Proteasome-associated autoinflammatory syndrome 2

Summary

Proteasome-associated autoinflammatory syndrome 2 (MONDO:0054700) is a disease caused by POMP (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: POMP (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	proteasome-associated autoinflammatory syndrome 2
Mondo ID	MONDO:0054700
OMIM	618048
DOID	DOID:0060914
UMLS	C4747989
MedGen	1648482
GARD	0018447
Is cancer (heuristic)	no

Also known as: PRAAS2 · proteasome-associated autoinflammatory syndrome 2

Data availability: 5 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › proteosome-associated autoinflammatory syndrome › proteasome-associated autoinflammatory syndrome 2

Related subtypes (5): proteasome-associated autoinflammatory syndrome 5, proteasome-associated autoinflammatory syndrome 4, proteasome-associated autoinflammatory syndrome 1, proteasome-associated autoinflammatory syndrome 3, proteasome-associated autoinflammatory syndrome 6

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

5 retrieved; paginated sample, class counts are floors:

3 pathogenic, 1 benign/likely benign, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
522801	NM_015932.6(POMP):c.334_335del (p.Ile112fs)	POMP	Pathogenic	criteria provided, multiple submitters, no conflicts
548959	NM_015932.6(POMP):c.340_344dup (p.Glu115fs)	POMP	Pathogenic	no assertion criteria provided
548960	NM_015932.6(POMP):c.342_348delinsACC (p.Phe114fs)	POMP	Pathogenic	no assertion criteria provided
1492095	NM_015932.6(POMP):c.91C>T (p.Leu31Phe)	POMP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1168426	NM_015932.6(POMP):c.101+9G>A	POMP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 2 · 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
NT5C3A	Strong	Autosomal dominant	proteasome-associated autoinflammatory syndrome 2	13
POMP	Strong	Autosomal dominant	proteasome-associated autoinflammatory syndrome 2	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NT5C3A	Orphanet:35120	Hemolytic anemia due to pyrimidine 5’ nucleotidase deficiency
POMP	Orphanet:281201	Keratosis linearis-ichthyosis congenita-sclerosing keratoderma 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
NT5C3A	HGNC:17820	ENSG00000122643	Q9H0P0	Cytosolic 5’-nucleotidase 3A	gencc,clinvar
POMP	HGNC:20330	ENSG00000132963	Q9Y244	Proteasome maturation protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NT5C3A	Cytosolic 5’-nucleotidase 3A	Nucleotidase which shows specific activity towards cytidine monophosphate (CMP) and 7-methylguanosine monophosphate (m(7)GMP).
POMP	Proteasome maturation protein	Molecular chaperone essential for the assembly of standard proteasomes and immunoproteasomes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NT5C3A	Enzyme (other)	yes	3.1.3.91	Pyrimidine_nucleotidase_eu, HAD_sf, HAD-like_sf
POMP	Other/Unknown	no		Ump1

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
leukocyte	1
monocyte	1
quadriceps femoris	1
biceps brachii	1
heart right ventricle	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NT5C3A	138	ubiquitous	marker	quadriceps femoris, monocyte, leukocyte
POMP	288	ubiquitous	marker	heart right ventricle, biceps brachii, mucosa of sigmoid colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POMP	1,596
NT5C3A	1,223

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POMP	Q9Y244	11
NT5C3A	Q9H0P0	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Pyrimidine catabolism	1	439.2×	0.005	NT5C3A
Proteasome assembly	1	102.0×	0.010	POMP

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
pyrimidine nucleoside metabolic process	1	2106.5×	0.001	NT5C3A
dTMP catabolic process	1	1404.3×	0.001	NT5C3A
CMP catabolic process	1	1053.2×	0.001	NT5C3A
UMP catabolic process	1	1053.2×	0.001	NT5C3A
dCMP catabolic process	1	936.2×	0.001	NT5C3A
dUMP catabolic process	1	936.2×	0.001	NT5C3A
proteasome assembly	1	766.0×	0.001	POMP
defense response to virus	1	34.7×	0.029	NT5C3A

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
NT5C3A	0	0
POMP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NT5C3A	3.1.3.91	7-methylguanosine nucleotidase

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	1	NT5C3A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	POMP

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)
NT5C3A	0	—
POMP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.