosomal dominant
palmoplantar pustulosis	Supportive	Autosomal dominant
psoriasis 14, pustular	Supportive	Autosomal recessive

Mondo (3): psoriasis 15, pustular, susceptibility to (MONDO:0014494), palmoplantar pustulosis (MONDO:0015597), psoriasis 14, pustular (MONDO:0013626)

Orphanet (1): Generalized pustular psoriasis (Orphanet:247353)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000083	Renal insufficiency
HP:0000554	Uveitis
HP:0001019	Erythroderma
HP:0001369	Arthritis
HP:0001513	Obesity
HP:0001597	Abnormal nail morphology
HP:0001635	Congestive heart failure
HP:0001888	Decreased total lymphocyte count
HP:0001945	Fever
HP:0001974	Increased total leukocyte count
HP:0002829	Arthralgia
HP:0002901	Hypocalcemia
HP:0002902	Hyponatremia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003073	Hypoalbuminemia
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0003765	Psoriasiform dermatitis
HP:0008404	Nail dystrophy
HP:0010741	Pedal edema
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0012378	Fatigue
HP:0012531	Pain
HP:0025252	Geographic tongue
HP:0025474	Erythematous plaque
HP:0025502	Overweight
HP:0100806	Sepsis
HP:0100825	Cheilitis
HP:0100847	Palmoplantar pustulosis
HP:0200039	Pustule

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002794_14	Airway wall thickness	5.000000e-08
GCST002794_5	Airway wall thickness	9.000000e-06
GCST002794_8	Airway wall thickness	2.000000e-06
GCST003542_31	Night sleep phenotypes	5.000000e-06
GCST006032_4	Sodium levels	4.000000e-13
GCST006633_4	Initial alcohol sensitivity	7.000000e-07
GCST007798_50	Asthma	1.000000e-06
GCST007800_98	Asthma (childhood onset)	3.000000e-13
GCST010043_103	Asthma	2.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006898	airway wall thickness measurement
EFO:0009282	sodium measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
entinostat	increases expression, affects cotreatment	2
Air Pollutants	increases expression, affects expression, increases abundance	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
urushiol	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases methylation	1
trichostatin A	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
methylparaben	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Zoledronic Acid	increases expression	1
Vorinostat	increases expression	1
Acetaminophen	increases expression	1
Acetylglucosamine	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SC76	HAP1 AP1S3 (-) 1	Cancer cell line	Male
CVCL_SC77	HAP1 AP1S3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

27 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05710185	PHASE4	TERMINATED	Deucravacitinib for the Treatment of Palmoplantar Pustulosis
NCT07503652	PHASE4	RECRUITING	Clinical Observation of Xeligekimab in the Treatment of Moderate to Severe Palmoplantar Pustulosis
NCT02641730	PHASE3	COMPLETED	An Efficacy and Safety of Guselkumab in Participants With Palmoplantar Pustulosis
NCT04061252	PHASE3	COMPLETED	A Study of KHK4827 in Subjects With Palmoplantar Pustulosis
NCT04451720	PHASE3	COMPLETED	Study of Subcutaneous Risankizumab Injection to Assess Change in Palmoplantar Pustulosis Area and Severity Index [PPPASI] in Adult Japanese Participants With Palmoplantar Pustulosis
NCT05174065	PHASE3	COMPLETED	Phase 3, Randomized Study of Apremilast in Japanese Participants With Palmoplantar Pustulosis (PPP)
NCT07219420	PHASE3	RECRUITING	A Study to Evaluate the Efficacy and Safety of Bimekizumab in Study Participants With Palmoplantar Pustulosis
NCT07530367	PHASE3	NOT_YET_RECRUITING	A Phase III Randomized Controlled Trial Evaluating the Efficacy and Safety of Tofacitinib Combined With Imatinib in Patients With Moderate-to-Severe Palmoplantar Pustulosis
NCT00301002	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Alefacept to Treat Palmar Plantar Pustulosis
NCT01794117	PHASE2	COMPLETED	Anakinra for Inflammatory Pustular Skin Diseases
NCT03633396	PHASE2	COMPLETED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in Adults With Palmoplantar Pustulosis
NCT03988335	PHASE2	COMPLETED	A Study to Evaluate RIST4721 in Palmoplantar Pustulosis (PPP)
NCT04015518	PHASE2	COMPLETED	A Study to Test How Effective and Safe Different Doses of BI 655130 Are in Patients With a Moderate to Severe Form of the Skin Disease Palmoplantar Pustulosis
NCT04493424	PHASE2	TERMINATED	A Study to Test Long-term Treatment With Spesolimab in People With Palmoplantar Pustulosis (PPP) Who Took Part in Previous Studies With Spesolimab
NCT04572997	PHASE2	COMPLETED	Apremilast in Patients With Moderate to Severe Palmoplantar Pustulosis (PPP) (APLANTUS)
NCT05194839	PHASE2	TERMINATED	A Phase 2b Study to Evaluate RIST4721 in Palmoplantar Pustulosis (PPP)
NCT07013201	PHASE2	RECRUITING	A 16-week Trial to Investigate the Efficacy and Safety of Delgocitinib Cream 20 mg/g in Adult Participants With Mild to Severe Palmoplantar Pustulosis
NCT03972280	PHASE1	COMPLETED	Safety and Pharmacokinetics of Repeat Doses of CSL324 in Subjects With Hidradenitis Suppurativa and Palmoplantar Pustulosis
NCT01780857	Not specified	COMPLETED	Immune Signature of Palmoplantar Pustulosis
NCT04459507	Not specified	COMPLETED	A Registry Study of Palmoplantar Pustulosis (PPP) Treatment Patterns, Disease Burden and Treatment Outcomes in Japan
NCT04566471	Not specified	UNKNOWN	Palmoplantar Pustulosis and Generalized Pustular Psoriasis: A National Population-based Analysis of Prevalence
NCT05994976	Not specified	RECRUITING	Collection of Samples From Subjects With Various Skin Conditions and Healthy Volunteers
NCT06790940	Not specified	NOT_YET_RECRUITING	Construction of a Psoriasis and Psoriatic Arthritis Diagnostic Model Based on Multidimensional Nail Information
NCT07000630	Not specified	TERMINATED	Efficacy and Tolerability of Deucravacitinib in the Management of Palmoplantar Pustulosis
NCT07270003	Not specified	RECRUITING	A Prospective, Single-arm, Open-label Clinical Trial to Evaluate the Efficacy and Safety of Ivarmacitinib in the Treatment of Palmoplantar Pustulosis
NCT07428915	Not specified	COMPLETED	Evaluating Legit.Health Plus Support for Improving Diagnosis of Generalized Pustular Psoriasis and Other Skin Conditions Among Primary Care Physicians and Dermatologists
NCT07552454	Not specified	RECRUITING	Picankibart in Palmoplantar Pustulosis