Psoriasis 14, pustular

Summary

Psoriasis 14, pustular (MONDO:0013626) is a disease caused by IL36RN (GenCC Strong), with 2 cohort genes (2 GWAS associations across 1 studies) and 26 clinical trials. Top therapeutic interventions include cravacitinib, tofacitinib, and spesolimab.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: IL36RN (GenCC Strong)
• Cohort genes: 2
• GWAS associations: 2
• ClinVar variants: 23
• Clinical trials: 26

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	6	Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	psoriasis 14, pustular
Mondo ID	MONDO:0013626
OMIM	614204
Orphanet	163931, 404546
DOID	DOID:0080474
NCIT	C119057
SNOMED CT	83839005
UMLS	C0392439
MedGen	581114
GARD	0017679
Is cancer (heuristic)	no

Also known as: acrodermatitis continua of Hallopeau · acrodermatitis continua suppurativa of Hallopeau · deficiency of IL-36R antagonist · deficiency of IL-36Ra · deficiency of the interleukin-36 receptor antagonist · DITRA · familial generalised pustular psoriasis · generalised pustular psoriasis · GPP · IL36RN psoriasis · Interleukin 36 receptor antagonist deficiency · palmoplantar pustulosis · psoriasis 14, pustular · psoriasis caused by mutation in IL36RN · PSORP · PSORS14

Data availability: 23 ClinVar variants · 2 GWAS associations (1 study) · 8 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › epidermal disease › psoriasis 14, pustular

Related subtypes (24): porokeratosis, Darier disease, absence of fingerprints-congenital milia syndrome, hyperkeratosis lenticularis perstans, keratolytic winter erythema, Hailey-Hailey disease, VPS13A-related neurodegenerative disease, acanthosis nigricans-insulin resistance-muscle cramps-acral enlargement syndrome, keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome, seborrhea-like dermatitis with psoriasiform elements, palmoplantar pustulosis, hereditary poikiloderma, congenital erosive and vesicular dermatosis, neonatal inflammatory skin and bowel disease, 13q12.3 microdeletion syndrome, zinc-responsive necrolytic acral erythema, keratosis pilaris atrophicans, ichthyosis, erythrokeratoderma, hereditary palmoplantar keratoderma, inherited epidermolysis bullosa, punctate acrokeratoderma freckle-like pigmentation, aquagenic palmoplantar keratoderma, phrynoderma

Genetics & variants

GWAS landscape

2 GWAS associations across 1 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs148755083	1e-18	IL36RN	C	8.24
HLA-C*06:02	8e-12		?	2.98

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90274859	Zhang Q	2023	161	0	Identification of the BTN3A3 gene as a molecule implicated in generalized pustular psoriasis in a Chinese population.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	1

MAF distribution

Bucket	Variants
common (>=0.05)	0
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
splice_donor_region_variant	1
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs148755083	2	113060943	T>C	0.02	splice_donor_region_variant	IL36RN	1e-18	Tier 2: splice/UTR
HLA-C*06:02							8e-12	Tier 4: intronic/intergenic

ClinVar germline variants

23 retrieved; paginated sample, class counts are floors:

10 conflicting classifications of pathogenicity, 7 uncertain significance, 3 pathogenic, 1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
30489	NM_012275.3(IL36RN):c.80T>C (p.Leu27Pro)	IL36RN	Pathogenic	criteria provided, multiple submitters, no conflicts
3776767	NM_012275.3(IL36RN):c.205_212del (p.Ser69fs)	IL36RN	Pathogenic	criteria provided, single submitter
40005	NM_012275.3(IL36RN):c.115+6T>C	IL36RN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40006	NM_012275.3(IL36RN):c.368C>G (p.Thr123Arg)	IL36RN	Pathogenic	no assertion criteria provided
2579641	NM_012275.3(IL36RN):c.338C>A (p.Ser113Ter)	IL36RN	Likely pathogenic	criteria provided, single submitter
30490	NM_012275.3(IL36RN):c.338C>T (p.Ser113Leu)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330783	NM_012275.3(IL36RN):c.*222T>C	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330784	NM_012275.3(IL36RN):c.*276A>G	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330787	NM_012275.3(IL36RN):c.*326C>A	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330789	NM_012275.3(IL36RN):c.*401A>T	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330790	NM_012275.3(IL36RN):c.*418A>G	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330792	NM_012275.3(IL36RN):c.*560C>G	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40007	NM_012275.3(IL36RN):c.28C>T (p.Arg10Ter)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
575254	NM_012275.3(IL36RN):c.227C>T (p.Pro76Leu)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
662407	NM_012275.3(IL36RN):c.368C>T (p.Thr123Met)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1058368	NM_012275.3(IL36RN):c.266A>G (p.Tyr89Cys)	IL36RN	Uncertain significance	criteria provided, multiple submitters, no conflicts
160373	NM_012275.3(IL36RN):c.104A>G (p.Lys35Arg)	IL36RN	Uncertain significance	criteria provided, single submitter
160374	NM_012275.3(IL36RN):c.304C>T (p.Arg102Trp)	IL36RN	Uncertain significance	criteria provided, multiple submitters, no conflicts
30491	NM_012275.3(IL36RN):c.142C>T (p.Arg48Trp)	IL36RN	Uncertain significance	criteria provided, single submitter
3393268	NM_012275.3(IL36RN):c.179G>T (p.Gly60Val)	IL36RN	Uncertain significance	criteria provided, single submitter
4078998	NM_012275.3(IL36RN):c.115G>T (p.Gly39Cys)	IL36RN	Uncertain significance	criteria provided, single submitter
632327	NM_012275.3(IL36RN):c.-28+1G>A	IL36RN	Uncertain significance	criteria provided, single submitter
529887	NM_012275.3(IL36RN):c.140A>G (p.Asn47Ser)	IL36RN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
AP1S3	Strong	Autosomal dominant	psoriasis 15, pustular, susceptibility to	5
IL36RN	Strong	Autosomal recessive	psoriasis 14, pustular	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL36RN	Orphanet:163927	Pustulosis palmaris et plantaris
IL36RN	Orphanet:163931	Acrodermatitis continua of Hallopeau
IL36RN	Orphanet:247353	Generalized pustular psoriasis
IL36RN	Orphanet:404546	DITRA
AP1S3	Orphanet:163927	Pustulosis palmaris et plantaris
AP1S3	Orphanet:163931	Acrodermatitis continua of Hallopeau
AP1S3	Orphanet:247353	Generalized pustular psoriasis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IL36RN	HGNC:15561	ENSG00000136695	Q9UBH0	Interleukin-36 receptor antagonist protein	gencc,clinvar
AP1S3	HGNC:18971	ENSG00000152056	Q96PC3	AP-1 complex subunit sigma-3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL36RN	Interleukin-36 receptor antagonist protein	Inhibits the activity of interleukin-36 (IL36A,IL36B and IL36G) by binding to receptor IL1RL2 and preventing its association with the coreceptor IL1RAP for signaling.
AP1S3	AP-1 complex subunit sigma-3	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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL36RN	Other/Unknown	no		IL-1_fam, IL-1RA/IL-36, IL1/FGF
AP1S3	Other/Unknown	no		Clathrin_sm-chain_CS, Longin-like_dom_sf, AP_complex_ssu

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
amniotic fluid	1
gingiva	1
upper arm skin	1
islet of Langerhans	1
male germ line stem cell (sensu Vertebrata) in testis	1
placenta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL36RN	106	tissue_specific	yes	amniotic fluid, upper arm skin, gingiva
AP1S3	135	ubiquitous	marker	islet of Langerhans, placenta, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL36RN	1,137
AP1S3	746

Intra-cohort edges

A	B	Sources
AP1S3	IL36RN	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AP1S3	Q96PC3	20
IL36RN	Q9UBH0	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-36 pathway	1	815.7×	0.013	IL36RN
Nef mediated downregulation of MHC class I complex cell surface expression	1	571.0×	0.013	AP1S3
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1	317.2×	0.013	AP1S3
The role of Nef in HIV-1 replication and disease pathogenesis	1	317.2×	0.013	AP1S3
Host Interactions of HIV factors	1	167.9×	0.017	AP1S3
Lysosome Vesicle Biogenesis	1	163.1×	0.017	AP1S3
trans-Golgi Network Vesicle Budding	1	126.9×	0.019	AP1S3
Golgi Associated Vesicle Biogenesis	1	100.2×	0.021	AP1S3
HIV Infection	1	59.5×	0.032	AP1S3
MHC class II antigen presentation	1	44.6×	0.038	AP1S3
Membrane Trafficking	1	18.5×	0.080	AP1S3
Vesicle-mediated transport	1	17.4×	0.080	AP1S3
Viral Infection Pathways	1	15.4×	0.080	AP1S3
Adaptive Immune System	1	14.9×	0.080	AP1S3
Infectious disease	1	12.4×	0.089	AP1S3
Disease	1	6.5×	0.148	AP1S3
Immune System	1	6.5×	0.148	AP1S3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
antifungal humoral response	1	1685.2×	0.007	IL36RN
negative regulation of cytokine-mediated signaling pathway	1	936.2×	0.007	IL36RN
negative regulation of interleukin-17 production	1	526.6×	0.008	IL36RN
melanosome assembly	1	443.5×	0.008	AP1S3
platelet dense granule organization	1	337.0×	0.008	AP1S3
negative regulation of type II interferon production	1	191.5×	0.010	IL36RN
protein targeting	1	183.2×	0.010	AP1S3
negative regulation of interleukin-6 production	1	175.5×	0.010	IL36RN
cellular response to lipopolysaccharide	1	49.0×	0.029	IL36RN
vesicle-mediated transport	1	48.1×	0.029	AP1S3
intracellular protein transport	1	32.4×	0.039	AP1S3
immune response	1	23.5×	0.049	IL36RN
inflammatory response	1	18.9×	0.056	IL36RN
innate immune response	1	16.8×	0.059	IL36RN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IL36RN	0	0
AP1S3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	IL36RN, AP1S3

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
IL36RN	0	—
AP1S3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 26.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE2	8
PHASE3	6
PHASE4	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07503652	PHASE4	RECRUITING	Clinical Observation of Xeligekimab in the Treatment of Moderate to Severe Palmoplantar Pustulosis
NCT05710185	PHASE4	TERMINATED	Deucravacitinib for the Treatment of Palmoplantar Pustulosis
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
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)
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
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)
NCT03972280	PHASE1	COMPLETED	Safety and Pharmacokinetics of Repeat Doses of CSL324 in Subjects With Hidradenitis Suppurativa and Palmoplantar Pustulosis
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
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
NCT07552454	Not specified	RECRUITING	Picankibart in 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
NCT07000630	Not specified	TERMINATED	Efficacy and Tolerability of Deucravacitinib in the Management 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

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CRAVACITINIB	4	6
TOFACITINIB	4	3
SPESOLIMAB	4	2
ANAKINRA	4	1
APREMILAST	4	1
BIMEKIZUMAB	4	1
BRODALUMAB	4	1
GUSELKUMAB	4	1
IMATINIB	4	1
RISANKIZUMAB	4	1
DELGOCITINIB	3	1
IMSIDOLIMAB	3	1
IVARMACITINIB	3	1
VIMNERIXIN	2	2
PICANKIBART	2	1
CHEMBL475165	0	2
CHEMBL5220618	0	1
CHEMBL5421204	0	1