HAS2

Summary

HAS2 (hyaluronan synthase 2, HGNC:4819) is a protein-coding gene on chromosome 8q24.13, encoding Hyaluronan synthase 2 (Q92819). Catalyzes the addition of GlcNAc or GlcUA monosaccharides to the nascent hyaluronan polymer.

Hyaluronan or hyaluronic acid (HA) is a high molecular weight unbranched polysaccharide synthesized by a wide variety of organisms from bacteria to mammals, and is a constituent of the extracellular matrix. It consists of alternating glucuronic acid and N-acetylglucosamine residues that are linked by beta-1-3 and beta-1-4 glycosidic bonds. HA is synthesized by membrane-bound synthase at the inner surface of the plasma membrane, and the chains are extruded through pore-like structures into the extracellular space. It serves a variety of functions, including space filling, lubrication of joints, and provision of a matrix through which cells can migrate. HA is actively produced during wound healing and tissue repair to provide a framework for ingrowth of blood vessels and fibroblasts. Changes in the serum concentration of HA are associated with inflammatory and degenerative arthropathies such as rheumatoid arthritis. In addition, the interaction of HA with the leukocyte receptor CD44 is important in tissue-specific homing by leukocytes, and overexpression of HA receptors has been correlated with tumor metastasis. HAS2 is a member of the newly identified vertebrate gene family encoding putative hyaluronan synthases, and its amino acid sequence shows significant homology to glycosaminoglycan synthetase (DG42) from Xenopus laevis, and human and murine hyaluronan synthase 1.

Source: NCBI Gene 3037 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Limited, ClinGen)
• GWAS associations: 14
• Clinical variants (ClinVar): 40 total — 1 pathogenic
• MANE Select transcript: NM_005328

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4819
Approved symbol	HAS2
Name	hyaluronan synthase 2
Location	8q24.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170961
Ensembl biotype	protein_coding
OMIM	601636
Entrez	3037

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000303924

RefSeq mRNA: 1 — MANE Select: NM_005328 NM_005328

CCDS: CCDS6335

Canonical transcript exons

ENST00000303924 — 4 exons

Exon	Start	End
ENSE00001166179	121612116	121615038
ENSE00001175306	121617105	121617206
ENSE00001386262	121640853	121641440
ENSE00001628352	121628714	121629340

Expression profiles

Bgee: expression breadth ubiquitous, 194 present calls, max score 88.75.

FANTOM5 (CAGE): breadth broad, TPM avg 9.7168 / max 997.1908, expressed in 782 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
94667	8.1212	712
94666	0.8875	301
94669	0.2884	141
94668	0.1803	91
94670	0.1272	40
94664	0.1122	53

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	88.75	gold quality
stromal cell of endometrium	CL:0002255	84.75	gold quality
tibia	UBERON:0000979	81.32	gold quality
synovial joint	UBERON:0002217	77.95	gold quality
sperm	CL:0000019	77.61	gold quality
calcaneal tendon	UBERON:0003701	77.30	gold quality
gall bladder	UBERON:0002110	76.99	gold quality
rectum	UBERON:0001052	76.81	gold quality
islet of Langerhans	UBERON:0000006	75.46	gold quality
male germ cell	CL:0000015	75.35	gold quality
colonic epithelium	UBERON:0000397	74.78	gold quality
superficial temporal artery	UBERON:0001614	74.09	gold quality
mucosa of stomach	UBERON:0001199	73.13	gold quality
vermiform appendix	UBERON:0001154	72.93	gold quality
secondary oocyte	CL:0000655	72.26	gold quality
right atrium auricular region	UBERON:0006631	72.13	gold quality
layer of synovial tissue	UBERON:0007616	71.88	silver quality
skin of hip	UBERON:0001554	71.77	gold quality
omental fat pad	UBERON:0010414	71.28	gold quality
peritoneum	UBERON:0002358	71.20	gold quality
smooth muscle tissue	UBERON:0001135	70.67	gold quality
adipose tissue of abdominal region	UBERON:0007808	70.64	gold quality
epithelial cell of pancreas	CL:0000083	70.39	silver quality
cardiac atrium	UBERON:0002081	70.28	gold quality
caecum	UBERON:0001153	70.08	gold quality
heart right ventricle	UBERON:0002080	69.56	gold quality
tibial nerve	UBERON:0001323	68.15	gold quality
tendon	UBERON:0000043	68.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	67.99	gold quality
left uterine tube	UBERON:0001303	67.97	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-7037	yes	8902.74
E-MTAB-7249	yes	3221.02
E-MTAB-8271	yes	518.11
E-MTAB-9388	yes	122.38
E-ANND-3	yes	14.86
E-GEOD-93593	yes	4.56
E-CURD-11	no	24.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMP7, GLI1, HNF4G, IL1B, MYC, PAX6, PDGFB, RARG, SP1, SP3, STAT3, YY1

miRNA regulators (miRDB)

165 targeting HAS2, 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-3064-3P	100.00	70.09	1254
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-23A-3P	99.95	74.24	3163

Literature-anchored findings (GeneRIF, showing 40)

• hyaluronan synthase expression in prostate adenocarcinoma cells (PMID:11790779)
• Expression of each hyaluronan synthase isoform is regulated differently by growth factors and cytokines in vascular endothelial cells. Expressed in proliferative membranes from proliferative vitreoretinal diseases. May affect progression of diseases. (PMID:14636845)
• Upregulation of HAS2 expression via EP(2) and IP receptors might contribute to the accumulation of HA during human atherosclerosis, thereby mediating proatherosclerotic functions of COX2. (PMID:14752026)
• Base sequence of this gene’s promoter is sequenced. (PMID:14988410)
• Fusion with PLAG1 protein in lipoblastoma. (PMID:15642402)
• IL-1beta induction of HAS2 expression involves multiple signaling pathways that act in concert, thus leading to an increase in expression of hyaluronan by jejunum-derived mesenchymal cells (PMID:15677552)
• Has2 gene is a potent primary EGF and all-trans-RA responding gene with a complex regulation (PMID:15722343)
• natural antisense mRNAs of HAS2 may have an important and novel regulatory role in the control of HAS2, hyaluronan biosynthesis, and HA-dependent cell functions (PMID:15843373)
• Antisense inhibition of HAS2 in osteosarcoma cells inhibits hyaluronan retention and tumorigenicity. (PMID:15922739)
• mRNA for HAS1 is undetectable but HAS3 mRNA can be readily detected in freshly isolated CD133+ as well as in CD133- umbilical cord blood (UCB) cells. mRNA for HAS2 can only be detected in CD133+ progenitor cells. (PMID:16564133)
• Sp1 and Sp3 are principal mediators of HAS2 constitutive transcription (PMID:16603733)
• hyaluronan synthase 2 and TSG-6 have roles in hyaluronan distribution and function in proximal tubular epithelial cells (PMID:16687630)
• The aim of this study was to evaluate how TNF-alpha, IFN-gamma,IL-1beta, and exposition to oxidative stress may modulate HAS activities in normal human skin fibroblasts. (PMID:16786194)
• osteopontin-transfected cells express high levels of hyaluronan synthase 2, which is associated with increased HA production and matrix retention and is necessary for tumor cell adhesion to bone marrow endothelial cells and anchorage-independent growth (PMID:16807238)
• explain the induction of HAS2 mRNA by all-trans-retinoic acid and tumor necrosis factor-alpha (PMID:17307735)
• RNA interference-mediated suppression of HAS2 led to a less aggressive phenotype of the breast tumor cells, as assessed by cell growth, both in anchorage-dependent and anchorage-independent cultures. (PMID:17315194)
• Interleukin-1beta stimulation resulted in induction of HAS1 and HAS2 transcription but did not induce phenotypic differentiation or induce hyaluronan coat assembly (PMID:17611197)
• HAS2 plays an important role in regulating hyaluronan synthesis and human embryonic stem cell differentiation. (PMID:17872502)
• Hyaluronan synthase (HAS2 and HAS3) and hyaluronan may mediate cellular invasion via changes in MMP-7 expression in SW620 colon carcinoma cells. (PMID:19231585)
• MED1 and NCoR1 are central for the all-trans-RA induction of the HAS2 gene and CBP dominates its forskolin response (PMID:19416972)
• HAS1, HAS2 and HAS3 expression is not consistently elevated in ovarian carcinomas. (PMID:19435493)
• Transfection with siHAS2 and siHAS1 showed that mainly HAS1 synthesized high molecular weight HA regulates HT1080 cell motility. (PMID:19577615)
• Data show that a significant in expression levels of HA synthases (HASs) and hyaluronidases (Hyals) was observed in vitro on stimulation of epithelial ovarian carcinoma cells by gonadotropins. (PMID:20072653)
• interleukin 1beta and tumor necrosis factors alpha and beta, but not transforming growth factors alpha and beta, strongly induced HA synthesis by NF-kappaB pathway, activating hyaluronan synthase 2 (PMID:20522558)
• Hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in the accumulation of hyaluronan in endometrioid endometrial carcinoma (PMID:20875124)
• The combined HAS2-HYAL-1 biomarker detected bladder cancer and significantly predicted its recurrence. (PMID:20960509)
• Hyaluronan synthesis is inhibited by adenosine monophosphate-activated protein kinase through the regulation of HAS2 activity in human aortic smooth muscle cells. (PMID:21228273)
• transcriptional induction of HAS2-AS1 and HAS2 occurs simultaneously in PTCs and suggest that transcription of the antisense RNA stabilizes or augments HAS2 mRNA expression in these cells via RNA/mRNA heteroduplex formation. (PMID:21357421)
• pulsatile, arterial-like shear stress conditions induced enzyme and hyaluronan effectively, while lower shear stress that continuously changed its direction did not induce any differences in comparison with control cultures not exposed to shear stress. (PMID:21551265)
• HAS2-HYAL2/CD44 system may support spontaneous chemokinesis of human cancer cells through self-degradation of HMW-HA to produce LMW-HA by an autocrine mechanism. (PMID:21743962)
• Altered binding of SP1 and YY1 to the promoter correlated with cellular UDP-N-acetylhexosamines content and inhibition of HAS2 expression. (PMID:21795679)
• Hyaluronan synthase 2 (HAS2) promotes breast cancer cell invasion by suppression of tissue metalloproteinase inhibitor 1 (TIMP-1) (PMID:22016393)
• Findings show a critical role of HAS2 in the development of a prometastatic microenvironment. (PMID:22113945)
• The difference in control of HAS2 expression allows the activation of one of the mechanisms underlying Graves ophthalmopathy, adipogenesis, to be linked biologically with the second, Hyaluronan overproduction. (PMID:22162480)
• We identified a previously unknown downstream target of beta-catenin, HAS2, in prostate cancer (PMID:22298898)
• HAS 2 may be a potential therapeutic target for the treatment of oral cavity cancer (PMID:22473523)
• analysis of changes in cervical glycosaminoglycan composition during normal pregnancy and preterm birth: Has1 is expressed in preterm birth, while Has2 is induced at term (PMID:22529214)
• HA chains synthesized by HAS1 and HAS2 contribute to outflow resistance, while hyaluronan produced by HAS3 does not appear to play a significant role. (PMID:22695958)
• no significant difference (P > 0.05) was found between the level of HAS2 synthesized by control cells and NCTC 2544 cells treated with Plantaricin A preparations (PMID:22742591)
• Melanoma cell-derived factors stimulate hyaluronan synthesis in dermal fibroblasts by upregulating HAS2 through PDGFR-PI3K-AKT and p38 signaling (PMID:22825838)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	has2	ENSDARG00000036987
mus_musculus	Has2	ENSMUSG00000022367
rattus_norvegicus	Has2	ENSRNOG00000004854

Paralogs (2): HAS3 (ENSG00000103044), HAS1 (ENSG00000105509)

Protein

Protein identifiers

Hyaluronan synthase 2 — Q92819 (reviewed: Q92819)

Alternative names: Hyaluronate synthase 2, Hyaluronic acid synthase 2

All UniProt accessions (1): Q92819

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the addition of GlcNAc or GlcUA monosaccharides to the nascent hyaluronan polymer. Therefore, it is essential to hyaluronan synthesis a major component of most extracellular matrices that has a structural role in tissues architectures and regulates cell adhesion, migration and differentiation. This is one of three isoenzymes responsible for cellular hyaluronan synthesis and it is particularly responsible for the synthesis of high molecular mass hyaluronan.

Subunit / interactions. Homodimer; dimerization promotes enzymatic activity. Forms heterodimer with HAS3. Forms heterodimer with HAS1.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane. Vesicle. Golgi apparatus membrane. Lysosome.

Tissue specificity. Expressed in fibroblasts.

Post-translational modifications. Phosphorylation at Thr-328 is essential for hyaluronan synthase activity. Phosphorylation at Thr-110 is required for transport from ER to Golgi. O-GlcNAcylation at Ser-221 increases the stability of HAS2 and plasma membrane localization. Ubiquitination at Lys-190; this ubiquitination is essential for hyaluronan synthase activity and homo- or hetero-oligomerization. Can also be poly-ubiquitinated. Deubiquitinated by USP17 and USP4. USP17 efficiently removes ‘Lys-63’- and ‘Lys-48’-linked polyubiquitin chains, whereas USP4 preferentially removes monoubiquitination and, partially, both ‘Lys-63’- and ‘Lys-48’-linked polyubiquitin chain.

Disease relevance. A chromosomal aberration involving HAS2 may be a cause of lipoblastomas, which are benign tumors resulting from transformation of adipocytes, usually diagnosed in children. 8q12.1 to 8q24.1 intrachromosomal rearrangement with PLAG1.

Activity regulation. Regulated by several post-translational modifications such as ubiquitination/deubiquitination, phosphorylation and O-GlcNAcylation. The enzymatic activity depends on the availability of UDP-GlcUA and UDP-GlcNAc.

Induction. During cell cycle progression is induced at the G1-S and G2-M transitions. Up-regulated in a panel of cancer cell lines.

Pathway. Glycan biosynthesis; hyaluronan biosynthesis.

Similarity. Belongs to the NodC/HAS family.

RefSeq proteins (1): NP_005319* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029044	Nucleotide-diphossugar_trans	Homologous_superfamily

Pfam: PF03142

Enzyme classification (BRENDA):

• EC 2.4.1.212 — hyaluronan synthase (BRENDA: 17 organisms, 94 substrates, 53 inhibitors, 81 Km, 9 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
UDP-N-ACETYL-D-GLUCOSAMINE	0.053–1.1	31
UDP-D-GLUCURONATE	0.032–0.93	28
UDP-D-GLUCOSAMINE	0.258–0.84	5
UDP-ALPHA-D-GLUCURONATE	0.014–0.8	2
HYALURONAN OLIGOMER HA4	0.7	1
HYALURONAN OLIGOMER HA5	0.6	1
HYALURONAN OLIGOMER HA6	1	1
HYALURONAN OLIGOMER HA8	0.7	1
HYALURONIC ACID TETRASACCHARIDE	0.91	1
UDP-ALPHA-N-ACETYL-D-GLUCOSAMINE	0.66	1
UDP-N-ACETYL-ALPHA-D-GLUCOSAMINE	23.4	1

Catalyzed reactions (Rhea), 2 shown:

• N-acetyl-beta-D-glucosaminyl-(1->4)-hyaluronan + UDP-alpha-D-glucuronate = hyaluronan + UDP + H(+) (RHEA:12528)
• hyaluronan + UDP-N-acetyl-alpha-D-glucosamine = N-acetyl-beta-D-glucosaminyl-(1->4)-hyaluronan + UDP + H(+) (RHEA:20465)

UniProt features (26 total): topological domain 8, transmembrane region 7, mutagenesis site 6, modified residue 2, chain 1, glycosylation site 1, cross-link 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92819-F1	90.63	0.79

Functional residue map

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

Post-translational modifications (3): 110, 328, 190

Glycosylation sites (1): 221

Mutagenesis-validated functional residues (6):

Position	Phenotype
110	completely abolishes hyaluronan synthase activity. not detected in cytoplasmic vesicles nor at cell membrane. inability
190	completely abolishes hyaluronan synthase activity. cumulates at plasma membrane.
221	prevents o-glcnacylation. increases protein stability. reduces hyaluronan synthase activity.
221	increases protein degradation. abolishes hyaluronan synthase activity. does not affect subcellular location.
328	abolishes hyaluronan synthase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2142845	Hyaluronan metabolism

MSigDB gene sets: 373 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, YAATNRNNNYNATT_UNKNOWN, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, PAL_PRMT5_TARGETS_UP, NKX25_02, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS, LI_WILMS_TUMOR, GOBP_KERATINOCYTE_PROLIFERATION, ATACCTC_MIR202, MODULE_64

GO Biological Process (26): polysaccharide biosynthetic process (GO:0000271), vasculogenesis (GO:0001570), kidney development (GO:0001822), positive regulation of cell population proliferation (GO:0008284), positive regulation of keratinocyte proliferation (GO:0010838), positive regulation of smooth muscle cell migration (GO:0014911), hyaluronan biosynthetic process (GO:0030213), positive regulation of cell migration (GO:0030335), positive regulation of urine volume (GO:0035810), cellular response to platelet-derived growth factor stimulus (GO:0036120), atrioventricular canal development (GO:0036302), estrous cycle (GO:0044849), positive regulation of keratinocyte migration (GO:0051549), bone morphogenesis (GO:0060349), renal water absorption (GO:0070295), cellular response to interleukin-1 (GO:0071347), cellular response to tumor necrosis factor (GO:0071356), cellular response to fluid shear stress (GO:0071498), extracellular matrix assembly (GO:0085029), endocardial cushion to mesenchymal transition (GO:0090500), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026), positive regulation of hyaluronan biosynthetic process (GO:1900127), positive regulation of monocyte aggregation (GO:1900625), regulation of extracellular matrix assembly (GO:1901201), glycosaminoglycan biosynthetic process (GO:0006024), hyaluronan metabolic process (GO:0030212)

GO Molecular Function (5): identical protein binding (GO:0042802), hyaluronan synthase activity (GO:0050501), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (12): Golgi membrane (GO:0000139), lysosome (GO:0005764), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), cytoplasmic vesicle (GO:0031410), plasma membrane raft (GO:0044853), extracellular vesicle (GO:1903561), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), vesicle (GO:0031982)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glycosaminoglycan metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular response to cytokine stimulus	2
endomembrane system	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
polysaccharide metabolic process	1
macromolecule biosynthetic process	1
carbohydrate biosynthetic process	1
cell differentiation	1
blood vessel morphogenesis	1
animal organ development	1
renal system development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
positive regulation of epithelial cell proliferation	1
smooth muscle cell migration	1
regulation of smooth muscle cell migration	1
positive regulation of cell migration	1
glycosaminoglycan biosynthetic process	1
hyaluronan metabolic process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
regulation of urine volume	1
response to platelet-derived growth factor	1
cellular response to growth factor stimulus	1
heart development	1
anatomical structure development	1
ovulation cycle	1
positive regulation of epithelial cell migration	1
keratinocyte migration	1
regulation of keratinocyte migration	1
animal organ morphogenesis	1
skeletal system morphogenesis	1
bone development	1
renal water transport	1
renal absorption	1

Protein interactions and networks

STRING

3916 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HAS2	HYAL1	Q12794	823
HAS2	CD44	P16070	815
HAS2	HYAL2	Q12891	811
HAS2	SPAM1	P38567	784
HAS2	TNFAIP6	P98066	771
HAS2	ACAN	P16112	734
HAS2	HMMR	O75330	676
HAS2	DCN	P07585	663
HAS2	UGDH	O60701	660
HAS2	HABP2	Q14520	640
HAS2	PTGER4	P35408	631
HAS2	PTX3	P26022	608
HAS2	BGN	P13247	601
HAS2	VCAN	P13611	600
HAS2	GDF9	O60383	599

IntAct

28 interactions, top by confidence:

A	B	Type	Score
HAS2	HAS1	psi-mi:“MI:0915”(physical association)	0.550
HAS1	HAS2	psi-mi:“MI:0403”(colocalization)	0.550
HAS2	HAS3	psi-mi:“MI:0403”(colocalization)	0.550
HAS2	HAS1	psi-mi:“MI:2364”(proximity)	0.550
HAS3	HAS2	psi-mi:“MI:2364”(proximity)	0.550
HAS1	HAS2	psi-mi:“MI:2364”(proximity)	0.550
HAS2	HAS3	psi-mi:“MI:2364”(proximity)	0.550
HAS2	HAS3	psi-mi:“MI:0915”(physical association)	0.550
HAS2	HAS2	psi-mi:“MI:0403”(colocalization)	0.440
HAS2	HAS2	psi-mi:“MI:2364”(proximity)	0.440

BioGRID (4): USP4 (Co-localization), USP17L22 (Co-localization), HAS2 (Affinity Capture-Western), HAS3 (Affinity Capture-Western)

ESM2 similar proteins: A2X8A7, A2Y8U6, B1WB39, B8AT51, D3ZEH5, E9EFH8, G2WS43, G5AY81, O00219, O01346, O08650, O35776, O57424, O57425, O57426, O57427, O80605, O88693, O95427, O97711, P13563, P70312, Q0JAW2, Q0VCR6, Q16739, Q1PET6, Q2V4F9, Q3SYY9, Q4R5E3, Q5BL38, Q5U4S8, Q5ZI05, Q61647, Q658H5, Q6EPQ3, Q6R5J2, Q8AY29, Q8CIF6, Q8K0B2, Q8K4X7

Diamond homologs: B1WB39, G5AY81, O00219, O08650, O35776, O57424, O57425, O57426, O57427, O57428, O97711, P04341, P13563, P17862, P70312, Q07755, Q61647, Q92819, Q92839, P50356, P72334, Q8SSI7, P26024, P0C0H0, P0C0H1, P0DB60, P0DB61, P50357, Q5X9A9, Q8NKX1

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
HNF4G	“up-regulates quantity by expression”	HAS2	“transcriptional regulation”
PRKAA2	“down-regulates activity”	HAS2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	31
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3391849	GRCh37/hg19 8q23.2-24.3(chr8:111432348-146295771)x3	Pathogenic

SpliceAI

498 predictions. Top by Δscore:

Variant	Effect	Δscore
8:121615039:C:CC	acceptor_gain	1.0000
8:121617102:TAC:T	donor_loss	1.0000
8:121617202:CAAAC:C	acceptor_gain	1.0000
8:121617203:AAAC:A	acceptor_gain	1.0000
8:121617204:AAC:A	acceptor_gain	1.0000
8:121617204:AACC:A	acceptor_loss	1.0000
8:121617205:AC:A	acceptor_gain	1.0000
8:121617205:ACCT:A	acceptor_loss	1.0000
8:121617206:CC:C	acceptor_gain	1.0000
8:121617207:C:CC	acceptor_gain	1.0000
8:121617208:T:C	acceptor_loss	1.0000
8:121615036:AAT:A	acceptor_gain	0.9900
8:121617126:TCCA:T	donor_gain	0.9900
8:121617205:ACCTG:A	acceptor_gain	0.9900
8:121617206:CCTGC:C	acceptor_gain	0.9900
8:121617210:C:CT	acceptor_gain	0.9900
8:121615034:AAAAT:A	acceptor_gain	0.9800
8:121615035:AAAT:A	acceptor_gain	0.9800
8:121615036:AATCT:A	acceptor_loss	0.9800
8:121615037:AT:A	acceptor_gain	0.9800
8:121615037:ATCT:A	acceptor_loss	0.9800
8:121615038:TC:T	acceptor_loss	0.9800
8:121615039:C:T	acceptor_loss	0.9800
8:121615040:T:G	acceptor_loss	0.9800
8:121617103:A:AC	donor_gain	0.9800
8:121617104:C:CC	donor_gain	0.9800
8:121617152:CTT:C	donor_gain	0.9800
8:121617153:TTT:T	donor_gain	0.9800
8:121617154:TTT:T	donor_gain	0.9800
8:121617204:AACCT:A	acceptor_gain	0.9800

AlphaMissense

3638 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:121614379:C:A	W463C	1.000
8:121614379:C:G	W463C	1.000
8:121614381:A:G	W463R	1.000
8:121614381:A:T	W463R	1.000
8:121614689:C:G	R360P	1.000
8:121614706:C:A	W354C	1.000
8:121614706:C:G	W354C	1.000
8:121614707:C:G	W354S	1.000
8:121614708:A:G	W354R	1.000
8:121614708:A:T	W354R	1.000
8:121614711:G:T	R353S	1.000
8:121614718:C:A	Q350H	1.000
8:121614718:C:G	Q350H	1.000
8:121614729:A:G	W347R	1.000
8:121614729:A:T	W347R	1.000
8:121614760:G:C	C336W	1.000
8:121614762:A:G	C336R	1.000
8:121614809:C:G	R320P	1.000
8:121614818:A:G	L317P	1.000
8:121614824:C:A	R315M	1.000
8:121614826:G:C	D314E	1.000
8:121614826:G:T	D314E	1.000
8:121614827:T:A	D314V	1.000
8:121614827:T:C	D314G	1.000
8:121614827:T:G	D314A	1.000
8:121614828:C:A	D314Y	1.000
8:121614828:C:G	D314H	1.000
8:121614830:T:A	D313V	1.000
8:121614830:T:G	D313A	1.000
8:121614831:C:G	D313H	1.000

dbSNP variants (sampled 300 via entrez): RS1000063050 (8:121618776 C>T), RS1000163480 (8:121619570 C>T), RS1000196189 (8:121626739 T>C), RS1000378275 (8:121616524 C>T), RS1000407939 (8:121616227 T>C), RS1000534510 (8:121626260 G>A), RS1000888415 (8:121623630 T>C), RS1001068341 (8:121620324 C>A,G), RS1001127655 (8:121641253 A>C,G), RS1001182992 (8:121613403 TAGAG>T,TAG), RS1001309352 (8:121619689 T>G), RS1001503814 (8:121616090 C>T), RS1001583153 (8:121634165 A>G), RS1001694658 (8:121622918 G>C,T), RS1001699027 (8:121633806 G>A,T)

Disease associations

OMIM: gene MIM:601636 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital heart disease	Limited	AD

Mondo (1): congenital heart disease (MONDO:0005453)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001066_10	Dialysis-related mortality	6.000000e-06
GCST001762_793	Obesity-related traits	5.000000e-06
GCST002312_3	Periodontal disease-related phenotype (Socransky)	6.000000e-06
GCST003989_38	Chin dimples	5.000000e-10
GCST004032_7	JT interval (sulfonylurea treatment interaction)	1.000000e-06
GCST006479_135	Diverticular disease	4.000000e-09
GCST008070_9	HDL cholesterol levels	3.000000e-06
GCST008075_118	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-14
GCST008075_71	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	5.000000e-09
GCST008084_132	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	7.000000e-06
GCST008084_191	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	7.000000e-16
GCST008084_86	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-09
GCST008085_176	HDL cholesterol levels in current drinkers	2.000000e-07
GCST011348_18	High density lipoprotein cholesterol levels	4.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007885	JT interval
EFO:0007922	response to sulfonylurea
EFO:0009959	diverticular disease
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	increases expression, affects cotreatment, decreases expression	8
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	7
bisphenol A	affects cotreatment, increases methylation, decreases expression	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases expression	3
Asbestos, Crocidolite	affects expression, increases expression	3
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, decreases expression, increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases activity, decreases reaction, increases expression	2
Arsenic Trioxide	decreases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	increases expression, affects cotreatment	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Benzo(a)pyrene	affects response to substance, increases expression, decreases methylation	2
Cadmium	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
Doxorubicin	decreases expression, increases expression	2
Formaldehyde	decreases expression	2
T-2 Toxin	increases expression, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Tretinoin	increases reaction, decreases expression, increases expression, affects binding	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
methylmercuric chloride	decreases expression	1
sodium arsenate	increases abundance, increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
3,4-dichloroaniline	increases expression	1
methylparaben	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE