Periodic fever syndrome

Summary

Periodic fever syndrome (MONDO:0015137) is a disease with 2 cohort genes and 2 clinical trials.

At a glance

• Cohort genes: 2
• ClinVar variants: 2
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	periodic fever syndrome
Mondo ID	MONDO:0015137
Orphanet	101995
NCIT	C118240
UMLS	C3889979
MedGen	855463
GARD	0019812
MedDRA	10034533
Is cancer (heuristic)	no

Data availability: 2 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › autoinflammatory syndrome › periodic fever syndrome

Related subtypes (36): cherubism, chronic recurrent multifocal osteomyelitis, Pelger-Huet-like anomaly and episodic fever with abdominal pain, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, psoriasis 14, pustular, autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation, infantile onset panniculitis with uveitis and systemic granulomatosis, idiopathic recurrent pericarditis, pyoderma gangrenosum-acne-suppurative hidradenitis syndrome, neonatal inflammatory skin and bowel disease, magic syndrome, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, Schnitzler syndrome, PFAPA syndrome, pyoderma gangrenosum, SAPHO syndrome, sarcoidosis, adult-onset Still disease, systemic-onset juvenile idiopathic arthritis, VEXAS syndrome, autoinflammatory syndrome, familial, Behcet-like, CEBPE-associated autoinflammation-immunodeficiency-neutrophil dysfunction syndrome, type 1 interferonopathy, autoinflammatory disease, X-linked, autoinflammatory syndrome with immunodeficiency, early-onset pulmonary and cutaneous vasculitis, autoinflammatory syndrome due to TBK1 deficiency, F12-associated cold autoinflammatory syndrome, neonatal-onset severe multisystemic autoinflammatory disease with increased IL18, SAMD9L-associated autoinflammatory syndrome, autoinflammatory syndrome of childhood, autoinflammatory disease, systemic, with vasculitis, granulomatous autoinflammatory syndrome of childhood, autoinflammatory disease, multisystem, with immune dysregulation, X-linked, PAPASH syndrome, Sharpin-related autoinflammatory syndrome

Subtypes (3): unexplained periodic fever syndrome, hereditary periodic fever syndrome, periodic fever syndrome of childhood

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
4075149	NM_022489.4(INF2):c.187G>T (p.Gly63Cys)	INF2	Uncertain significance	criteria provided, single submitter
440985	NM_144687.4(NLRP12):c.1027C>T (p.Arg343Trp)	NLRP12	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NLRP12	Orphanet:247868	NLRP12-associated hereditary periodic fever syndrome
INF2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
INF2	Orphanet:93114	Autosomal dominant intermediate Charcot-Marie-Tooth disease type E

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
NLRP12	HGNC:22938	ENSG00000142405	P59046	NACHT, LRR and PYD domains-containing protein 12	clinvar
INF2	HGNC:23791	ENSG00000203485	Q27J81	Inverted formin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NLRP12	NACHT, LRR and PYD domains-containing protein 12	Plays an essential role as an potent mitigator of inflammation.
INF2	Inverted formin-2	Severs actin filaments and accelerates their polymerization and depolymerization.

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)
NLRP12	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase
INF2	Other/Unknown	no		WH2_dom, FH3_dom, GTPase-bd

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
blood	1
leukocyte	1
monocyte	1
nerve	1
sural nerve	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NLRP12	117	tissue_specific	marker	blood, monocyte, leukocyte
INF2	260	ubiquitous	marker	sural nerve, nerve, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INF2	2,070
NLRP12	1,451

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INF2	Q27J81	10
NLRP12	P59046	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SARS-CoV-2-host interactions	1	119.0×	0.029	NLRP12
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	89.2×	0.029	NLRP12
SARS-CoV-2 Infection	1	80.4×	0.029	NLRP12
SARS-CoV Infections	1	55.4×	0.032	NLRP12
Viral Infection Pathways	1	30.8×	0.045	NLRP12
Infectious disease	1	24.8×	0.047	NLRP12
Disease	1	13.1×	0.076	NLRP12

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
regulation of interleukin-18 production	1	8426.0×	0.003	NLRP12
negative regulation of Toll signaling pathway	1	4213.0×	0.003	NLRP12
negative regulation of interleukin-1 production	1	1404.3×	0.004	NLRP12
positive regulation of MHC class I biosynthetic process	1	1404.3×	0.004	NLRP12
regulation of mitochondrial fission	1	1053.2×	0.004	INF2
dendritic cell migration	1	936.2×	0.004	NLRP12
cellular response to cytokine stimulus	1	271.8×	0.008	NLRP12
negative regulation of cytokine production	1	255.3×	0.008	NLRP12
negative regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.008	NLRP12
actin filament polymerization	1	240.7×	0.008	INF2
regulation of canonical NF-kappaB signal transduction	1	240.7×	0.008	NLRP12
negative regulation of signal transduction	1	187.2×	0.010	NLRP12
negative regulation of interleukin-6 production	1	175.5×	0.010	NLRP12
ERK1 and ERK2 cascade	1	159.0×	0.010	NLRP12
positive regulation of interleukin-1 beta production	1	129.6×	0.011	NLRP12
positive regulation of non-canonical NF-kappaB signal transduction	1	127.7×	0.011	NLRP12
negative regulation of ERK1 and ERK2 cascade	1	108.0×	0.012	NLRP12
negative regulation of canonical NF-kappaB signal transduction	1	86.0×	0.014	NLRP12
regulation of inflammatory response	1	84.3×	0.014	NLRP12
positive regulation of inflammatory response	1	72.6×	0.015	NLRP12
negative regulation of inflammatory response	1	68.5×	0.015	NLRP12
signal transduction	1	8.0×	0.121	NLRP12

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NLRP12	0	0
INF2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
INF2	1	Binding:1

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	NLRP12, INF2

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)
NLRP12	0	—
INF2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05027373	PHASE1	UNKNOWN	Safety, Tolerability and Pharmacokinetic of Recombinant Anti-IL-1β Humanized Monoclonal Antibody Injection
NCT05995288	Not specified	COMPLETED	Homeopathic Treatment of Children Suffering From PFAPA