Familial cold autoinflammatory syndrome 2

Summary

Familial cold autoinflammatory syndrome 2 (MONDO:0012724) is a disease caused by NLRP12 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NLRP12 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 1,295

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	familial cold autoinflammatory syndrome 2
Mondo ID	MONDO:0012724
MeSH	C567090
OMIM	611762
Orphanet	247868
DOID	DOID:0090063
NCIT	C119043
UMLS	C2673198
MedGen	435869
GARD	0017201
Is cancer (heuristic)	no

Also known as: familial cold autoinflammatory syndrome 2 · familial cold autoinflammatory syndrome caused by mutation in NLRP12 · familial cold autoinflammatory syndrome type 2 · FCAS2 · NALP12-associated hereditary periodic fever syndrome · NAPS12 · NLRP12 familial cold autoinflammatory syndrome · NLRP12-associated hereditary periodic fever syndrome

Data availability: 1,295 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › cryopyrin-associated periodic syndrome › familial cold autoinflammatory syndrome › familial cold autoinflammatory syndrome 2

Related subtypes (3): familial cold autoinflammatory syndrome 1, familial cold autoinflammatory syndrome 3, familial cold autoinflammatory syndrome 4

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

600 retrieved; paginated sample, class counts are floors:

359 uncertain significance, 194 likely benign, 29 conflicting classifications of pathogenicity, 11 benign, 4 benign/likely benign, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1299510	NM_144687.4(NLRP12):c.2072+1G>C	NLRP12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687186	NM_144687.4(NLRP12):c.770del (p.Gln257fs)	NLRP12	Likely pathogenic	criteria provided, single submitter
1711851	NM_144687.4(NLRP12):c.957del (p.Thr320fs)	NLRP12	Likely pathogenic	criteria provided, single submitter
1009704	NM_144687.4(NLRP12):c.3089G>A (p.Arg1030Gln)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1021028	NM_144687.4(NLRP12):c.2360dup (p.Met787fs)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1123571	NM_144687.4(NLRP12):c.2384G>A (p.Arg795Gln)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1149572	NM_144687.4(NLRP12):c.2253G>A (p.Arg751=)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1151225	NM_144687.4(NLRP12):c.1403G>T (p.Gly468Val)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1324810	NM_144687.4(NLRP12):c.2879T>A (p.Leu960Ter)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1357125	NM_144687.4(NLRP12):c.2055C>G (p.His685Gln)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1364638	NM_144687.4(NLRP12):c.2337C>T (p.Gly779=)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1371380	NM_144687.4(NLRP12):c.2244G>A (p.Arg748=)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1381937	NM_144687.4(NLRP12):c.908del (p.Phe303fs)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1401846	NM_144687.4(NLRP12):c.2757-1G>T	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1413845	NM_144687.4(NLRP12):c.2188dup (p.Val730fs)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1520033	NM_144687.4(NLRP12):c.2661_2664del (p.Arg887fs)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1556303	NM_144687.4(NLRP12):c.1908C>A (p.Ile636=)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1566788	NM_144687.4(NLRP12):c.2754G>A (p.Leu918=)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1596	NM_144687.4(NLRP12):c.850C>T (p.Arg284Ter)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1597	NM_144687.4(NLRP12):c.2072+2dup	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1624820	NM_144687.4(NLRP12):c.436C>T (p.Arg146Cys)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1629219	NM_144687.4(NLRP12):c.78G>A (p.Lys26=)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1636919	NM_144687.4(NLRP12):c.3042T>C (p.Gly1014=)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694388	NM_144687.4(NLRP12):c.1060C>G (p.Leu354Val)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694413	NM_144687.4(NLRP12):c.2487G>C (p.Leu829=)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694415	NM_144687.4(NLRP12):c.2766C>T (p.Ile922=)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694416	NM_144687.4(NLRP12):c.2887G>A (p.Glu963Lys)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1937161	NM_144687.4(NLRP12):c.2652G>C (p.Gln884His)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2000598	NM_144687.4(NLRP12):c.575del (p.Ser192fs)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
208384	NM_144687.4(NLRP12):c.858C>G (p.Pro286=)	NLRP12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
NLRP12	Strong	Autosomal dominant	familial cold autoinflammatory syndrome 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NLRP12	Orphanet:247868	NLRP12-associated hereditary periodic fever syndrome

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	gencc,clinvar
RAPGEFL1	HGNC:17428	ENSG00000108352	Q9UHV5	Rap guanine nucleotide exchange factor-like 1	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.
RAPGEFL1	Rap guanine nucleotide exchange factor-like 1	Probable guanine nucleotide exchange factor (GEF).

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
RAPGEFL1	Other/Unknown	no		RASGEF_cat_dom, Ras-like_GEF, Ras_GEF_dom_sf

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
lower esophagus mucosa	1
skin of abdomen	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NLRP12	117	tissue_specific	marker	blood, monocyte, leukocyte
RAPGEFL1	223	broad	marker	lower esophagus mucosa, skin of abdomen, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NLRP12	1,451
RAPGEFL1	497

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NLRP12	P59046	3
RAPGEFL1	Q9UHV5	1

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
dendritic cell migration	1	936.2×	0.005	NLRP12
cellular response to cytokine stimulus	1	271.8×	0.011	NLRP12
negative regulation of cytokine production	1	255.3×	0.011	NLRP12
negative regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.011	NLRP12
regulation of canonical NF-kappaB signal transduction	1	240.7×	0.011	NLRP12
negative regulation of signal transduction	1	187.2×	0.012	NLRP12
negative regulation of interleukin-6 production	1	175.5×	0.012	NLRP12
ERK1 and ERK2 cascade	1	159.0×	0.012	NLRP12
positive regulation of interleukin-1 beta production	1	129.6×	0.013	NLRP12
positive regulation of non-canonical NF-kappaB signal transduction	1	127.7×	0.013	NLRP12
negative regulation of ERK1 and ERK2 cascade	1	108.0×	0.014	NLRP12
Ras protein signal transduction	1	102.8×	0.014	RAPGEFL1
negative regulation of canonical NF-kappaB signal transduction	1	86.0×	0.015	NLRP12
regulation of inflammatory response	1	84.3×	0.015	NLRP12
positive regulation of inflammatory response	1	72.6×	0.017	NLRP12
negative regulation of inflammatory response	1	68.5×	0.017	NLRP12
nervous system development	1	23.0×	0.047	RAPGEFL1
G protein-coupled receptor signaling pathway	1	18.1×	0.057	RAPGEFL1
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: 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
NLRP12	0	0
RAPGEFL1	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	NLRP12, RAPGEFL1

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	—
RAPGEFL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.