HAS3

Summary

HAS3 (hyaluronan synthase 3, HGNC:4820) is a protein-coding gene on chromosome 16q22.1, encoding Hyaluronan synthase 3 (O00219). Catalyzes the addition of GlcNAc or GlcUA monosaccharides to the nascent hyaluronan polymer.

The protein encoded by this gene is involved in the synthesis of the unbranched glycosaminoglycan hyaluronan, or hyaluronic acid, which is a major constituent of the extracellular matrix. This gene is a member of the NODC/HAS gene family. Compared to the proteins encoded by other members of this gene family, this protein appears to be more of a regulator of hyaluronan synthesis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 3038 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 87 total
• MANE Select transcript: NM_001199280

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4820
Approved symbol	HAS3
Name	hyaluronan synthase 3
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000103044
Ensembl biotype	protein_coding
OMIM	602428
Entrez	3038

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000219322, ENST00000306560, ENST00000566118, ENST00000568321, ENST00000569188, ENST00000851819, ENST00000851820, ENST00000911949, ENST00000911950, ENST00000911951, ENST00000911952, ENST00000911953

RefSeq mRNA: 3 — MANE Select: NM_001199280 NM_001199280, NM_005329, NM_138612

CCDS: CCDS10870, CCDS10871

Canonical transcript exons

ENST00000569188 — 4 exons

Exon	Start	End
ENSE00000691074	69113441	69113542
ENSE00001785957	69109396	69110031
ENSE00002591681	69114343	69117660
ENSE00002622621	69105653	69105787

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 97.15.

FANTOM5 (CAGE): breadth broad, TPM avg 2.9044 / max 182.9510, expressed in 590 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154796	2.3522	544
154794	0.3808	156
154795	0.1713	69

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.15	gold quality
oocyte	CL:0000023	95.96	gold quality
cartilage tissue	UBERON:0002418	90.61	gold quality
oviduct epithelium	UBERON:0004804	87.88	gold quality
esophagus mucosa	UBERON:0002469	85.91	gold quality
cortical plate	UBERON:0005343	83.95	gold quality
urinary bladder	UBERON:0001255	82.53	gold quality
tendon of biceps brachii	UBERON:0008188	81.83	gold quality
mucosa of transverse colon	UBERON:0004991	78.72	gold quality
esophagus squamous epithelium	UBERON:0006920	77.75	gold quality
vagina	UBERON:0000996	77.24	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.71	gold quality
lower esophagus mucosa	UBERON:0035834	75.28	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	75.16	gold quality
skin of abdomen	UBERON:0001416	74.07	gold quality
medial globus pallidus	UBERON:0002477	73.26	gold quality
oral cavity	UBERON:0000167	73.23	gold quality
esophagus	UBERON:0001043	73.13	gold quality
mammary duct	UBERON:0001765	72.90	gold quality
epithelium of mammary gland	UBERON:0003244	72.77	gold quality
nasal cavity mucosa	UBERON:0001826	72.76	gold quality
zone of skin	UBERON:0000014	72.09	gold quality
mammalian vulva	UBERON:0000997	72.01	gold quality
right lobe of thyroid gland	UBERON:0001119	71.61	gold quality
skin of leg	UBERON:0001511	71.50	gold quality
thyroid gland	UBERON:0002046	70.76	gold quality
left lobe of thyroid gland	UBERON:0001120	70.68	gold quality
buccal mucosa cell	CL:0002336	70.65	silver quality
gall bladder	UBERON:0002110	70.39	gold quality
upper leg skin	UBERON:0004262	70.18	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ENAD-21	yes	275.13
E-ANND-3	yes	9.81
E-MTAB-7303	no	115.79

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
HYAL1	Activation
HYAL2	Activation

Upstream regulators (CollecTRI, top): PDGFB

miRNA regulators (miRDB)

12 targeting HAS3, 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-4677-5P	99.70	70.09	1940
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-219A-2-3P	98.62	68.78	797
HSA-MIR-3136-5P	98.53	67.68	793
HSA-MIR-4439	98.53	67.53	793
HSA-MIR-6511A-3P	97.60	66.61	713
HSA-MIR-6511B-3P	97.60	66.61	713
HSA-MIR-526B-5P	97.41	67.99	1074
HSA-MIR-3121-5P	97.30	66.62	1146
HSA-MIR-1913	97.07	66.20	1417

Literature-anchored findings (GeneRIF, showing 34)

• hyaluronan synthase expression in prostate adenocarcinoma cells (PMID:11790779)
• Hyaluronan and HAS3 function in the growth and progression of colon carcinoma (PMID:14566823)
• 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)
• 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)
• 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)
• Hyaluronan synthase (HAS2 and HAS3) and hyaluronan may mediate cellular invasion via changes in MMP-7 expression in SW620 colon carcinoma cells. (PMID:19231585)
• HAS1, HAS2 and HAS3 expression is not consistently elevated in ovarian carcinomas. (PMID:19435493)
• Nodular basal cell carcinoma is associated with increased levels of hyaluronic acid concomitant with upregulation of gene expression of HAS3, HYAL3 and RHAMM, when compared with normal adjacent skin. (PMID:20849445)
• Hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in the accumulation of hyaluronan in endometrioid endometrial carcinoma (PMID:20875124)
• Data show that mRNA of HAS isoform 3 (HAS3) was upregulated in ESCC biopsies. (PMID:21429221)
• 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)
• Hyaluronan synthase 1 (HAS1) requires higher cellular UDP-GlcNAc concentration than HAS2 and HAS3 (PMID:23303191)
• Inverse expression of hyaluronidase 2 and hyaluronan synthases 1-3 is associated with reduced hyaluronan content in malignant cutaneous melanoma. (PMID:23560496)
• Data indicate that oxLDL doubled the transcripts of hyaluronan synthases HAS2 and HAS3 and hyaluronan deposition via the scavenger receptor LOX-1. (PMID:23979132)
• Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) -induced cardiac injury. (PMID:24470002)
• Rab10 silencing increased the plasma membrane residence of HAS3, resulting in a significant increase of hyaluronan secretion and an enlarged cell surface HA coat, whereas Rab10 overexpression suppressed hyaluronan synthesis. (PMID:24509846)
• HAS3 mRNA expression level increases in atopic dermatitis lesions compared with healthy and non-lesional skin (PMID:24658508)
• Hyaluronan accumulation by HAS3 favors pancreatic cancer growth. (PMID:25147816)
• Transcriptional factor binding analysis indicated that HAS3 gene promoter lacks of canonical TATA box, but contains classical GC box as well as other putative binding sites for transcriptional factors (PMID:25843802)
• HAS3 underexpression is associated with advanced tumor stage and adverse pathological features, as well as implies inferior clinical outcomes for both groups of patients with UTUCs and UBUCs, suggesting its critical role in tumor progression (PMID:25934334)
• Overexpression of HAS3 decreased ERK1/2 phosphorylation suggesting that inhibition of MAP-kinase signaling was responsible for decreased melanoma cell adhesion, migration and proliferation. (PMID:26222208)
• The study describes novel regulatory mechanisms governed by UDP-sugars in hyaluronan synthesis, i.e. the intracellular trafficking and extracellular shedding of HAS3. The control mechanisms reveal the significance of these glucose metabolites in hyaluronan synthesis, which is particularly important in the interactions of malignant cells with their microenvironment, and hence the progression of tumors, like melanoma. (PMID:26883802)
• Hyaluronan synthase 3 (HAS3) and tumor necrosis factor-alpha (TNF-alpha) formed an inter-regulation loop to enhance tumorigenesis in oral cancer. (PMID:28107185)
• Study shows that HAS3 is induced by IL-1beta in vascular smooth muscle cells and that HAS3 is critically involved in early macrophage driven inflammation. (PMID:28987865)
• miR-29a-3p can inhibit gastric cancer cells proliferation and metastasis by regulation HAS3 expression. These findings reveal a new mechanism by which, at least partially, miR-29a-3p may act as a candidate tumor suppressor. (PMID:29693123)
• There was a higher HAS1 and HAS2 reactivity and lower HAS3 reactivity in the PCOS endometrium compared to women with regular menstrual cycles in the proliferative phase. (PMID:30614308)
• HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells. (PMID:31820036)
• The regulation of HAS3 by miR-10b and miR-29a in neuroendocrine transdifferentiated LNCaP prostate cancer cells. (PMID:31948751)
• Endothelial Hyaluronan Synthase 3 Augments Postischemic Arteriogenesis Through CD44/eNOS Signaling. (PMID:34380333)
• A Connecting Link between Hyaluronan Synthase 3-Mediated Hyaluronan Production and Epidermal Function. (PMID:35269567)
• Hyaluronan synthase 3 is protective after cardiac ischemia-reperfusion by preserving the T cell response. (PMID:35998871)
• 4-Methylumebelliferone Enhances Radiosensitizing Effects of Radioresistant Oral Squamous Cell Carcinoma Cells via Hyaluronan Synthase 3 Suppression. (PMID:36497040)
• Melatonin inhibits the stemness of head and neck squamous cell carcinoma by modulating HA synthesis via the FOSL1/HAS3 axis. (PMID:38402581)
• Epidermal keratinocytes regulate hyaluronan metabolism via extracellularly secreted hyaluronidase 1 and hyaluronan synthase 3. (PMID:38844132)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	has3	ENSDARG00000057210
mus_musculus	Has3	ENSMUSG00000031910
rattus_norvegicus	Tango6	ENSRNOG00000022524

Paralogs (2): HAS1 (ENSG00000105509), HAS2 (ENSG00000170961)

Protein

Protein identifiers

Hyaluronan synthase 3 — O00219 (reviewed: O00219)

Alternative names: Hyaluronate synthase 3, Hyaluronic acid synthase 3

All UniProt accessions (2): O00219, H3BRH5

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.

Subunit / interactions. Homodimers. Forms heterodimers with HAS2 and HAS1.

Subcellular location. Cell membrane. Golgi apparatus membrane. Golgi apparatus. trans-Golgi network membrane. Early endosome.

Post-translational modifications. O-GlcNAcylation increases the hyaluronan synthase activity, HAS3 stability and its plasma membrane residence. The concentration of UDP-GlcNAc controls the level of O-GlcNAc modification.

Activity regulation. The enzymatic activity depends on the availability of cytosolic levels of UDP-GlcUA and UDP-GlcNAc.

Pathway. Glycan biosynthesis; hyaluronan biosynthesis.

Similarity. Belongs to the NodC/HAS family.

Isoforms (2)

UniProt ID	Names	Canonical?
O00219-1	1	yes
O00219-2	2

RefSeq proteins (3): NP_001186209, NP_005320, NP_619515 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029044	Nucleotide-diphossugar_trans	Homologous_superfamily

Pfam: PF13641

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 (20 total): topological domain 8, transmembrane region 7, chain 1, glycosylation site 1, splice variant 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00219-F1	91.09	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.

Glycosylation sites (1): 462

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2142845	Hyaluronan metabolism

MSigDB gene sets: 132 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GSE45365_NK_CELL_VS_BCELL_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, chr16q22, AAGTCCA_MIR422B_MIR422A, MODULE_64, GOBP_EXTRACELLULAR_MATRIX_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_AMINOGLYCAN_BIOSYNTHETIC_PROCESS, GOBP_HYALURONAN_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, MARTINEZ_RB1_TARGETS_DN, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS

GO Biological Process (7): polysaccharide biosynthetic process (GO:0000271), carbohydrate metabolic process (GO:0005975), hyaluronan biosynthetic process (GO:0030213), positive regulation of DNA-templated transcription (GO:0045893), extracellular matrix assembly (GO:0085029), positive regulation of hyaluranon cable assembly (GO:1900106), glycosaminoglycan biosynthetic process (GO:0006024)

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 (9): Golgi membrane (GO:0000139), nucleus (GO:0005634), early endosome (GO:0005769), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020), hyaluranon cable (GO:0036117), cytoplasm (GO:0005737), endosome (GO:0005768)

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
cellular anatomical structure	3
intracellular membrane-bounded organelle	2
endomembrane system	2
polysaccharide metabolic process	1
macromolecule biosynthetic process	1
carbohydrate biosynthetic process	1
primary metabolic process	1
glycosaminoglycan biosynthetic process	1
hyaluronan metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
cellular component assembly	1
extracellular matrix organization	1
hyaluranon cable assembly	1
positive regulation of cellular component biogenesis	1
positive regulation of cellular component organization	1
regulation of hyaluranon cable assembly	1
aminoglycan biosynthetic process	1
glycosaminoglycan metabolic process	1
protein binding	1
UDP-glycosyltransferase activity	1
hexosyltransferase activity	1
binding	1
catalytic activity	1
transferase activity	1
Golgi apparatus	1
bounding membrane of organelle	1
endosome	1
cytoplasm	1
membrane	1
cell periphery	1
extracellular region	1
intracellular anatomical structure	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

2708 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HAS3	CD44	P16070	806
HAS3	HYAL2	Q12891	687
HAS3	HYAL1	Q12794	656
HAS3	ACAN	P16112	651
HAS3	SPAM1	P38567	644
HAS3	UGDH	O60701	619
HAS3	HAPLN1	P10915	611
HAS3	HMMR	O75330	589
HAS3	EGFR	P00533	572
HAS3	HABP2	Q14520	537
HAS3	HYAL3	O43820	520
HAS3	TNFAIP6	P98066	513
HAS3	HYAL4	Q2M3T9	469
HAS3	CEMIP	Q8WUJ3	438
HAS3	ITIH2	P19823	420

IntAct

34 interactions, top by confidence:

A	B	Type	Score
HAS2	HAS3	psi-mi:“MI:0403”(colocalization)	0.550
HAS3	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
HAS3	HAS1	psi-mi:“MI:0915”(physical association)	0.520
HAS3	HAS3	psi-mi:“MI:0915”(physical association)	0.520
HAS1	HAS3	psi-mi:“MI:0403”(colocalization)	0.520
HAS3	HAS3	psi-mi:“MI:0403”(colocalization)	0.520
HAS3	HAS3	psi-mi:“MI:2364”(proximity)	0.520
HAS3	HAS1	psi-mi:“MI:2364”(proximity)	0.520
HAS1	HAS3	psi-mi:“MI:2364”(proximity)	0.520
HAS3	TPM2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (17): TPM2 (Affinity Capture-MS), HAS3 (Two-hybrid), PLP1 (Two-hybrid), APOL3 (Two-hybrid), CMTM7 (Two-hybrid), C14orf180 (Two-hybrid), LHFPL5 (Two-hybrid), BSCL2 (Affinity Capture-MS), HAS3 (Affinity Capture-MS), HAS3 (Affinity Capture-MS), HAS3 (Affinity Capture-RNA), HAS3 (Co-fractionation), HAS3 (Co-fractionation), HAS3 (Co-fractionation), HAS3 (Co-fractionation)

ESM2 similar proteins: A6QQX9, A9CMA6, B0UY98, D3ZG27, F1NCD6, F2Z4R5, O00219, O08650, P48651, P51798, Q00576, Q13507, Q17QZ3, Q1JQC1, Q27963, Q2KHY9, Q4R766, Q5M7T4, Q5PQL5, Q5QJU3, Q5R5F8, Q5R7Q1, Q5XIC4, Q5ZIT9, Q5ZJD7, Q5ZKS8, Q5ZM65, Q69YG0, Q6GLN7, Q6ICY4, Q8BRU6, Q8C407, Q8C996, Q8IVW8, Q8N2K0, Q8NBT3, Q8TC26, Q8VCW4, Q8VD53, Q91VM4

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, A0A0H3JPC6, A0A0H3JVA1, A2QC57, G5EB74, H6C7U6, O13281, O13395, P04340, P04677, P04678, P04679, P0C0H0, P0C0H1, P0DB60, P0DB61, P24151, P50357

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

764 predictions. Top by Δscore:

Variant	Effect	Δscore
16:69105783:GCAGG:G	donor_gain	1.0000
16:69105786:GG:G	donor_gain	1.0000
16:69105787:GG:G	donor_gain	1.0000
16:69105788:G:GA	donor_loss	1.0000
16:69105789:T:A	donor_loss	1.0000
16:69110030:AGGTA:A	donor_loss	1.0000
16:69110032:G:A	donor_loss	1.0000
16:69110032:G:GG	donor_gain	1.0000
16:69110033:T:G	donor_loss	1.0000
16:69113438:CAGGT:C	acceptor_loss	1.0000
16:69113439:A:AG	acceptor_gain	1.0000
16:69113439:AG:A	acceptor_gain	1.0000
16:69113439:AGGT:A	acceptor_gain	1.0000
16:69113440:G:GC	acceptor_gain	1.0000
16:69113440:GG:G	acceptor_gain	1.0000
16:69113440:GGT:G	acceptor_gain	1.0000
16:69113440:GGTG:G	acceptor_gain	1.0000
16:69113440:GGTGT:G	acceptor_gain	1.0000
16:69113539:CCAG:C	donor_loss	1.0000
16:69113540:CAG:C	donor_loss	1.0000
16:69113543:GTAAG:G	donor_loss	1.0000
16:69113544:T:A	donor_loss	1.0000
16:69105784:CAGG:C	donor_gain	0.9900
16:69105788:G:GG	donor_gain	0.9900
16:69105792:G:GG	donor_gain	0.9900
16:69109390:C:A	acceptor_gain	0.9900
16:69109392:CCA:C	acceptor_loss	0.9900
16:69109393:CAG:C	acceptor_loss	0.9900
16:69109394:A:AG	acceptor_gain	0.9900
16:69109394:AGAT:A	acceptor_gain	0.9900

AlphaMissense

3592 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:69109974:G:C	K193N	1.000
16:69109974:G:T	K193N	1.000
16:69113448:A:C	D215A	1.000
16:69113448:A:G	D215G	1.000
16:69113448:A:T	D215V	1.000
16:69113449:C:A	D215E	1.000
16:69113449:C:G	D215E	1.000
16:69113451:C:T	S216F	1.000
16:69113453:G:C	D217H	1.000
16:69113454:A:C	D217A	1.000
16:69113454:A:G	D217G	1.000
16:69113454:A:T	D217V	1.000
16:69114403:T:C	F267L	1.000
16:69114405:C:A	F267L	1.000
16:69114405:C:G	F267L	1.000
16:69114508:T:A	W302R	1.000
16:69114508:T:C	W302R	1.000
16:69114523:T:C	F307L	1.000
16:69114525:C:A	F307L	1.000
16:69114525:C:G	F307L	1.000
16:69114548:G:A	G315E	1.000
16:69114550:G:C	D316H	1.000
16:69114551:A:T	D316V	1.000
16:69114553:G:C	D317H	1.000
16:69114554:A:C	D317A	1.000
16:69114554:A:G	D317G	1.000
16:69114554:A:T	D317V	1.000
16:69114555:C:A	D317E	1.000
16:69114555:C:G	D317E	1.000
16:69114566:C:T	T321I	1.000

dbSNP variants (sampled 300 via entrez): RS1000068891 (16:69088143 C>T), RS1000117781 (16:69106632 G>A), RS1000135289 (16:69104474 T>G), RS1000251775 (16:69098377 A>C,G), RS1000312809 (16:69091514 A>G), RS1000471558 (16:69084805 C>A,G,T), RS1000475580 (16:69112068 C>G), RS1000560131 (16:69092733 G>A), RS1000585811 (16:69086572 T>C,G), RS1000618038 (16:69085215 G>C), RS1000673814 (16:69099939 C>G,T), RS1000679227 (16:69100319 G>A), RS1000766148 (16:69111764 C>G,T), RS1000779018 (16:69092521 A>G), RS1000805627 (16:69083117 C>A,T)

Disease associations

OMIM: gene MIM:602428 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000281_4	Attention deficit hyperactivity disorder	4.000000e-06
GCST005951_13	Body mass index	5.000000e-11
GCST006630_75	Diastolic blood pressure	9.000000e-13
GCST010703_183	Brain morphology (MOSTest)	5.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0006336	diastolic blood pressure
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2232228	Toxicity	3	anthracyclines and related substances	Cardiomyopathies

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2232228	HAS3	3	3.50	1	anthracyclines and related substances

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	5
sodium arsenite	affects expression, increases expression	4
Estradiol	affects cotreatment, decreases expression, increases expression	3
trichostatin A	increases expression	2
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Nickel	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	decreases expression, affects binding, affects cotreatment	2
Particulate Matter	affects cotreatment, increases expression, decreases expression, increases abundance	2
sotorasib	affects cotreatment, increases expression	1
propionaldehyde	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	increases methylation	1
butyraldehyde	increases expression	1
4-phenylenediamine	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression, decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
inotodiol	increases expression	1
licochalcone B	increases expression	1
NSC 689534	affects binding, decreases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1

Clinical trials (associated diseases)

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