HS3ST6

Summary

HS3ST6 (heparan sulfate-glucosamine 3-sulfotransferase 6, HGNC:14178) is a protein-coding gene on chromosome 16p13.3, encoding Heparan sulfate glucosamine 3-O-sulfotransferase 6 (Q96QI5). Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to heparan sulfate.

Predicted to enable [heparan sulfate]-glucosamine 3-sulfotransferase activity. Predicted to be involved in heparan sulfate proteoglycan biosynthetic process. Predicted to act upstream of or within blastocyst hatching. Predicted to be located in Golgi membrane. Implicated in hereditary angioedema.

Source: NCBI Gene 64711 — RefSeq curated summary.

At a glance

• Gene–disease (curated): angioedema, hereditary, 8 (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 83 total — 1 pathogenic
• Phenotypes (HPO): 9
• MANE Select transcript: NM_001009606

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14178
Approved symbol	HS3ST6
Name	heparan sulfate-glucosamine 3-sulfotransferase 6
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000162040
Ensembl biotype	protein_coding
OMIM	619210
Entrez	64711

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000454677

RefSeq mRNA: 1 — MANE Select: NM_001009606 NM_001009606

CCDS: CCDS45381

Canonical transcript exons

ENST00000293937 — 0 exons

Expression profiles

Bgee: expression breadth broad, 71 present calls, max score 92.42.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3138 / max 88.2077, expressed in 79 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155877	0.3138	79

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	92.42	gold quality
skin of abdomen	UBERON:0001416	92.03	gold quality
zone of skin	UBERON:0000014	91.98	gold quality
lower esophagus mucosa	UBERON:0035834	91.84	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	77.52	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.93	silver quality
esophagus mucosa	UBERON:0002469	74.44	gold quality
vagina	UBERON:0000996	70.64	gold quality
mucosa of transverse colon	UBERON:0004991	68.68	gold quality
placenta	UBERON:0001987	65.02	gold quality
right uterine tube	UBERON:0001302	64.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	64.05	gold quality
ectocervix	UBERON:0012249	57.18	gold quality
urinary bladder	UBERON:0001255	56.30	gold quality
esophagus	UBERON:0001043	54.03	gold quality
mucosa of stomach	UBERON:0001199	52.10	gold quality
uterine cervix	UBERON:0000002	51.78	gold quality
metanephros cortex	UBERON:0010533	49.37	gold quality
transverse colon	UBERON:0001157	47.33	gold quality
fallopian tube	UBERON:0003889	47.04	gold quality
pituitary gland	UBERON:0000007	46.50	gold quality
adenohypophysis	UBERON:0002196	46.40	gold quality
minor salivary gland	UBERON:0001830	45.59	gold quality
saliva-secreting gland	UBERON:0001044	44.42	gold quality
prostate gland	UBERON:0002367	42.44	gold quality
right lung	UBERON:0002167	42.30	gold quality
endocervix	UBERON:0000458	41.93	gold quality
omental fat pad	UBERON:0010414	41.64	gold quality
colonic epithelium	UBERON:0000397	41.28	gold quality
colon	UBERON:0001155	41.18	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.02

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

4 targeting HS3ST6, 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-3148	99.97	75.06	6478
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-4752	98.71	68.04	833

Literature-anchored findings (GeneRIF, showing 1)

• generates both an antithrombin-binding site and an entry receptor for herpes simplex virus, type 1 (PMID:12138164)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	hs3st3l	ENSDARG00000059903
danio_rerio	si:ch211-216b21.2	ENSDARG00000060253
danio_rerio	hs3st3b1b	ENSDARG00000086645
mus_musculus	Hs3st6	ENSMUSG00000039628
rattus_norvegicus	Hs3st6	ENSRNOG00000014672
drosophila_melanogaster	Hs3st-B	FBGN0031005
caenorhabditis_elegans		WBGENE00044303

Paralogs (10): HS3ST1 (ENSG00000002587), NDST1 (ENSG00000070614), HS3ST2 (ENSG00000122254), HS3ST3B1 (ENSG00000125430), NDST4 (ENSG00000138653), HS3ST3A1 (ENSG00000153976), NDST3 (ENSG00000164100), NDST2 (ENSG00000166507), HS3ST4 (ENSG00000182601), HS3ST5 (ENSG00000249853)

Protein

Protein identifiers

Heparan sulfate glucosamine 3-O-sulfotransferase 6 — Q96QI5 (reviewed: Q96QI5)

Alternative names: Heparan sulfate D-glucosaminyl 3-O-sulfotransferase 6

All UniProt accessions (1): Q96QI5

UniProt curated annotations — full annotation on UniProt →

Function. Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to heparan sulfate. The substrate-specific O-sulfation generates an enzyme-modified heparan sulfate which acts as a binding receptor to Herpes Simplex Virus-1 (HSV-1) and permits its entry. Unlike 3-OST-1, does not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate.

Subcellular location. Golgi apparatus membrane.

Disease relevance. Angioedema, hereditary, 8 (HAE8) [MIM:619367] A form of angioedema, a disorder characterized by episodic local swelling involving subcutaneous or submucous tissue of the upper respiratory and gastrointestinal tracts, face, extremities, and genitalia. HAE8 inheritance is autosomal dominant. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the sulfotransferase 1 family.

RefSeq proteins (1): NP_001009606* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000863	Sulfotransferase_dom	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR037359	NST/OST	Family

Pfam: PF00685

Enzyme classification (BRENDA):

• EC 2.8.2.23 — [heparan sulfate]-glucosamine 3-sulfotransferase 1 (BRENDA: 5 organisms, 26 substrates, 5 inhibitors, 3 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3’-PHOSPHOADENOSINE 5’-PHOSPHOSULFATE	0.01	1
GLCNSO3(6-OSO3)-GLCA-GLCNSO3(6-OSO3)-IDOA(2-OSO3	0.006	1

Catalyzed reactions (Rhea), 1 shown:

• alpha-D-glucosaminyl-heparan sulfate + 3’-phosphoadenylyl sulfate = 3-sulfo-alpha-D-glucosaminyl-heparan sulfate + adenosine 3’,5’-bisphosphate + H(+) (RHEA:15461)

UniProt features (19 total): binding site 7, topological domain 2, sequence conflict 2, region of interest 2, chain 1, glycosylation site 1, disulfide bond 1, sequence variant 1, transmembrane region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96QI5-F1	85.30	0.73

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 (7): 181; 189; 220–221; 305–309; 100–104; 122–128; 153–156

Disulfide bonds (1): 288–300

Glycosylation sites (1): 281

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2022928	HS-GAG biosynthesis

MSigDB gene sets: 201 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_REGULATION_OF_COAGULATION, GOZGIT_ESR1_TARGETS_DN, MEF2_02, GOBP_SULFATION, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_COAGULATION, EVI1_05, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, GOBP_REGULATION_OF_BIOLOGICAL_PROCESS_INVOLVED_IN_SYMBIOTIC_INTERACTION, BRN2_01, GOBP_HEPARAN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GATA6_01

GO Biological Process (2): blastocyst hatching (GO:0001835), heparan sulfate proteoglycan biosynthetic process (GO:0015012)

GO Molecular Function (3): [heparan sulfate]-glucosamine 3-sulfotransferase activity (GO:0008467), sulfotransferase activity (GO:0008146), transferase activity (GO:0016740)

GO Cellular Component (3): Golgi membrane (GO:0000139), Golgi apparatus (GO:0005794), 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
blastocyst development	1
hatching	1
proteoglycan biosynthetic process	1
heparan sulfate proteoglycan metabolic process	1
protein O-linked glycosylation via xylose	1
heparan sulfate sulfotransferase activity	1
transferase activity, transferring sulphur-containing groups	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

500 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HS3ST6	HS2ST1	Q7LGA3	711
HS3ST6	GLCE	O94923	647
HS3ST6	HS6ST1	O60243	637
HS3ST6	HS6ST3	Q8IZP7	635
HS3ST6	K7EP71	K7EP71	613
HS3ST6	HS6ST2	Q96MM7	543
HS3ST6	EXT1	Q16394	514
HS3ST6	EXTL3	O43909	501
HS3ST6	EXTL2	Q9UBQ6	500
HS3ST6	CSGALNACT2	Q8N6G5	478
HS3ST6	MYOF	Q9NZM1	475
HS3ST6	EXTL1	Q92935	467
HS3ST6	CHST12	Q9NRB3	460
HS3ST6	EXT2	Q93063	458
HS3ST6	CHST7	Q9NS84	451

IntAct

3 interactions, top by confidence:

A	B	Type	Score
ROS1	ODAD3	psi-mi:“MI:0914”(association)	0.350
HS3ST6	LRRC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): LRRC1 (Affinity Capture-MS), HS3ST2 (Affinity Capture-MS), JMJD4 (Affinity Capture-MS), HS3ST6 (Affinity Capture-MS), HS3ST6 (Positive Genetic), HS3ST6 (Protein-RNA)

ESM2 similar proteins: A7MB73, G3MZR2, O00587, O09008, O19058, P17405, P21217, P22083, P51993, P56433, P56434, Q05923, Q0VD19, Q10979, Q11126, Q11127, Q11128, Q11130, Q11131, Q17QZ8, Q32NY4, Q5GFD5, Q5T4B2, Q62994, Q659K9, Q6IQX7, Q6UX72, Q6ZMB0, Q712G6, Q8HYJ3, Q8HYJ4, Q8HYJ5, Q8HYJ6, Q8HYJ7, Q8HZR3, Q8IZ52, Q8N3Y3, Q8NET6, Q8NI29, Q8VD52

Diamond homologs: O14792, O35310, O95803, O97583, Q5GFD5, Q673U1, Q80W66, Q8BKN6, Q8BSL4, Q8IZT8, Q96QI5, Q9EQW8, Q9ESG5, Q9H3R1, Q9QZS6, Q9Y278, Q9Y661, Q9Y662, Q9Y663, P52849, Q60V90, Q966W3, Q9EQH7, Q9V3L1, P52848, P52850, Q02353, Q3UHN9, Q5U4X8, Q6GQK9, Q55GK8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	79
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1162308	NM_001009606.4(HS3ST6):c.430A>T (p.Thr144Ser)	Pathogenic

SpliceAI

2956 predictions. Top by Δscore:

Variant	Effect	Δscore
16:1912203:CTC:C	acceptor_gain	1.0000
6:114296495:CA:C	acceptor_gain	1.0000
16:1912201:GACTC:G	acceptor_gain	0.9900
16:1912202:ACTC:A	acceptor_gain	0.9900
16:1912203:CTCC:C	acceptor_gain	0.9900
16:1912204:TC:T	acceptor_gain	0.9900
16:1912204:TCCT:T	acceptor_gain	0.9900
16:1912205:CC:C	acceptor_gain	0.9900
16:1912205:CCT:C	acceptor_loss	0.9900
16:1912206:C:CC	acceptor_gain	0.9900
16:1912206:CTG:C	acceptor_loss	0.9900
16:1912207:T:C	acceptor_loss	0.9900
16:1912214:CGGG:C	acceptor_gain	0.9900
16:1912217:G:C	acceptor_gain	0.9900
6:114142389:T:TA	donor_gain	0.9900
6:114228777:CT:C	acceptor_gain	0.9900
6:114228779:C:CC	acceptor_gain	0.9900
6:114255003:A:C	donor_gain	0.9900
6:114295718:T:TA	donor_gain	0.9900
6:114296494:CCA:C	acceptor_gain	0.9900
6:114296496:A:C	acceptor_gain	0.9900
16:1912215:G:T	acceptor_gain	0.9800
16:1912217:G:GC	acceptor_gain	0.9800
16:1917905:GCTC:G	donor_loss	0.9800
16:1917906:CT:C	donor_loss	0.9800
16:1917907:TCACC:T	donor_loss	0.9800
16:1917908:CACC:C	donor_loss	0.9800
16:1917909:A:AT	donor_loss	0.9800
16:1917910:C:CG	donor_loss	0.9800
6:114058189:GC:G	acceptor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000371419 (16:1919394 C>T), RS1000523707 (16:1921382 T>C), RS1000627556 (16:1915776 C>A), RS1000680068 (16:1915926 G>A), RS1000742247 (16:1913872 G>A), RS1001238164 (16:1911445 C>T), RS1001412881 (16:1920888 C>A,T), RS1001856220 (16:1915998 A>C), RS1001974330 (16:1922140 C>T), RS1002016837 (16:1915019 C>T), RS1002041945 (16:1920798 G>A), RS1002095672 (16:1920577 C>T), RS1002322182 (16:1921865 G>A,T), RS1002421731 (16:1912013 G>A,C), RS1002451176 (16:1914765 C>T)

Disease associations

OMIM: gene MIM:619210 | disease phenotypes: MIM:619367

GenCC curated gene-disease

Disease	Classification	Inheritance
angioedema, hereditary, 8	Limited	Autosomal dominant

Mondo (1): angioedema, hereditary, 8 (MONDO:0030298)

Orphanet (0):

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000282	Facial edema
HP:0002014	Diarrhea
HP:0002027	Abdominal pain
HP:0002572	Episodic vomiting
HP:0007514	Edema of the dorsum of hands
HP:0012027	Laryngeal edema
HP:0031244	Swollen lip
HP:0100665	Angioedema

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003139_19	Glomerular filtration rate in chronic kidney disease	5.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation	2
Estradiol	decreases expression, affects cotreatment	2
Valproic Acid	increases expression, increases methylation	2
avobenzone	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
nutlin 3	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression, affects cotreatment	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Vorinostat	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	increases expression	1
Camptothecin	increases expression	1
Cisplatin	increases expression, affects cotreatment	1
Dactinomycin	affects cotreatment, increases expression	1
Endosulfan	increases expression	1
Nickel	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	increases abundance, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1
Particulate Matter	decreases expression	1

Clinical trials (associated diseases)

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