PAPSS2

Summary

PAPSS2 (3’-phosphoadenosine 5’-phosphosulfate synthase 2, HGNC:8604) is a protein-coding gene on chromosome 10q23.2-q23.31, encoding Bifunctional 3’-phosphoadenosine 5’-phosphosulfate synthase 2 (O95340). Bifunctional enzyme with both ATP sulfurylase and APS kinase activity, which mediates two steps in the sulfate activation pathway.

Sulfation is a common modification of endogenous (lipids, proteins, and carbohydrates) and exogenous (xenobiotics and drugs) compounds. In mammals, the sulfate source is 3’-phosphoadenosine 5’-phosphosulfate (PAPS), created from ATP and inorganic sulfate. Two different tissue isoforms encoded by different genes synthesize PAPS. This gene encodes one of the two PAPS synthetases. Defects in this gene cause the Pakistani type of spondyloepimetaphyseal dysplasia. Two alternatively spliced transcript variants that encode different isoforms have been described for this gene.

Source: NCBI Gene 9060 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spondyloepimetaphyseal dysplasia, PAPSS2 type (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 406 total — 28 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 14
• Druggable target: yes
• MANE Select transcript: NM_001015880

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8604
Approved symbol	PAPSS2
Name	3’-phosphoadenosine 5’-phosphosulfate synthase 2
Location	10q23.2-q23.31
Locus type	gene with protein product
Status	Approved
Aliases	ATPSK2
Ensembl gene	ENSG00000198682
Ensembl biotype	protein_coding
OMIM	603005
Entrez	9060

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000361175, ENST00000456849, ENST00000465996, ENST00000482258, ENST00000904622, ENST00000904623, ENST00000904624, ENST00000904625, ENST00000928413, ENST00000947766, ENST00000947767

RefSeq mRNA: 2 — MANE Select: NM_001015880 NM_001015880, NM_004670

CCDS: CCDS44453, CCDS7385

Canonical transcript exons

ENST00000456849 — 13 exons

Exon	Start	End
ENSE00001420168	87659878	87660008
ENSE00002477037	87721756	87721770
ENSE00003554441	87709196	87709313
ENSE00003566610	87713075	87713310
ENSE00003889631	87745002	87745231
ENSE00003889720	87714985	87715098
ENSE00003891134	87745832	87747705
ENSE00003892049	87715732	87715843
ENSE00003892768	87741235	87741370
ENSE00003892862	87727284	87727489
ENSE00003893065	87714044	87714182
ENSE00003893791	87714745	87714863
ENSE00003895436	87743373	87743641

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 99.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.9447 / max 261.2061, expressed in 1464 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106022	13.2873	1443
106023	0.4767	243
106024	0.1806	106

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.61	gold quality
adrenal tissue	UBERON:0018303	99.45	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.37	gold quality
colonic mucosa	UBERON:0000317	99.35	gold quality
lower lobe of lung	UBERON:0008949	99.34	gold quality
cartilage tissue	UBERON:0002418	99.22	gold quality
type B pancreatic cell	CL:0000169	99.09	gold quality
visceral pleura	UBERON:0002401	98.66	gold quality
islet of Langerhans	UBERON:0000006	98.65	gold quality
adrenal cortex	UBERON:0001235	98.23	gold quality
right adrenal gland	UBERON:0001233	98.18	gold quality
right adrenal gland cortex	UBERON:0035827	98.13	gold quality
jejunal mucosa	UBERON:0000399	98.12	gold quality
left adrenal gland cortex	UBERON:0035825	98.10	gold quality
left adrenal gland	UBERON:0001234	98.07	gold quality
ileal mucosa	UBERON:0000331	97.84	gold quality
pleura	UBERON:0000977	97.80	gold quality
pericardium	UBERON:0002407	97.77	gold quality
adrenal gland	UBERON:0002369	97.58	gold quality
right lung	UBERON:0002167	97.52	gold quality
parietal pleura	UBERON:0002400	97.37	gold quality
mucosa of transverse colon	UBERON:0004991	96.92	gold quality
stromal cell of endometrium	CL:0002255	96.82	gold quality
upper lobe of lung	UBERON:0008948	96.72	gold quality
lung	UBERON:0002048	96.60	gold quality
upper lobe of left lung	UBERON:0008952	96.53	gold quality
rectum	UBERON:0001052	96.52	gold quality
germinal epithelium of ovary	UBERON:0001304	96.45	gold quality
placenta	UBERON:0001987	95.47	gold quality
duodenum	UBERON:0002114	95.40	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	18197.66
E-ANND-3	yes	15.53
E-GEOD-125970	yes	15.38
E-GEOD-130148	yes	5.84
E-GEOD-100618	no	168.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPG, DBP, MAFB, SP1, SP2, SP3

miRNA regulators (miRDB)

104 targeting PAPSS2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-545-3P	99.95	70.74	2783
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-6809-3P	99.91	71.45	3814

Literature-anchored findings (GeneRIF, showing 19)

• Transcriptional regulation of human 3’-phosphoadenosine 5’-phosphosulphate synthase 2. (PMID:11931653)
• Thirty-seven novel SNPs in the PAPSS2 gene and in two intergenic regions on chromosomes 2q33.1 and 18p11.32 were associated with exercise participation. (PMID:19727025)
• Unusual localisation signals of both PAPS synthase isoforms, are described. (PMID:22242175)
• Papss2 expression is reduced in articular cartilage following transforming growth factor-beta administration. (PMID:22394585)
• PAPSS2 is the disease gene for an autosomal recessive brachyolmia. (PMID:22791835)
• PAPSS2-brachyolmia includes phenotypes of the conventional clinical concept of brachyolmia, the Hobaek and Toledo types, and is associated with abnormal androgen metabolism. (PMID:23824674)
• Direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. (PMID:25594860)
• Results suggest that the loss of the susceptible region on chromosome 10q, which implicates PTEN, FAS and PAPSS2 may serve as genetic predictors of PSA recurrence after radical prostatectomy. (PMID:25679447)
• Our results indicate that FGFR2 and PAPSS2 may play an important role in the regulation of magnesium homeostasis in children of European-American ancestry. (PMID:26685716)
• In an Amish population, using expression profiling of genes within regions identified by a meta-analysis GWAS of survival to age 90, we localized PAPSS2 as a candidate gene for extended life span. These results provide novel evidence for genetic loci implicated in longevity and incorporate gene expression results from a unique population to locate positional candidates. (PMID:26896383)
• Silencing of SULT1A1 and PAPSS2 led to a significant decrease in aristolactam-DNA levels in both cell lines following exposure to AA-I, indicating the critical role for sulfonation in the activation of AA-I in vivo Since HK-2 cells proved relatively resistant to knockdown with siRNAs (PMID:27207664)
• Energy-dependent scoring of docking solutions identified the interaction as specific for the PAPSS2 and SULT2A1 isoforms (PMID:29743239)
• Depletion of PAPSS2 in MCF7 and MDA-MB-231 cells results in reduced cell migration, while overexpression of PAPSS2 promotes cell migration. (PMID:29955124)
• In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. (PMID:31313512)
• Intestinal Sulfation Is Essential to Protect Against Colitis and Colonic Carcinogenesis. (PMID:33819483)
• Structural basis for the substrate recognition mechanism of ATP-sulfurylase domain of human PAPS synthase 2. (PMID:34818583)
• Identification of variants in ACAN and PAPSS2 leading to spondyloepi(meta)physeal dysplasias in four Chinese families. (PMID:35261200)
• Redox switching mechanism of the adenosine 5’-phosphosulfate kinase domain (APSK2) of human PAPS synthase 2. (PMID:37207644)
• Bone Phenotype is Always Present But Androgen Excess is Less Frequently Seen in PAPSS2 Deficiency. (PMID:38084048)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	papss2b	ENSDARG00000056600
danio_rerio	papss2a	ENSDARG00000071021
mus_musculus	Papss2	ENSMUSG00000024899
rattus_norvegicus	Papss2	ENSRNOG00000011068
drosophila_melanogaster	Papss	FBGN0020389
caenorhabditis_elegans		WBGENE00004091

Paralogs (1): PAPSS1 (ENSG00000138801)

Protein

Protein identifiers

Bifunctional 3’-phosphoadenosine 5’-phosphosulfate synthase 2 — O95340 (reviewed: O95340)

Alternative names: Sulfurylase kinase 2

All UniProt accessions (2): O95340, Q5TB52

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional enzyme with both ATP sulfurylase and APS kinase activity, which mediates two steps in the sulfate activation pathway. The first step is the transfer of a sulfate group to ATP to yield adenosine 5’-phosphosulfate (APS), and the second step is the transfer of a phosphate group from ATP to APS yielding 3’-phosphoadenylylsulfate/PAPS, the activated sulfate donor used by sulfotransferases. In mammals, PAPS is the sole source of sulfate while APS appears to only be an intermediate in the sulfate-activation pathway. Plays indirectly an important role in skeletogenesis during postnatal growth.

Tissue specificity. Expressed in cartilage and adrenal gland.

Disease relevance. Brachyolmia type 4 with mild epiphyseal and metaphyseal changes (BCYM4) [MIM:612847] A form of brachyolmia, a clinically and genetically heterogeneous skeletal dysplasia primarily affecting the spine and characterized by a short trunk, short stature, and platyspondyly. BCYM4 is an autosomal recessive form with mild epiphyseal and metaphyseal changes. Clinical features include short stature evidenced at birth, short and bowed lower limbs, mild brachydactyly, kyphoscoliosis, abnormal gait, enlarged knee joints. Some BCYM4 patients may manifest premature pubarche and hyperandrogenism associated with skeletal dysplasia and short stature. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Sulfur metabolism; sulfate assimilation.

Similarity. In the N-terminal section; belongs to the APS kinase family. In the C-terminal section; belongs to the sulfate adenylyltransferase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95340-1	A	yes
O95340-2	B

RefSeq proteins (2): NP_001015880, NP_004661 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002650	Sulphate_adenylyltransferase	Family
IPR002891	APS	Family
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR015947	PUA-like_sf	Homologous_superfamily
IPR024951	Sulfurylase_cat_dom	Domain
IPR025980	ATP-Sase_PUA-like_dom	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR059117	APS_kinase_dom	Domain

Pfam: PF01583, PF01747, PF14306

Enzyme classification (BRENDA):

• EC 2.7.1.25 — adenylyl-sulfate kinase (BRENDA: 29 organisms, 42 substrates, 74 inhibitors, 68 Km, 23 kcat entries)
• EC 2.7.7.4 — sulfate adenylyltransferase (BRENDA: 80 organisms, 68 substrates, 98 inhibitors, 191 Km, 23 kcat entries)

Substrate kinetics (BRENDA)

23 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0077–2.6	62
DIPHOSPHATE	0.0007–19.41	41
ADENOSINE 5’-PHOSPHOSULFATE	0.0001–0.042	29
ATP	0.007–2.4	22
ADENYLYL SULFATE	0.0044–2.95	21
SO42-	0.18–3.3	16
ADENOSINE 5’-PHOSPHOSULFATE	0.0003–0.17	11
MOO42-	0.076–0.64	11
SULFATE	0.0021–17	7
3’-PHOSPHOADENOSINE 5’-PHOSPHOSULFATE	0.003–0.37	5
ADENYLYL SULFATE	0.002–0.0046	5
ADENYLYLSULFATE	0.0004–0.025	4
MGATP2-	0.23–1.1	3
SEO42-	0.1–1	3
ADENOSINE-5’-PHOSPHOSULFATE	0.0004–0.0007	2

Catalyzed reactions (Rhea), 2 shown:

• sulfate + ATP + H(+) = adenosine 5’-phosphosulfate + diphosphate (RHEA:18133)
• adenosine 5’-phosphosulfate + ATP = 3’-phosphoadenylyl sulfate + ADP + H(+) (RHEA:24152)

UniProt features (82 total): helix 25, strand 23, binding site 11, sequence variant 9, turn 6, sequence conflict 4, region of interest 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7FH3	X-RAY DIFFRACTION	1.8
7FHA	X-RAY DIFFRACTION	2
8I1O	X-RAY DIFFRACTION	2.4
2AX4	X-RAY DIFFRACTION	2.5
8I1N	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95340-F1	92.35	0.80

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (11): 197; 409–412; 511–515; 553; 52–57; 79–82; 91; 96–99; 122–123; 161; 174–175

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-174362	Transport and metabolism of PAPS
R-HSA-2408550	Metabolism of ingested H2SeO4 and H2SeO3 into H2Se
R-HSA-3560796	Defective PAPSS2 causes SEMD-PA

MSigDB gene sets: 309 (showing top): CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOZGIT_ESR1_TARGETS_DN, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, RODRIGUES_NTN1_TARGETS_DN, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GTGCCTT_MIR506, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_UP, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, WANG_LMO4_TARGETS_DN, RAMALHO_STEMNESS_DN

GO Biological Process (3): sulfate assimilation (GO:0000103), hormone metabolic process (GO:0042445), 3’-phosphoadenosine 5’-phosphosulfate biosynthetic process (GO:0050428)

GO Molecular Function (9): adenylylsulfate kinase activity (GO:0004020), sulfate adenylyltransferase (ATP) activity (GO:0004781), ATP binding (GO:0005524), nucleotidyltransferase activity (GO:0016779), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (2): nucleus (GO:0005634), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Glycosaminoglycan metabolism	1
Selenoamino acid metabolism	1
Diseases associated with glycosaminoglycan metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transferase activity, transferring phosphorus-containing groups	2
sulfur compound metabolic process	1
metabolic process	1
regulation of hormone levels	1
purine ribonucleotide biosynthetic process	1
purine ribonucleoside bisphosphate biosynthetic process	1
sulfur compound biosynthetic process	1
3’-phosphoadenosine 5’-phosphosulfate metabolic process	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
sulfate adenylyltransferase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1938 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAPSS2	DYM	Q7RTS9	930
PAPSS2	SLC26A2	P50443	919
PAPSS2	SULT1B1	O43704	851
PAPSS2	SULT1C3	Q6IMI6	848
PAPSS2	SULT1C4	O75897	842
PAPSS2	SULT2A1	Q06520	765
PAPSS2	ENTPD3	O75355	667
PAPSS2	ENTPD8	Q5MY95	666
PAPSS2	ENTPD1	P49961	585
PAPSS2	BPNT1	O95861	549
PAPSS2	BPNT2	Q9NX62	539
PAPSS2	TST	Q16762	529
PAPSS2	HSD3B2	P26439	524
PAPSS2	SQOR	Q9Y6N5	509
PAPSS2	SULT1E1	P49888	501

IntAct

43 interactions, top by confidence:

A	B	Type	Score
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
PAPSS2	CEP19	psi-mi:“MI:0915”(physical association)	0.560
HSF2BP	PAPSS2	psi-mi:“MI:0915”(physical association)	0.560
PAPSS2	OPTN	psi-mi:“MI:0915”(physical association)	0.560
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
MCRIP2	CASC3	psi-mi:“MI:0914”(association)	0.530
PAPSS2	DAPK1	psi-mi:“MI:0407”(direct interaction)	0.440
PAPSS2	PAPSS1	psi-mi:“MI:0915”(physical association)	0.400
PAPSS2	RBM3	psi-mi:“MI:0915”(physical association)	0.400
PAPSS1	PAPSS2	psi-mi:“MI:0915”(physical association)	0.400
Papss1	TCOF1	psi-mi:“MI:0914”(association)	0.350
TEX101	PSMD12	psi-mi:“MI:0914”(association)	0.350
TEX101	NDUFA4	psi-mi:“MI:0914”(association)	0.350
DNAJC18	PAPSS2	psi-mi:“MI:0914”(association)	0.350
PRPS2	SMCHD1	psi-mi:“MI:0914”(association)	0.350
SPANXB1	PAPSS2	psi-mi:“MI:0914”(association)	0.350
PCNP	PAPSS2	psi-mi:“MI:0914”(association)	0.350
TBX18	PAPSS2	psi-mi:“MI:0914”(association)	0.350
C8B	PAPSS2	psi-mi:“MI:0914”(association)	0.350
WDR6	PAPSS2	psi-mi:“MI:0914”(association)	0.350
RNF115	IGLC7	psi-mi:“MI:0914”(association)	0.350
SARAF	A2ML1	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
DNAJA2	ENC1	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
HPN	DDX39A	psi-mi:“MI:0914”(association)	0.350

BioGRID (79): PAPSS2 (Co-fractionation), PAPSS2 (Co-fractionation), PAPSS2 (Affinity Capture-MS), PAPSS2 (Affinity Capture-MS), PAPSS2 (Affinity Capture-MS), PAPSS2 (Affinity Capture-MS), PAPSS2 (Affinity Capture-MS), PAPSS2 (Reconstituted Complex), PAPSS2 (Proximity Label-MS), PAPSS2 (Affinity Capture-MS), PAPSS2 (Affinity Capture-MS), PAPSS2 (Affinity Capture-MS), PAPSS2 (Two-hybrid), PAPSS2 (Two-hybrid), PAPSS2 (Affinity Capture-MS)

ESM2 similar proteins: A0A061AE05, A1CJC1, A1D858, A5CXS6, A5WEH0, A9A541, B0JW81, B1XLP7, B2J5M3, B4SAM9, B7JVS6, O43252, O54820, O88428, O95340, P08536, P0CN04, P0CN05, P56862, P78937, P94281, Q0CC19, Q0V6P9, Q0VRM0, Q111K4, Q12555, Q12650, Q1EAF9, Q1QAY1, Q27128, Q2H454, Q3AQ83, Q4FST7, Q4I1N3, Q4P460, Q4WWN8, Q60967, Q60FC6, Q6BSU5, Q6CFD2

Diamond homologs: A0A061AE05, A0KTI5, A1AEU4, A1RGG0, A1S9N4, A1U3X8, A3D819, A4WDV5, A4Y9X0, A5G863, A5N960, A6TD42, A6WJU6, A7MJ70, A7ZQJ4, A8A3M9, A8ANW4, A8H0A6, A9ENT2, A9G7W0, A9L392, A9MF25, A9N2D7, B0CAX3, B0TTD2, B1IUS9, B1LQ71, B1XCS6, B2TZI1, B2VG00, B4T460, B4TFX0, B4TTW4, B5BEY7, B5F414, B5FTS8, B5QW21, B5RDQ6, B5XV31, B5Z3B2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

406 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	28
Likely pathogenic	8
Uncertain significance	165
Likely benign	131
Benign	48

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074284	NM_001015880.2(PAPSS2):c.1666C>T (p.Arg556Ter)	Pathogenic
1076661	NM_001015880.2(PAPSS2):c.724G>T (p.Glu242Ter)	Pathogenic
1676681	NM_001015880.2(PAPSS2):c.1317C>A (p.Tyr439Ter)	Pathogenic
1683431	NM_001015880.2(PAPSS2):c.1721+2T>C	Pathogenic
1686003	NM_001015880.2(PAPSS2):c.386G>A (p.Arg129His)	Pathogenic
197704	NM_001015880.2(PAPSS2):c.639+1G>T	Pathogenic
2118413	NM_001015880.2(PAPSS2):c.520+1G>A	Pathogenic
2118414	NM_001015880.2(PAPSS2):c.998T>A (p.Leu333Ter)	Pathogenic
2791800	NM_001015880.2(PAPSS2):c.1273del (p.Leu425fs)	Pathogenic
3012764	NM_001015880.2(PAPSS2):c.28G>T (p.Glu10Ter)	Pathogenic
3621073	NM_001015880.2(PAPSS2):c.1129C>T (p.Gln377Ter)	Pathogenic
39642	NM_001015880.2(PAPSS2):c.337dup (p.Ala113fs)	Pathogenic
39643	NM_001015880.2(PAPSS2):c.616_634del (p.Val206fs)	Pathogenic
39644	NM_001015880.2(PAPSS2):c.1309_1310del (p.Arg437fs)	Pathogenic
39645	NM_001015880.2(PAPSS2):c.477_480dup (p.Lys161fs)	Pathogenic
39646	NM_001015880.2(PAPSS2):c.661del (p.Ile221fs)	Pathogenic
4292898	NM_001015880.2(PAPSS2):c.316del (p.Val106fs)	Pathogenic
4687926	NM_001015880.2(PAPSS2):c.1056del (p.Thr353fs)	Pathogenic
4743834	NM_001015880.2(PAPSS2):c.1417G>T (p.Glu473Ter)	Pathogenic
4750649	NM_001015880.2(PAPSS2):c.492T>A (p.Tyr164Ter)	Pathogenic
572534	NM_001015880.2(PAPSS2):c.683_684del (p.Phe228fs)	Pathogenic
6686	NM_001015880.2(PAPSS2):c.1439C>A (p.Ser480Ter)	Pathogenic
6687	NM_001015880.2(PAPSS2):c.143C>G (p.Thr48Arg)	Pathogenic
6688	NM_001015880.2(PAPSS2):c.1000C>T (p.Arg334Ter)	Pathogenic
932064	NM_001015880.2(PAPSS2):c.121C>T (p.Arg41Ter)	Pathogenic
988297	NM_001015880.2(PAPSS2):c.1476T>A (p.Tyr492Ter)	Pathogenic
988389	NM_001015880.2(PAPSS2):c.1078del (p.His360fs)	Pathogenic
988515	NM_001015880.2(PAPSS2):c.1053G>A (p.Trp351Ter)	Pathogenic
1506358	NM_001015880.2(PAPSS2):c.1828_1829insGAGATTATTACAGGTCCCGA (p.Thr610fs)	Likely pathogenic
1679873	NM_001015880.2(PAPSS2):c.1464_1466del (p.Pro489del)	Likely pathogenic

SpliceAI

2597 predictions. Top by Δscore:

Variant	Effect	Δscore
10:87660005:GACG:G	donor_gain	1.0000
10:87713073:A:AC	acceptor_loss	1.0000
10:87713308:AAGG:A	donor_loss	1.0000
10:87713311:GTA:G	donor_loss	1.0000
10:87714743:A:AG	acceptor_gain	1.0000
10:87714743:AG:A	acceptor_gain	1.0000
10:87714744:G:GG	acceptor_gain	1.0000
10:87714744:GG:G	acceptor_gain	1.0000
10:87714744:GGA:G	acceptor_gain	1.0000
10:87714744:GGAT:G	acceptor_gain	1.0000
10:87714860:GCAG:G	donor_gain	1.0000
10:87714863:GGTA:G	donor_loss	1.0000
10:87714864:G:C	donor_loss	1.0000
10:87714864:G:GG	donor_gain	1.0000
10:87714979:TTTCA:T	acceptor_loss	1.0000
10:87714982:CAGA:C	acceptor_loss	1.0000
10:87714983:A:AG	acceptor_gain	1.0000
10:87714984:G:GG	acceptor_gain	1.0000
10:87714984:GA:G	acceptor_gain	1.0000
10:87714984:GAA:G	acceptor_gain	1.0000
10:87714984:GAAC:G	acceptor_gain	1.0000
10:87714984:GAACA:G	acceptor_gain	1.0000
10:87715097:AGG:A	donor_loss	1.0000
10:87715099:G:GA	donor_loss	1.0000
10:87715099:G:GG	donor_gain	1.0000
10:87715100:T:G	donor_loss	1.0000
10:87715841:ATGG:A	donor_loss	1.0000
10:87715842:TGGTA:T	donor_loss	1.0000
10:87715843:GGTA:G	donor_loss	1.0000
10:87715844:GTAT:G	donor_loss	1.0000

AlphaMissense

4078 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:87743387:T:C	F408L	1.000
10:87743389:C:A	F408L	1.000
10:87743389:C:G	F408L	1.000
10:87743401:T:A	N412K	1.000
10:87743401:T:G	N412K	1.000
10:87743408:C:G	H415D	1.000
10:87745871:G:C	R582S	1.000
10:87745871:G:T	R582S	1.000
10:87709304:T:A	W46R	0.999
10:87709304:T:C	W46R	0.999
10:87713093:A:T	K55I	0.999
10:87713200:T:C	F91L	0.999
10:87713202:C:A	F91L	0.999
10:87713202:C:G	F91L	0.999
10:87713231:G:C	R101P	0.999
10:87713234:G:C	R102P	0.999
10:87713248:G:C	A107P	0.999
10:87713287:A:C	S120R	0.999
10:87713289:C:A	S120R	0.999
10:87713289:C:G	S120R	0.999
10:87715768:T:A	W264R	0.999
10:87715768:T:C	W264R	0.999
10:87743388:T:C	F408S	0.999
10:87743396:C:A	R411S	0.999
10:87743397:G:C	R411P	0.999
10:87743399:A:G	N412D	0.999
10:87743403:C:A	P413H	0.999
10:87743406:T:A	V414D	0.999
10:87743410:C:A	H415Q	0.999
10:87743410:C:G	H415Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000076247 (10:87745766 C>T), RS1000099472 (10:87709466 C>A,T), RS1000150858 (10:87745392 C>T), RS1000183456 (10:87665403 G>T), RS1000189995 (10:87721379 G>A,T), RS1000198320 (10:87705094 A>G), RS1000199487 (10:87670992 A>G), RS1000235121 (10:87685192 G>T), RS1000242205 (10:87721122 T>G), RS1000323170 (10:87676174 T>C), RS1000326886 (10:87688807 A>G,T), RS1000338598 (10:87682861 T>C,G), RS1000344839 (10:87738954 A>T), RS1000352626 (10:87727685 G>A,T), RS1000409290 (10:87712413 A>AT)

Disease associations

OMIM: gene MIM:603005 | disease phenotypes: MIM:612847

GenCC curated gene-disease

Disease	Classification	Inheritance
spondyloepimetaphyseal dysplasia, PAPSS2 type	Definitive	Autosomal recessive
autosomal recessive brachyolmia	Supportive	Autosomal recessive

Mondo (4): spondyloepimetaphyseal dysplasia, PAPSS2 type (MONDO:0019666), skeletal dysplasia (MONDO:0018230), brachyolmia (MONDO:0015262), autosomal recessive brachyolmia (MONDO:0018662)

Orphanet (4): Spondyloepimetaphyseal dysplasia, PAPSS2 type (Orphanet:93282), Primary bone dysplasia (Orphanet:364526), Brachyolmia (Orphanet:1293), Autosomal recessive brachyolmia (Orphanet:448242)

HPO phenotypes

14 total (14 of 14 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000869	Secondary amenorrhea
HP:0000926	Platyspondyly
HP:0001007	Hirsutism
HP:0001061	Acne
HP:0001156	Brachydactyly
HP:0002651	Spondyloepimetaphyseal dysplasia
HP:0002751	Kyphoscoliosis
HP:0002979	Bowing of the legs
HP:0003301	Irregular vertebral endplates
HP:0004322	Short stature
HP:0004626	Lumbar scoliosis
HP:0009816	Lower limb undergrowth
HP:0012411	Premature pubarche

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000474_2	Leisure-time exercise behaviour	4.000000e-06
GCST003195_1	Magnesium levels	4.000000e-07
GCST006979_597	Heel bone mineral density	4.000000e-11
GCST006979_598	Heel bone mineral density	1.000000e-12
GCST010396_235	Gut microbiota (bacterial taxa, hurdle binary method)	5.000000e-06
GCST012020_578	Serum metabolite levels	2.000000e-11
GCST012021_95	Serum metabolite levels	2.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0000483	exercise
EFO:0004845	magnesium measurement
EFO:0009270	heel bone mineral density
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537098	Brachyolmia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105790 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

67 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases expression, decreases reaction, affects expression, affects binding, increases expression (+1 more)	7
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	5
trichostatin A	affects cotreatment, decreases expression	3
bisphenol A	affects cotreatment, increases methylation, increases expression	2
Benzo(a)pyrene	increases methylation, decreases expression	2
Nickel	increases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
testosterone enanthate	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
glycidyl methacrylate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
2,3-pentanedione	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	decreases expression, affects cotreatment	1
diisodecyl phthalate	decreases expression	1
avobenzone	increases expression	1
cetrorelix	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
Am 580	increases expression	1
4-octylphenol	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4036829	Binding	Binding affinity to SK2 (unknown origin)	Discovery of a Series of Indazole TRPA1 Antagonists. — ACS Med Chem Lett

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1ZW	Abcam HeLa PAPSS2 KO	Cancer cell line	Female
CVCL_TC03	HAP1 PAPSS2 (-) 1	Cancer cell line	Male
CVCL_TC04	HAP1 PAPSS2 (-) 2	Cancer cell line	Male
CVCL_TC05	HAP1 PAPSS2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

7 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00001754	Not specified	COMPLETED	Study of Skeletal Disorders and Short Stature
NCT02762318	Not specified	TERMINATED	Identification and Characterization of Bone-related Genetic Variants in Families
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT05247645	Not specified	RECRUITING	Data Collection of Patients With Rare Bone Diseases
NCT05876416	Not specified	RECRUITING	Decoding the Genetic Landscape of Skeletal Diseases
NCT05991609	Not specified	ACTIVE_NOT_RECRUITING	Extreme Morphology and Metabolic Health
NCT06002373	Not specified	UNKNOWN	Assessment of Artificial Intelligence for Treatment Decision Recommendation of Adult Skeletal Class III Patients