spondyloepimetaphyseal dysplasia, PAPSS2 type

Summary

spondyloepimetaphyseal dysplasia, PAPSS2 type (MONDO:0019666) is a disease caused by PAPSS2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PAPSS2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 274

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	spondyloepimetaphyseal dysplasia, PAPSS2 type
Mondo ID	MONDO:0019666
OMIM	612847
Orphanet	93282
DOID	DOID:0050812
SNOMED CT	719172003
UMLS	C2748516
MedGen	440564
GARD	0016813
Is cancer (heuristic)	no

Also known as: BCYM4 · brachyolmia 4 with mild epiphyseal and metaphyseal changes · brachyolmia type 4 with mild epiphyseal and metaphyseal changes · spondyloepimetaphyseal dysplasia, Pakistani type

Data availability: 274 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › spondyloepimetaphyseal dysplasia, PAPSS2 type

Related subtypes (12): iron metabolism disease, phosphorus metabolism disease, potassium deficiency disease, calcium metabolic disease, spondyloepiphyseal dysplasia with congenital joint dislocations, diastrophic dysplasia, multiple epiphyseal dysplasia type 4, atelosteogenesis type II, achondrogenesis type IB, chondrodysplasia with joint dislocations, gPAPP type, acquired mineral metabolism disease, sulfur metabolism disease

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

274 retrieved; paginated sample, class counts are floors:

109 uncertain significance, 105 likely benign, 26 pathogenic, 14 benign, 8 benign/likely benign, 6 likely pathogenic, 3 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074284	NM_001015880.2(PAPSS2):c.1666C>T (p.Arg556Ter)	PAPSS2	Pathogenic	criteria provided, single submitter
1076661	NM_001015880.2(PAPSS2):c.724G>T (p.Glu242Ter)	PAPSS2	Pathogenic	criteria provided, single submitter
1676681	NM_001015880.2(PAPSS2):c.1317C>A (p.Tyr439Ter)	PAPSS2	Pathogenic	criteria provided, single submitter
1679876	NM_001015880.2(PAPSS2):c.640-1G>C	PAPSS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683431	NM_001015880.2(PAPSS2):c.1721+2T>C	PAPSS2	Pathogenic	criteria provided, single submitter
1686003	NM_001015880.2(PAPSS2):c.386G>A (p.Arg129His)	PAPSS2	Pathogenic	criteria provided, single submitter
2118413	NM_001015880.2(PAPSS2):c.520+1G>A	PAPSS2	Pathogenic	criteria provided, single submitter
2118414	NM_001015880.2(PAPSS2):c.998T>A (p.Leu333Ter)	PAPSS2	Pathogenic	criteria provided, single submitter
2791800	NM_001015880.2(PAPSS2):c.1273del (p.Leu425fs)	PAPSS2	Pathogenic	criteria provided, single submitter
3012764	NM_001015880.2(PAPSS2):c.28G>T (p.Glu10Ter)	PAPSS2	Pathogenic	criteria provided, single submitter
3621073	NM_001015880.2(PAPSS2):c.1129C>T (p.Gln377Ter)	PAPSS2	Pathogenic	criteria provided, single submitter
39642	NM_001015880.2(PAPSS2):c.337dup (p.Ala113fs)	PAPSS2	Pathogenic	no assertion criteria provided
39643	NM_001015880.2(PAPSS2):c.616_634del (p.Val206fs)	PAPSS2	Pathogenic	no assertion criteria provided
39644	NM_001015880.2(PAPSS2):c.1309_1310del (p.Arg437fs)	PAPSS2	Pathogenic	no assertion criteria provided
39645	NM_001015880.2(PAPSS2):c.477_480dup (p.Lys161fs)	PAPSS2	Pathogenic	no assertion criteria provided
39646	NM_001015880.2(PAPSS2):c.661del (p.Ile221fs)	PAPSS2	Pathogenic	no assertion criteria provided
4292898	NM_001015880.2(PAPSS2):c.316del (p.Val106fs)	PAPSS2	Pathogenic	criteria provided, single submitter
4687926	NM_001015880.2(PAPSS2):c.1056del (p.Thr353fs)	PAPSS2	Pathogenic	criteria provided, single submitter
4743834	NM_001015880.2(PAPSS2):c.1417G>T (p.Glu473Ter)	PAPSS2	Pathogenic	criteria provided, single submitter
4750649	NM_001015880.2(PAPSS2):c.492T>A (p.Tyr164Ter)	PAPSS2	Pathogenic	criteria provided, single submitter
505568	NM_001015880.2(PAPSS2):c.222C>G (p.Tyr74Ter)	PAPSS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
572534	NM_001015880.2(PAPSS2):c.683_684del (p.Phe228fs)	PAPSS2	Pathogenic	criteria provided, single submitter
6686	NM_001015880.2(PAPSS2):c.1439C>A (p.Ser480Ter)	PAPSS2	Pathogenic	criteria provided, single submitter
6687	NM_001015880.2(PAPSS2):c.143C>G (p.Thr48Arg)	PAPSS2	Pathogenic	no assertion criteria provided
6688	NM_001015880.2(PAPSS2):c.1000C>T (p.Arg334Ter)	PAPSS2	Pathogenic	criteria provided, multiple submitters, no conflicts
932064	NM_001015880.2(PAPSS2):c.121C>T (p.Arg41Ter)	PAPSS2	Pathogenic	criteria provided, multiple submitters, no conflicts
932326	NM_001015880.2(PAPSS2):c.712C>T (p.Arg238Ter)	PAPSS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988297	NM_001015880.2(PAPSS2):c.1476T>A (p.Tyr492Ter)	PAPSS2	Pathogenic	criteria provided, multiple submitters, no conflicts
988389	NM_001015880.2(PAPSS2):c.1078del (p.His360fs)	PAPSS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1506358	NM_001015880.2(PAPSS2):c.1828_1829insGAGATTATTACAGGTCCCGA (p.Thr610fs)	PAPSS2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
PAPSS2	Definitive	Autosomal recessive	spondyloepimetaphyseal dysplasia, PAPSS2 type	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAPSS2	Orphanet:448242	Autosomal recessive brachyolmia
PAPSS2	Orphanet:93282	Spondyloepimetaphyseal dysplasia, PAPSS2 type

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PAPSS2	HGNC:8604	ENSG00000198682	O95340	Bifunctional 3’-phosphoadenosine 5’-phosphosulfate synthase 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PAPSS2	Bifunctional 3’-phosphoadenosine 5’-phosphosulfate synthase 2	Bifunctional enzyme with both ATP sulfurylase and APS kinase activity, which mediates two steps in the sulfate activation pathway.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PAPSS2	Kinase	yes	2.7.1.25	Sulphate_adenylyltransferase, APS, Rossmann-like_a/b/a_fold

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
mucosa of sigmoid colon	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PAPSS2	272	ubiquitous	marker	tibia, adrenal tissue, mucosa of sigmoid colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAPSS2	2,060

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAPSS2	O95340	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 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
Defective PAPSS2 causes SEMD-PA	1	11420.0×	3e-04	PAPSS2
Metabolism of ingested H2SeO4 and H2SeO3 into H2Se	1	2855.0×	5e-04	PAPSS2
Transport and metabolism of PAPS	1	1631.4×	6e-04	PAPSS2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sulfate assimilation	1	8426.0×	2e-04	PAPSS2
3’-phosphoadenosine 5’-phosphosulfate biosynthetic process	1	8426.0×	2e-04	PAPSS2
hormone metabolic process	1	887.0×	0.001	PAPSS2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PAPSS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PAPSS2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PAPSS2	2.7.1.25, 2.7.7.4	adenylyl-sulfate kinase, sulfate adenylyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	PAPSS2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PAPSS2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.