HYAL2

Summary

HYAL2 (hyaluronidase 2, HGNC:5321) is a protein-coding gene on chromosome 3p21.31, encoding Hyaluronidase-2 (Q12891). Catalyzes hyaluronan degradation into small fragments that are endocytosed and degraded in lysosomes by HYAL1 and exoglycosidases.

This gene encodes a weak acid-active hyaluronidase. The encoded protein is similar in structure to other more active hyaluronidases. Hyaluronidases degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan and fragments of hyaluronan are thought to be involved in cell proliferation, migration and differentiation. Although it was previously thought to be a lysosomal hyaluronidase that is active at a pH below 4, the encoded protein is likely a GPI-anchored cell surface protein. This hyaluronidase serves as a receptor for the oncogenic virus Jaagsiekte sheep retrovirus. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. This gene encodes two alternatively spliced transcript variants which differ only in the 5’ UTR.

Source: NCBI Gene 8692 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Muggenthaler-Chowdhury-Chioza syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 110 total — 4 pathogenic, 4 likely-pathogenic
• MANE Select transcript: NM_003773

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5321
Approved symbol	HYAL2
Name	hyaluronidase 2
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	LuCa-2, LUCA2
Ensembl gene	ENSG00000068001
Ensembl biotype	protein_coding
OMIM	603551
Entrez	8692

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 19 protein_coding, 1 retained_intron

ENST00000357750, ENST00000395139, ENST00000415028, ENST00000424190, ENST00000426286, ENST00000428028, ENST00000442581, ENST00000447092, ENST00000458018, ENST00000481597, ENST00000891560, ENST00000891561, ENST00000891562, ENST00000891563, ENST00000891564, ENST00000945863, ENST00000945864, ENST00000945865, ENST00000945866, ENST00000945867

RefSeq mRNA: 2 — MANE Select: NM_003773 NM_003773, NM_033158

CCDS: CCDS2818

Canonical transcript exons

ENST00000357750 — 4 exons

Exon	Start	End
ENSE00000768863	50318956	50319045
ENSE00001655338	50322653	50322745
ENSE00001926082	50317808	50318539
ENSE00003679781	50319569	50320535

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 99.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.4717 / max 671.5267, expressed in 1788 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42314	23.4978	1785
42315	13.7943	435
42316	2.7821	368
42313	1.3975	974

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	99.15	gold quality
spleen	UBERON:0002106	98.80	gold quality
upper lobe of left lung	UBERON:0008952	98.60	gold quality
upper lobe of lung	UBERON:0008948	98.26	gold quality
metanephros cortex	UBERON:0010533	96.79	gold quality
right lobe of thyroid gland	UBERON:0001119	96.57	gold quality
left uterine tube	UBERON:0001303	96.48	gold quality
left lobe of thyroid gland	UBERON:0001120	96.26	gold quality
pericardium	UBERON:0002407	95.98	gold quality
omental fat pad	UBERON:0010414	95.73	gold quality
peritoneum	UBERON:0002358	95.70	gold quality
lung	UBERON:0002048	95.33	gold quality
gall bladder	UBERON:0002110	95.25	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.23	gold quality
apex of heart	UBERON:0002098	95.22	gold quality
body of uterus	UBERON:0009853	95.05	gold quality
stromal cell of endometrium	CL:0002255	95.04	gold quality
thyroid gland	UBERON:0002046	94.95	gold quality
left adrenal gland cortex	UBERON:0035825	94.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.65	gold quality
left adrenal gland	UBERON:0001234	94.52	gold quality
adrenal cortex	UBERON:0001235	94.48	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.39	gold quality
right adrenal gland	UBERON:0001233	94.21	gold quality
ectocervix	UBERON:0012249	93.97	gold quality
right atrium auricular region	UBERON:0006631	93.88	gold quality
right adrenal gland cortex	UBERON:0035827	93.88	gold quality
heart left ventricle	UBERON:0002084	93.81	gold quality
cardiac ventricle	UBERON:0002082	93.69	gold quality
adrenal gland	UBERON:0002369	93.54	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-HCAD-15	yes	2477.13
E-GEOD-135922	yes	1347.95
E-MTAB-10287	yes	74.54
E-HCAD-1	yes	52.83
E-HCAD-11	yes	49.85
E-MTAB-10553	yes	47.56
E-HCAD-10	yes	37.61
E-MTAB-6701	yes	34.52
E-MTAB-8410	yes	33.04
E-CURD-46	yes	28.41
E-MTAB-6678	yes	14.01
E-MTAB-9543	yes	9.77
E-CURD-112	yes	8.58
E-GEOD-130148	yes	5.50
E-MTAB-10137	no	1264.79

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMP7, HAS3, PDGFB

miRNA regulators (miRDB)

21 targeting HYAL2, 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-5692A	100.00	74.40	6850
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-508-5P	99.41	64.25	1248
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-5687	96.10	64.83	226

Literature-anchored findings (GeneRIF, showing 36)

• more elevated in human brain metastases than in primary brain tumours (PMID:12174938)
• suppresses transformation by the Env proteins of jaagsiekte sheep retrovirus and enzootic nasal tumor virus in rodent fibroblasts by increasing Env degradation (PMID:12584308)
• Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus. (PMID:12676986)
• Down-regulation of HYAL2 is associated with small cell lung cancer and glioma (PMID:12684632)
• soluble active form expressed and characterized as Jaagsiekte sheep retrovirus receptor (PMID:15596803)
• In chondrocytes, HYAL-2 appears to be constitutively expressed and not inducibly regulated by catabolic agents. As such, it appears that the expression of lysosomal hyaluronidase participates little in the overall regulation of hyaluronan catabolism. (PMID:15923194)
• Association of hyaluronidases 1/2 expresion with neurons in the infarcted and peri-infarcted regions of the middle cerebral artery. (PMID:16837837)
• purified human Hyal2 is a weak acid-active hyaluronidase (PMID:17229709)
• alternative splicing variants, M-RIP, HYAL2, CDCA1, and MSMB genes showed differential expressions between cancer cells and corresponding normal tissues. (PMID:19081476)
• Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer (PMID:19140316)
• HYAL1, but not HYAL2, expression is reduced and correlates with the accumulation of hyaluronan in ovarian carcinomas. (PMID:19435493)
• platelets and megakaryocytes contain only hyaluronidase 2 (HYAL2) but not HYAL1 (PMID:19443707)
• 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)
• ROS induce Hyal2, suggesting that Hyal2 is likely responsible for the sustained HA fragmentation in the airway lumen observed in inflammatory conditions associated with oxidative stress. (PMID:20554532)
• Overexpression of HYAL2 is associated with colorectal cancer. (PMID:20849597)
• Hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in the accumulation of hyaluronan in endometrioid endometrial carcinoma (PMID:20875124)
• 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)
• Inverse expression of hyaluronidase 2 and hyaluronan synthases 1-3 is associated with reduced hyaluronan content in malignant cutaneous melanoma. (PMID:23560496)
• A strong association between decreased HYAL2 methylation in peripheral blood and BC. (PMID:25213452)
• HYAL2 plays a redundant role in the catalysis of megadalton HA to its 20 kDa intermediate during fertilization. (PMID:25232017)
• Lower platelet HYAL2 levels and activity are associated with inflammatory bowel disease. (PMID:25411425)
• CD44 knock-down in bovine and human chondrocytes results in release of bound HYAL2. (PMID:25864644)
• High expression of S100P and HYAL2 is significantly associated with advanced disease and shorter survival of triple-negative breast cancer and S100P and HYAL2 could be potential prognostic markers of TNBC. (PMID:26112095)
• Data show that DNA methylation at CpG island of hyaluronoglucosaminidase 2 (HYLA2) could be used to identify stage II and III colon cancer patients who are most likely to benefit from 5-flourouracil chemotherapy with respect to progression-free survival. (PMID:26453961)
• our data uncover a previously unsuspected mechanism of how hyaluronan and Hyal-2 control platelet generation. (PMID:27398974)
• Knocking down HYAL2 in HUVECs protected against HA degradation in the glycocalyx by inhibiting the expression and activity of HYAL2 and further blocked the dephosphorylation of eNOS-Ser-633 and the decrease in NO production in response to LSS. (PMID:27798230)
• HYAL2 mutations identified as a cause of syndromic orofacial clefting and cor triatriatum sinister in amish families. (PMID:28081210)
• genetic variation in HYAL2 influences platelet aggregation (PMID:28300864)
• an important role for HYAL2 in CD44 alternative splicing. (PMID:29162741)
• we discovered the existence of p47(phox) /Hyal2 complex. LSS induced the dissociation of p47(phox) /Hyal2 complex, which was inhibited by LKB1 overexpression and AICAR. Furthermore, knockdown of Hyal2 performed a positive feedback on LKB1 activity (PMID:30078213)
• HYAL1/2 suppress colorectal cancer cell metastasis by regulating MMPs/TIMPs balance and rearranging F-actin distribution, inhibiting invasion and migration of cancer cells. (PMID:30972813)
• Expression and activity of hyaluronidases HYAL-1, HYAL-2 and HYAL-3 in the human intervertebral disc. (PMID:31758257)
• Hyal2 Expression in Tumor-Associated Myeloid Cells Mediates Cancer-Related Inflammation in Bladder Cancer. (PMID:33239427)
• Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency. (PMID:34906488)
• [Detection of DNA methylation of HYAL2 gene for differentiating malignant from benign thyroid tumors]. (PMID:35249879)
• Similar in structure to hyaluronidases, which intracellularly degrade hyaluronan. The accumulation of hyaluronan (HA) in the renal cortex is a characteristic feature of inflammatory renal diseases and could participate in immune renal injury. (PMID:9933825)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hyal2a	ENSDARG00000059931
danio_rerio	hyal2b	ENSDARG00000062997
mus_musculus	Hyal2	ENSMUSG00000010047
rattus_norvegicus	Hyal2	ENSRNOG00000031420
caenorhabditis_elegans		WBGENE00011923

Paralogs (4): HYAL4 (ENSG00000106302), SPAM1 (ENSG00000106304), HYAL1 (ENSG00000114378), HYAL3 (ENSG00000186792)

Protein

Protein identifiers

Hyaluronidase-2 — Q12891 (reviewed: Q12891)

Alternative names: Hyaluronoglucosaminidase-2, Lung carcinoma protein 2

All UniProt accessions (6): Q12891, C9J700, C9JBF5, C9JSD1, C9JSI7, C9K016

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes hyaluronan degradation into small fragments that are endocytosed and degraded in lysosomes by HYAL1 and exoglycosidases. Essential for the breakdown of extracellular matrix hyaluronan.

Subunit / interactions. Interacts with MST1R.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed (at protein level).

Disease relevance. Muggenthaler-Chowdhury-Chioza syndrome (MCCS) [MIM:621063] An autosomal recessive disorder characterized by distinctive craniofacial dysmorphism with frontal bossing, hypertelorism, a broad and flattened nasal tip, and cupped ears with superior helices. Other common but variable clinical manifestations are unilateral or bilateral cleft lip and palate, congenital cardiac anomalies, ocular features including mild to severe myopia and cataracts, single palmar crease, and pectus excavatum. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the glycosyl hydrolase 56 family.

RefSeq proteins (2): NP_003764, NP_149348 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR018155	Hyaluronidase	Family

Pfam: PF01630

Enzyme classification (BRENDA):

• EC 3.2.1.35 — hyaluronoglucosaminidase (BRENDA: 70 organisms, 156 substrates, 263 inhibitors, 27 Km, 1 kcat entries)
• EC 4.2.2.1 — hyaluronate lyase (BRENDA: 69 organisms, 109 substrates, 155 inhibitors, 24 Km, 9 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HYALURONAN	0.038–0.367	11
HYALURONAN	0.0006–3.8	9
HYALURONIC ACID	0.285–0.71	4
HYALURONATE	0.38–0.44	2
CHONDROITIN	0.12	1
CHONDROITIN SULFATE	0.48	1
CHONDROITIN SULFATE A	0.66	1
CHONDROITIN SULFATE C	2.16	1
CHONDROITIN SULFATE D	0.5	1
HYALURONIC ACID	0.0009	1
HYALURONIC ACID FROM STREPTOCOCCUS PYOGENES (35	49.3	1
HYALURONAN HEXASACCHARIDE	0.08	1

UniProt features (31 total): sequence variant 12, disulfide bond 5, sequence conflict 5, glycosylation site 3, signal peptide 1, chain 1, propeptide 1, domain 1, active site 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12891-F1	91.70	0.86

Functional residue map

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

Catalytic / active sites (1): 135 (proton donor)

Post-translational modifications (1): 448

Disulfide bonds (5): 211–227, 365–376, 370–427, 429–438, 47–340

Glycosylation sites (3): 74, 103, 357

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2142845	Hyaluronan metabolism
R-HSA-2160916	Hyaluronan degradation

MSigDB gene sets: 379 (showing top): GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION, GOBP_RESPONSE_TO_PEPTIDE, GCANCTGNY_MYOD_Q6, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP

GO Biological Process (30): response to reactive oxygen species (GO:0000302), kidney development (GO:0001822), hematopoietic progenitor cell differentiation (GO:0002244), carbohydrate metabolic process (GO:0005975), glycosaminoglycan catabolic process (GO:0006027), response to virus (GO:0009615), negative regulation of fibroblast migration (GO:0010764), hyaluronan catabolic process (GO:0030214), negative regulation of cell growth (GO:0030308), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), positive regulation of urine volume (GO:0035810), monocyte activation (GO:0042117), positive regulation of protein import into nucleus (GO:0042307), cellular response to fibroblast growth factor stimulus (GO:0044344), positive regulation of transcription by RNA polymerase II (GO:0045944), response to antibiotic (GO:0046677), symbiont entry into host cell (GO:0046718), skeletal system morphogenesis (GO:0048705), positive regulation of inflammatory response (GO:0050729), cartilage development (GO:0051216), defense response to virus (GO:0051607), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), multicellular organismal-level iron ion homeostasis (GO:0060586), renal water absorption (GO:0070295), cellular response to interleukin-1 (GO:0071347), cellular response to tumor necrosis factor (GO:0071356), cellular response to UV-B (GO:0071493), cellular response to transforming growth factor beta stimulus (GO:0071560), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238)

GO Molecular Function (12): virus receptor activity (GO:0001618), transcription coactivator activity (GO:0003713), hyalurononglucosaminidase activity (GO:0004415), hyaluronic acid binding (GO:0005540), enzyme binding (GO:0019899), receptor signaling protein tyrosine kinase inhibitor activity (GO:0030294), receptor tyrosine kinase binding (GO:0030971), hyaluronoglucuronidase activity (GO:0033906), transforming growth factor beta binding (GO:0050431), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (17): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), lysosome (GO:0005764), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), plasma membrane (GO:0005886), microvillus (GO:0005902), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), apical plasma membrane (GO:0016324), endocytic vesicle (GO:0030139), cytoplasmic vesicle (GO:0031410), membrane raft (GO:0045121), perinuclear region of cytoplasm (GO:0048471), RNA polymerase II transcription regulator complex (GO:0090575), membrane (GO:0016020), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Glycosaminoglycan metabolism	1
Hyaluronan metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	4
positive regulation of cytokine production	2
positive regulation of DNA-templated transcription	2
membrane	2
response to oxidative stress	1
response to oxygen-containing compound	1
animal organ development	1
renal system development	1
hemopoiesis	1
cell differentiation	1
primary metabolic process	1
aminoglycan catabolic process	1
glycosaminoglycan metabolic process	1
response to other organism	1
fibroblast migration	1
regulation of fibroblast migration	1
negative regulation of cell migration	1
glycosaminoglycan catabolic process	1
hyaluronan metabolic process	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
interleukin-6 production	1
regulation of interleukin-6 production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
regulation of urine volume	1
myeloid leukocyte activation	1
protein import into nucleus	1
regulation of protein import into nucleus	1
positive regulation of nucleocytoplasmic transport	1
positive regulation of intracellular protein transport	1
positive regulation of protein localization to nucleus	1
cellular response to growth factor stimulus	1
response to fibroblast growth factor	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
response to chemical	1

Protein interactions and networks

STRING

1929 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HYAL2	CD44	P16070	888
HYAL2	MST1R	Q04912	823
HYAL2	SPAG9	O60271	818
HYAL2	HAS2	Q92819	811
HYAL2	TGFB1	P01137	739
HYAL2	HMMR	O75330	730
HYAL2	HAS3	O00219	687
HYAL2	HAS1	Q92839	684
HYAL2	WWOX	Q9NZC7	658
HYAL2	RDX	P35241	643
HYAL2	EZR	P15311	641
HYAL2	CYB561D2	O14569	608
HYAL2	CEMIP	Q8WUJ3	601
HYAL2	CEMIP2	Q9UHN6	581
HYAL2	NPRL2	Q8WTW4	515

IntAct

146 interactions, top by confidence:

A	B	Type	Score
B3GNT3	PGRMC1	psi-mi:“MI:0914”(association)	0.670
B3GAT3	GOLIM4	psi-mi:“MI:0914”(association)	0.640
	HYAL2	psi-mi:“MI:0915”(physical association)	0.560
FHL3	HYAL2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP3-2	HYAL2	psi-mi:“MI:0915”(physical association)	0.560
HYAL2	FHL3	psi-mi:“MI:0915”(physical association)	0.560
HYAL2	KRTAP3-2	psi-mi:“MI:0915”(physical association)	0.560
HYAL2	KRT31	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	HYAL2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP1-1	HYAL2	psi-mi:“MI:0915”(physical association)	0.560
KRT34	HYAL2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-3	HYAL2	psi-mi:“MI:0915”(physical association)	0.560
HYAL2	PELI2	psi-mi:“MI:0915”(physical association)	0.560
HYAL2	KRTAP6-2	psi-mi:“MI:0915”(physical association)	0.560
HYAL2	APP	psi-mi:“MI:0915”(physical association)	0.560
HYAL2		psi-mi:“MI:0915”(physical association)	0.560
HYAL2	GFAP	psi-mi:“MI:0915”(physical association)	0.560
NOS3	HYAL2	psi-mi:“MI:0915”(physical association)	0.560
HYAL2	PSEN1	psi-mi:“MI:0915”(physical association)	0.560
HYAL2	ATXN10	psi-mi:“MI:0915”(physical association)	0.560
HTT	HYAL2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (102): HYAL2 (Two-hybrid), KRTAP3-2 (Two-hybrid), KRTAP10-3 (Two-hybrid), HYAL2 (Affinity Capture-MS), HYAL2 (Affinity Capture-MS), HYAL2 (Affinity Capture-MS), HYAL2 (Affinity Capture-MS), HYAL2 (Affinity Capture-MS), HYAL2 (Affinity Capture-MS), HYAL2 (Affinity Capture-MS), PON2 (Affinity Capture-MS), HYAL2 (Affinity Capture-MS), HYAL2 (Affinity Capture-MS), HYAL2 (Affinity Capture-MS), HYAL2 (Affinity Capture-MS)

ESM2 similar proteins: A0JPH3, A3KGW5, A5PMF6, A7MB73, O00754, O09008, O18835, O46432, O77588, P24802, P26572, P27115, P27808, P56434, Q00973, Q02809, Q04519, Q09200, Q09325, Q0VD19, Q12891, Q32NJ7, Q5IGR6, Q5R9N3, Q5T4B2, Q5U309, Q5U367, Q5U483, Q5VSG8, Q5XPT3, Q60HE9, Q63321, Q66PG4, Q6NVG7, Q6P1J0, Q6P7A1, Q6P9A2, Q6PA90, Q8IYK4, Q8K1B9

Diamond homologs: A3QVN2, A3QVN3, A3QVN4, A3QVN5, A3QVN6, A3QVN9, A3QVP0, B3EWP2, C0HLL4, C0HLL5, E0XKJ9, G5ECE8, I0CME8, J3S820, O35632, O43820, P23613, P38566, P38567, P38568, P48794, P49370, P49371, P85841, P86100, P86687, P86875, Q05A56, Q08169, Q12794, Q12891, Q2M3T9, Q5D7H4, Q5E985, Q5REQ1, Q62803, Q6RHW2, Q6RHW4, Q76HM9, Q76HN1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 128 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Glycosaminoglycan metabolism	5	12.1×	8e-03
Metabolism of carbohydrates and carbohydrate derivatives	8	10.6×	4e-04
Neutrophil degranulation	14	3.5×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	4
Uncertain significance	80
Likely benign	11
Benign	3

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1065388	NM_003773.5(HYAL2):c.194C>G (p.Ser65Ter)	Pathogenic
1065396	NM_003773.5(HYAL2):c.1271_1272del (p.His424fs)	Pathogenic
1065397	NM_003773.5(HYAL2):c.1273T>G (p.Phe425Val)	Pathogenic
3572921	F425V	Pathogenic
1065389	NM_003773.5(HYAL2):c.443A>G (p.Lys148Arg)	Likely pathogenic
1065390	NM_003773.5(HYAL2):c.611G>C (p.Gly204Ala)	Likely pathogenic
1065395	NM_003773.5(HYAL2):c.1132C>T (p.Arg378Cys)	Likely pathogenic
3375477	NM_003773.5(HYAL2):c.782C>T (p.Ser261Phe)	Likely pathogenic

SpliceAI

496 predictions. Top by Δscore:

Variant	Effect	Δscore
3:50318535:GTCTC:G	acceptor_gain	1.0000
3:50318537:CTC:C	acceptor_gain	1.0000
3:50318538:TC:T	acceptor_gain	1.0000
3:50318539:CC:C	acceptor_gain	1.0000
3:50318539:CCT:C	acceptor_loss	1.0000
3:50318540:C:CC	acceptor_gain	1.0000
3:50318547:C:CT	acceptor_gain	1.0000
3:50318950:GCTTA:G	donor_loss	1.0000
3:50318951:CTTAC:C	donor_loss	1.0000
3:50318952:TTA:T	donor_loss	1.0000
3:50318953:T:TG	donor_loss	1.0000
3:50318954:A:C	donor_loss	1.0000
3:50318955:CCGTG:C	donor_gain	1.0000
3:50319042:CCAT:C	acceptor_gain	1.0000
3:50319043:CATC:C	acceptor_gain	1.0000
3:50319046:C:CC	acceptor_gain	1.0000
3:50319564:CATA:C	donor_loss	1.0000
3:50319565:ATACC:A	donor_loss	1.0000
3:50319566:TA:T	donor_loss	1.0000
3:50319567:ACCTC:A	donor_loss	1.0000
3:50319568:C:CG	donor_loss	1.0000
3:50319568:CCTCA:C	donor_gain	1.0000
3:50320536:C:CC	acceptor_gain	1.0000
3:50322648:CTCA:C	donor_loss	1.0000
3:50322649:TCA:T	donor_loss	1.0000
3:50322650:CA:C	donor_loss	1.0000
3:50322651:ACCT:A	donor_loss	1.0000
3:50322652:C:G	donor_loss	1.0000
3:50318548:A:T	acceptor_gain	0.9900
3:50318954:A:AC	donor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000998020 (3:50319478 C>A,T), RS1001663232 (3:50321787 G>A), RS1002114469 (3:50321104 C>T), RS1002675746 (3:50323536 C>G), RS1002790690 (3:50323750 G>A,T), RS1003516580 (3:50317680 T>C), RS1004190508 (3:50320492 T>C), RS1005164015 (3:50318740 T>C), RS1005593527 (3:50321547 G>A), RS1005815904 (3:50321393 G>A,T), RS1006578464 (3:50320082 G>A,C), RS1008372738 (3:50319973 T>C,G), RS1008678634 (3:50318431 C>T), RS1009116187 (3:50318704 T>C), RS1009346581 (3:50321150 G>A,C,T)

Disease associations

OMIM: gene MIM:603551 | disease phenotypes: MIM:621063, MIM:609284

GenCC curated gene-disease

Disease	Classification	Inheritance
Muggenthaler-Chowdhury-Chioza syndrome	Strong	Autosomal recessive
orofacial cleft	Moderate	Autosomal recessive

Mondo (3): Muggenthaler-Chowdhury-Chioza syndrome (MONDO:0976127), congenital myopathy 4B, autosomal recessive (MONDO:0012239), orofacial cleft (MONDO:0000358)

Orphanet (4): Cleft lip and palate-craniofacial dysmorphism-congenital heart defect-hearing loss syndrome (Orphanet:508476), Intermediate nemaline myopathy (Orphanet:171433), Childhood-onset nemaline myopathy (Orphanet:171439), Cap myopathy (Orphanet:171881)

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST005951_49	Body mass index	1.000000e-08
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538348	Nemaline myopathy 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases methylation	2
sodium arsenite	decreases expression	2
cobaltous chloride	decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cyclosporine	affects binding, affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
sodium bichromate	decreases expression	1
K 7174	decreases expression	1
oligofectamine	increases expression	1
abrine	decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
jinfukang	increases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzene	increases expression	1
Benzo(a)pyrene	increases methylation, decreases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Ketoconazole	increases expression	1
Progesterone	decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Dronabinol	decreases expression	1
Thiram	decreases expression	1
Valproic Acid	decreases expression, increases methylation	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04342234	Not specified	RECRUITING	Neural Network to Calculate Morphology of the Cleft Palate to Reduce Cleft Lip and Palate Treatment Burden.
NCT05867862	Not specified	COMPLETED	Implementation of a Program to Strengthen Oral Hygiene in Patient With Cleft Deformities
NCT06880094	Not specified	RECRUITING	Study of Congenital Orofacial Clefts by Implementing Optical Genome Mapping
NCT07340008	Not specified	RECRUITING	Analgosedation With Ketamine, Nalbuphine, or Dexmedetomidine for Suture Removal in Children After Cleft Surgery
NCT07557576	Not specified	RECRUITING	Effect of Opioid-Free vs Opioid-Based Anesthesia on Postoperative Pain and Emergence Agitation in Children Undergoing Cleft Surgery