HPSE2

Summary

HPSE2 (heparanase 2 (inactive), HGNC:18374) is a protein-coding gene on chromosome 10q24.2, encoding Inactive heparanase-2 (Q8WWQ2). Binds heparin and heparan sulfate with high affinity, but lacks heparanase activity.

This gene encodes a heparanase enzyme. The encoded protein is a endoglycosidase that degrades heparin sulfate proteoglycans located on the extracellular matrix and cell surface. This protein may be involved in biological processes involving remodeling of the extracellular matrix including angiogenesis and tumor progression. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 60495 — RefSeq curated summary.

At a glance

• Gene–disease (curated): urofacial syndrome type 1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 302 total — 15 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 17
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_021828

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18374
Approved symbol	HPSE2
Name	heparanase 2 (inactive)
Location	10q24.2
Locus type	gene with protein product
Status	Approved
Aliases	HPA2, HPR2
Ensembl gene	ENSG00000172987
Ensembl biotype	protein_coding
OMIM	613469
Entrez	60495

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000370546, ENST00000370549, ENST00000370552, ENST00000404542, ENST00000628193

RefSeq mRNA: 4 — MANE Select: NM_021828 NM_001166244, NM_001166245, NM_001166246, NM_021828

CCDS: CCDS53566, CCDS53567, CCDS53568, CCDS7477

Canonical transcript exons

ENST00000370552 — 12 exons

Exon	Start	End
ENSE00001195142	98482636	98482782
ENSE00001195146	98490051	98490196
ENSE00001195154	98614904	98615018
ENSE00001195160	98620602	98620708
ENSE00001195165	98641847	98641940
ENSE00001195169	98693900	98693947
ENSE00001195175	98721657	98721828
ENSE00001195179	98743883	98744056
ENSE00001304256	99232348	99232505
ENSE00001324252	99144238	99144399
ENSE00003898543	99235513	99235852
ENSE00003901039	98457077	98459739

Expression profiles

Bgee: expression breadth ubiquitous, 153 present calls, max score 93.85.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1078 / max 14.9086, expressed in 48 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110982	0.0477	23
110981	0.0306	16
110983	0.0295	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	93.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.08	gold quality
lower esophagus	UBERON:0013473	90.00	gold quality
endocervix	UBERON:0000458	88.76	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.45	gold quality
mucosa of stomach	UBERON:0001199	86.08	gold quality
ectocervix	UBERON:0012249	84.78	gold quality
diaphragm	UBERON:0001103	83.65	gold quality
popliteal artery	UBERON:0002250	82.25	gold quality
tibial artery	UBERON:0007610	82.21	gold quality
hypothalamus	UBERON:0001898	81.86	gold quality
caudate nucleus	UBERON:0001873	81.17	gold quality
putamen	UBERON:0001874	79.98	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	79.93	gold quality
aorta	UBERON:0000947	79.50	gold quality
substantia nigra	UBERON:0002038	79.42	gold quality
tendon	UBERON:0000043	79.22	gold quality
vagina	UBERON:0000996	78.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.28	gold quality
spinal cord	UBERON:0002240	78.00	gold quality
midbrain	UBERON:0001891	77.59	gold quality
esophagus	UBERON:0001043	76.65	gold quality
ascending aorta	UBERON:0001496	76.20	gold quality
thoracic aorta	UBERON:0001515	76.18	gold quality
descending thoracic aorta	UBERON:0002345	74.98	gold quality
uterine cervix	UBERON:0000002	74.05	gold quality
urinary bladder	UBERON:0001255	73.78	gold quality
lower esophagus mucosa	UBERON:0035834	73.17	gold quality
right frontal lobe	UBERON:0002810	72.87	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.55	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	2511.27
E-HCAD-35	yes	65.23
E-CURD-119	yes	13.18
E-ANND-3	no	5.35

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BCLAF1, BTF3, NFKB, TAF1

miRNA regulators (miRDB)

92 targeting HPSE2, 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-6833-3P	100.00	70.63	3197
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-1827	99.63	68.57	3265

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 35)

• HPSE plays a role in extracellular matrix remodeling and in increasing heparin-binding growth factor release during embryo implantation. (PMID:17989358)
• Heparanase 2 is involved in neoplastic proliferation, but it was not exclusively associated with the malignant process. (PMID:19955924)
• These results indicate a regulatory effect of heparanase on TFPI and TFPI-2 in trophoblasts, suggesting a potential involvement of heparanase in early miscarriages. (PMID:20031192)
• Results demonstrated that the effectors from heparanase peptide-immunized mice could effectively lyse various tumor cells that were heparanase positive and HLA-A*0201 matched. (PMID:20182872)
• We now report evidence that Heparanse 2 (HPSE2) is the culprit gene for the syndrome. Mutations with a loss of function in the Heparanase 2 (HPSE2) gene (PMID:20560209)
• Homozygous exonic deletions, nonsense mutations, and frameshift mutations in five further unrelated families confirmed HPSE2 as the causative gene for UFS (PMID:20560210)
• Studies indicate that cathepsin L as the heparanase activating protease. (PMID:21308479)
• HPSE2 c.631T>C (p.Y211H) is a novel benign SNP and c.1628A>T (p.N543I) is the disease-causing mutation in urofacial syndrome. (PMID:21332471)
• A large region of marker homozygosity was observed at 10q24, consistent with known autosomal recessive inheritance, family consanguinity and previous genetic mapping in other families with Ochoa syndrome. (PMID:21450525)
• Data indicate that the overexpression of HPSE1 and HPSE2 in the intervertebral degenerated discs suggests a role for these factors in mediating extracellular matrix remodeling in degenerative discs during disease development. (PMID:23370684)
• High expression of heparanase-2 is associated significantly with gastric tumor growth and differentiation (PMID:24139593)
• autonomic neural protein implicated in bladder emptying (PMID:25145936)
• Heparanase 2 is more intensely expressed in the glandular tissue of cancer than in nonneoplastic endometrium; the HPSE2 expression in the stromal tissue is higher in the nonneoplastic controls compared with cancer mainly in the secretory endometrium. (PMID:25423319)
• HPSE2 mutations were found in one Urofacial syndrome family but not detected in patients with non-neurogenic neurogenic bladder and severe lower urinary tract dysfunction (PMID:25924634)
• Our findings identified these 2 genes as a novel breast cancer biomarker gene set, which may facilitate the diagnosis and treatment in breast cancer clinical therapies. (PMID:26084486)
• our results suggest that heparanase 2 functions as a tumor suppressor in bladder cancer (PMID:26968815)
• we provide evidence that Hpa2 overexpression in head and neck cancer cells markedly reduces tumor growth (PMID:27013193)
• The most common HPA genotypes among Saudis were HPA-1 a + b- (75%), HPA-2 a + b- (62%), HPA-3 a + b- (51.5%), HPA-4 a + b- (99%), HPA-5 a + b- (76.5%), HPA-6 a + b- (100%) and HPA-15 a + b + (50%). The prevalent allele among the HPA systems was (a), except in the HPA-15 system where the (b) allele was found in 52% of the subjects. (PMID:27019315)
• The results of this study the Heparanase 2 appeared overexpressed at different stages of Alzheimer disease. (PMID:28387673)
• Study discovered novel homozygous missense LRIG2 variants that were predicted to be pathogenic in 2 individuals with non-syndromic bladder outlet obstruction. These observations provide evidence that a peripheral neuropathy is central to the pathobiology of functional bladder outlet obstruction in urofacial syndrome and emphasize the importance of LRIG2 and heparanase 2 for nerve patterning in the urinary tract. (PMID:30885509)
• Heparan sulfate (HS) is likely responsible for mediating the expression of heparanases in circulating lymphocytes. HS secreted by tumor cells might be carried by exosome particles, confirming the key role of tumor cells, as well as secreted HS, in upregulating the expression of heparanases, suggesting a possible mechanism of crosstalk between tumor cells and circulating lymphocytes. (PMID:30922347)
• Heparanase-2 protects from LPS-mediated endothelial injury by inhibiting TLR4 signalling. (PMID:31537875)
• gene cloning of HPSE2 (PMID:32274738)
• Heparanase 2 and Urofacial Syndrome, a Genetic Neuropathy (PMID:32274739)
• heparanase-2 functions as an inhibitor of the heparanase-1 enzyme and also inhibits neovascularization mediated by VEGF; the HPSE2 gene is repressed by the Polycomb complex, together suggesting a role as a tumor suppressor (PMID:32274740)
• Opposing Effects of Heparanase and Heparanase-2 in Head & Neck Cancer (PMID:32274741)
• Hypermethylation of heparanase 2 promotes colorectal cancer proliferation and is associated with poor prognosis. (PMID:33663522)
• Heparanase 2 (Hpa2) attenuates the growth of pancreatic carcinoma. (PMID:33839221)
• Heparanase 2 (Hpa2) attenuates tumor growth by inducing Sox2 expression. (PMID:34004353)
• Role of heparanase 2 (Hpa2) in gastric cancer. (PMID:34343822)
• Induction of heparanase 2 (Hpa2) expression by stress is mediated by ATF3. (PMID:34808335)
• Heparanase 2 (Hpa2) attenuates the growth of human sarcoma. (PMID:36122821)
• Effect of HPSE and HPSE2 SNPs on the Risk of Developing Primary Paraskeletal Multiple Myeloma. (PMID:36980254)
• Nuclear localization of heparanase 2 (Hpa2) attenuates breast carcinoma growth and metastasis. (PMID:38519456)
• Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome. (PMID:38990208)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hpse2	ENSDARG00000078163
mus_musculus	Hpse2	ENSMUSG00000074852
rattus_norvegicus	Hpse2	ENSRNOG00000064037
drosophila_melanogaster	CG14309	FBGN0038611

Paralogs (1): HPSE (ENSG00000173083)

Protein

Protein identifiers

Inactive heparanase-2 — Q8WWQ2 (reviewed: Q8WWQ2)

All UniProt accessions (2): Q8WWQ2, A0A0A0MSB9

UniProt curated annotations — full annotation on UniProt →

Function. Binds heparin and heparan sulfate with high affinity, but lacks heparanase activity. Inhibits HPSE, possibly by competing for its substrates (in vitro).

Subunit / interactions. Interacts with HPSE. Interacts with SDC1 (via glycan chains).

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Widely expressed, with the highest expression in brain, mammary gland, prostate, small intestine, testis and uterus. In the central nervous system, expressed in the spinal cord, caudate nucleus, thalamus, substantia nigra, medulla oblongata, putamen and pons. In the urinary bladder, expressed in longitudinal and circular layers of detrusor muscle. Found both in normal and cancer tissues.

Disease relevance. Urofacial syndrome 1 (UFS1) [MIM:236730] A rare autosomal recessive disorder characterized by facial grimacing when attempting to smile and failure of the urinary bladder to void completely despite a lack of anatomical bladder outflow obstruction or overt neurological damage. Affected individuals often have reflux of infected urine from the bladder to the upper renal tract, with a risk of kidney damage and renal failure. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the glycosyl hydrolase 79 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8WWQ2-1	1, HPA2c	yes
Q8WWQ2-2	2
Q8WWQ2-3	3, HPA2b
Q8WWQ2-4	4, HPA2a

RefSeq proteins (4): NP_001159716, NP_001159717, NP_001159718, NP_068600* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005199	Glyco_hydro_79	Family
IPR017853	GH_hydrolase_sf	Homologous_superfamily

Pfam: PF03662

UniProt features (12 total): splice variant 4, sequence conflict 2, glycosylation site 2, sequence variant 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WWQ2-F1	82.90	0.63

Functional residue map

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

Glycosylation sites (2): 254, 392

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2024096	HS-GAG degradation

MSigDB gene sets: 140 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, BENPORATH_ES_WITH_H3K27ME3, NKX25_02, GGGTGGRR_PAX4_03, AAAYRNCTG_UNKNOWN, CAGCTG_AP4_Q5, PAX2_01, MYOD_01, GATA6_01, IRF_Q6, NKX22_01, TATA_C, AACTTT_UNKNOWN, USF_02, FOXJ2_02

GO Biological Process (3): cell population proliferation (GO:0008283), positive regulation of cell population proliferation (GO:0008284), extracellular matrix organization (GO:0030198)

GO Molecular Function (3): heparanase activity (GO:0030305), heparan sulfate proteoglycan binding (GO:0043395), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), extracellular region (GO:0005576), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Heparan sulfate/heparin (HS-GAG) metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
extracellular structure organization	1
external encapsulating structure organization	1
hydrolase activity, hydrolyzing O-glycosyl compounds	1
proteoglycan binding	1
hydrolase activity	1
membrane	1
cell periphery	1
external encapsulating structure	1

Protein interactions and networks

STRING

514 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HPSE2	LRIG2	O94898	719
HPSE2	CNNM1	Q9NRU3	649
HPSE2	GP1BA	P07359	583
HPSE2	ELP3	Q9H9T3	581
HPSE2	VWF	P04275	580
HPSE2	ITGA2	P17301	573
HPSE2	GLYATL1	Q969I3	528
HPSE2	SDC1	P18827	471
HPSE2	LACRT	Q9GZZ8	454
HPSE2	KAT2A	Q92830	446
HPSE2	KAT2B	Q92831	434
HPSE2	HSP90AA1	P07900	416
HPSE2	CHD1L	Q86WJ1	400
HPSE2	DCLK2	Q8N568	399
HPSE2	HSPA1A	P08107	388

IntAct

4 interactions, top by confidence:

A	B	Type	Score
HPSE2	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
HPSE2	RNF13	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): HPSE2 (Affinity Capture-MS), HIST1H2BH (Proximity Label-MS), TIMM10B (Affinity Capture-MS), KBTBD7 (Affinity Capture-MS), EDEM2 (Affinity Capture-MS), TARBP2 (Affinity Capture-MS), ANKHD1-EIF4EBP3 (Affinity Capture-MS), PEX1 (Affinity Capture-MS), ANKRD17 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), NAF1 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), IFT22 (Affinity Capture-MS), DICER1 (Affinity Capture-MS), GPR98 (Affinity Capture-MS)

ESM2 similar proteins: A4Q9F4, A6QLH5, D3Z7P3, D3ZVU9, E9PV86, M0R7T9, O35652, O43414, O54804, O60242, O60347, O70512, O94925, P08887, P0C7M8, P13264, P35790, P85298, Q01134, Q08DW9, Q13202, Q13505, Q2HJ53, Q2TBM7, Q3UGX3, Q4R766, Q4R7M4, Q58DH2, Q5XI70, Q62225, Q6AYT7, Q6DN14, Q80T74, Q80UW0, Q80ZF8, Q86W50, Q8C460, Q8N2K0, Q8NBA8, Q8NHH1

Diamond homologs: B2RY83, Q6YGZ1, Q71RP1, Q8WWQ2, Q90YK5, Q9MYY0, Q9Y251, Q8L608, Q9FF10, X4Y2L4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
BTF3	“up-regulates quantity by expression”	HPSE2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	10
Uncertain significance	156
Likely benign	48
Benign	46

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1323070	NM_021828.5(HPSE2):c.902T>A (p.Leu301Ter)	Pathogenic
1344620	NM_021828.5(HPSE2):c.1099-2A>G	Pathogenic
1691124	NM_021828.5(HPSE2):c.429T>A (p.Tyr143Ter)	Pathogenic
1691127	NM_021828.5(HPSE2):c.1099-1G>A	Pathogenic
2426683	NC_000010.10:g.(?100481394)(100503833_?)del	Pathogenic
2426684	NC_000010.10:g.(?100453637)(100481605_?)del	Pathogenic
3905776	NM_021828.5(HPSE2):c.151dup (p.Arg51fs)	Pathogenic
4075938	GRCh37/hg19 10q24.2(chr10:100709229-100911811)x1	Pathogenic
60719	NM_021828.5(HPSE2):c.1628A>T (p.Asn543Ile)	Pathogenic
687772	GRCh37/hg19 10q24.2(chr10:100690060-100911811)x1	Pathogenic
85	NM_021828.5(HPSE2):c.241_242del (p.Leu81fs)	Pathogenic
86	NM_021828.5:c.1099-4166_1320+840delins23	Pathogenic
87	NG_023416.2:g.(88604_176551)_(176714_576894)del	Pathogenic
88	NM_021828.5(HPSE2):c.1414C>T (p.Arg472Ter)	Pathogenic
90	NM_021828.5(HPSE2):c.57dup (p.Ala20fs)	Pathogenic
1067728	NM_021828.5(HPSE2):c.785-2A>G	Likely pathogenic
1677856	NM_021828.5(HPSE2):c.1004+1G>A	Likely pathogenic
2839216	NM_021828.5(HPSE2):c.448+1G>C	Likely pathogenic
3589444	NM_021828.5(HPSE2):c.1407del (p.Pro470fs)	Likely pathogenic
3589471	NM_021828.5(HPSE2):c.1308del (p.Phe436fs)	Likely pathogenic
3589544	NM_021828.5(HPSE2):c.1145_1149del (p.Val382fs)	Likely pathogenic
3589552	NM_021828.5(HPSE2):c.1113del (p.Thr370_Tyr371insTer)	Likely pathogenic
3589700	NM_021828.5(HPSE2):c.291-1G>T	Likely pathogenic
3589704	NM_021828.5(HPSE2):c.250del (p.Asp84fs)	Likely pathogenic
4849308	NM_021828.5(HPSE2):c.1337_1338del (p.Leu446fs)	Likely pathogenic

SpliceAI

6332 predictions. Top by Δscore:

Variant	Effect	Δscore
10:98459735:CTGAC:C	acceptor_gain	1.0000
10:98459737:GACCT:G	acceptor_loss	1.0000
10:98459738:ACCTA:A	acceptor_loss	1.0000
10:98459740:C:A	acceptor_loss	1.0000
10:98482634:A:AC	donor_gain	1.0000
10:98482635:C:CC	donor_gain	1.0000
10:98482791:C:CT	acceptor_gain	1.0000
10:98482791:C:T	acceptor_gain	1.0000
10:98482792:A:T	acceptor_gain	1.0000
10:98482806:G:C	acceptor_gain	1.0000
10:98490049:A:AC	donor_gain	1.0000
10:98490050:C:CC	donor_gain	1.0000
10:98490194:GTCC:G	acceptor_loss	1.0000
10:98490195:TC:T	acceptor_gain	1.0000
10:98490196:CC:C	acceptor_gain	1.0000
10:98490197:C:CC	acceptor_gain	1.0000
10:98490197:CTGA:C	acceptor_loss	1.0000
10:98614897:CACTT:C	donor_loss	1.0000
10:98614898:ACTT:A	donor_loss	1.0000
10:98614900:TT:T	donor_loss	1.0000
10:98614901:TACTG:T	donor_loss	1.0000
10:98614902:A:AC	donor_gain	1.0000
10:98614902:AC:A	donor_loss	1.0000
10:98614903:C:CC	donor_gain	1.0000
10:98614903:CT:C	donor_gain	1.0000
10:98614903:CTG:C	donor_gain	1.0000
10:98614903:CTGGT:C	donor_gain	1.0000
10:98615015:CCAT:C	acceptor_gain	1.0000
10:98615016:CAT:C	acceptor_gain	1.0000
10:98615016:CATC:C	acceptor_gain	1.0000

AlphaMissense

3849 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:98459728:A:G	L542P	1.000
10:98482740:G:C	N503K	1.000
10:98482740:G:T	N503K	1.000
10:98490065:G:C	C484W	1.000
10:98459586:G:C	C589W	0.999
10:98459587:C:G	C589S	0.999
10:98459587:C:T	C589Y	0.999
10:98459588:A:G	C589R	0.999
10:98459588:A:T	C589S	0.999
10:98459620:A:G	F578S	0.999
10:98459724:A:C	N543K	0.999
10:98459724:A:T	N543K	0.999
10:98482676:A:C	Y525D	0.999
10:98482717:A:C	I511S	0.999
10:98482717:A:G	I511T	0.999
10:98482717:A:T	I511N	0.999
10:98482722:C:A	K509N	0.999
10:98482722:C:G	K509N	0.999
10:98482742:T:C	N503D	0.999
10:98482756:G:T	T498K	0.999
10:98490066:C:A	C484F	0.999
10:98490066:C:G	C484S	0.999
10:98490066:C:T	C484Y	0.999
10:98490067:A:G	C484R	0.999
10:98490067:A:T	C484S	0.999
10:98490072:G:T	A482D	0.999
10:98490084:A:G	L478P	0.999
10:98490165:A:G	L451P	0.999
10:98490190:A:G	W443R	0.999
10:98490190:A:T	W443R	0.999

dbSNP variants (sampled 300 via entrez): RS1000003332 (10:98587619 A>G), RS1000009545 (10:99316719 C>A,G), RS1000012385 (10:98520808 C>A), RS1000013034 (10:98654760 C>T), RS1000013533 (10:98478238 T>C), RS1000020259 (10:98646801 G>C,T), RS1000021656 (10:99132119 G>C), RS1000023576 (10:99206419 G>A), RS1000025684 (10:99219354 C>T), RS1000035493 (10:99218848 T>G), RS1000041071 (10:98826883 C>G), RS1000043451 (10:99022532 C>G,T), RS1000045387 (10:98868016 C>A,T), RS1000055992 (10:98775316 C>G), RS1000060857 (10:99069740 G>C)

Disease associations

OMIM: gene MIM:613469 | disease phenotypes: MIM:236730, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
urofacial syndrome type 1	Definitive	Autosomal recessive
Ochoa syndrome	Supportive	Autosomal recessive

Mondo (3): urofacial syndrome type 1 (MONDO:0009368), congenital anomaly of kidney and urinary tract (MONDO:0019719), Ochoa syndrome (MONDO:0000463)

Orphanet (2): Urofacial syndrome (Orphanet:2704), Renal or urinary tract malformation (Orphanet:93545)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000020	Urinary incontinence
HP:0000028	Cryptorchidism
HP:0000072	Hydroureter
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000126	Hydronephrosis
HP:0000796	Urethral obstruction
HP:0000805	Enuresis
HP:0000822	Hypertension
HP:0001959	Polydipsia
HP:0001999	Abnormal facial shape
HP:0002019	Constipation
HP:0002607	Bowel incontinence
HP:0005346	Abnormal facial expression
HP:0010481	Urethral valve

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001762_483	Obesity-related traits	9.000000e-06
GCST002088_7	Asthma (childhood onset)	5.000000e-08
GCST002366_6	Response to anti-retroviral therapy (ddI/d4T) in HIV-1 infection (Grade 1 peripheral neuropathy)	7.000000e-06
GCST003720_34	Migraine	3.000000e-10
GCST90011899_130	Aspartate aminotransferase levels	1.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement
EFO:0000180	HIV-1 infection
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C566906	Cakut (supp.)
C536480	Urofacial syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Aflatoxin B1	decreases methylation, affects methylation	2
bisphenol A	affects methylation, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
15-acetyldeoxynivalenol	increases expression	1
perfluorooctane sulfonic acid	affects methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Acetaminophen	increases expression	1
Copper	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	decreases expression	1
Methapyrilene	increases methylation	1
Phenylmercuric Acetate	affects cotreatment, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Valproic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT04537364	Not specified	COMPLETED	Prediction of Renal Parenchymal Damage of CAKUT
NCT06921733	Not specified	RECRUITING	Ultrasound Localization Microscopy in Patient With Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)