HAPLN3

Summary

HAPLN3 (hyaluronan and proteoglycan link protein 3, HGNC:21446) is a protein-coding gene on chromosome 15q26.1, encoding Hyaluronan and proteoglycan link protein 3 (Q96S86). May function in hyaluronic acid binding.

This gene belongs to the hyaluronan and proteoglycan binding link protein gene family. The protein encoded by this gene may function in hyaluronic acid binding and cell adhesion.

Source: NCBI Gene 145864 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 115 total
• MANE Select transcript: NM_178232

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21446
Approved symbol	HAPLN3
Name	hyaluronan and proteoglycan link protein 3
Location	15q26.1
Locus type	gene with protein product
Status	Approved
Aliases	HsT19883
Ensembl gene	ENSG00000140511
Ensembl biotype	protein_coding
Entrez	145864

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000359595, ENST00000558770, ENST00000562281, ENST00000562889, ENST00000563808, ENST00000868802, ENST00000868803, ENST00000868804, ENST00000933087, ENST00000933088, ENST00000969266, ENST00000969267, ENST00000969268

RefSeq mRNA: 2 — MANE Select: NM_178232 NM_001307952, NM_178232

CCDS: CCDS10346, CCDS76790

Canonical transcript exons

ENST00000359595 — 5 exons

Exon	Start	End
ENSE00001034912	88881357	88881725
ENSE00001426992	88877294	88878256
ENSE00001431641	88895459	88895544
ENSE00003574521	88878967	88879269
ENSE00003642824	88887175	88887345

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 95.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.7620 / max 325.4795, expressed in 1096 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151396	8.5368	1094
151395	0.2251	99

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
descending thoracic aorta	UBERON:0002345	95.41	gold quality
ascending aorta	UBERON:0001496	95.01	gold quality
thoracic aorta	UBERON:0001515	94.97	gold quality
right coronary artery	UBERON:0001625	94.15	gold quality
aorta	UBERON:0000947	92.30	gold quality
cartilage tissue	UBERON:0002418	91.81	gold quality
vermiform appendix	UBERON:0001154	90.80	gold quality
tibial artery	UBERON:0007610	90.50	gold quality
popliteal artery	UBERON:0002250	90.49	gold quality
left coronary artery	UBERON:0001626	89.79	gold quality
lymph node	UBERON:0000029	89.65	gold quality
coronary artery	UBERON:0001621	89.20	gold quality
granulocyte	CL:0000094	86.49	gold quality
left uterine tube	UBERON:0001303	86.21	gold quality
caecum	UBERON:0001153	85.96	gold quality
mucosa of stomach	UBERON:0001199	85.90	gold quality
omental fat pad	UBERON:0010414	84.55	gold quality
peritoneum	UBERON:0002358	84.50	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.50	gold quality
oocyte	CL:0000023	83.73	gold quality
adipose tissue of abdominal region	UBERON:0007808	83.58	gold quality
subcutaneous adipose tissue	UBERON:0002190	83.42	gold quality
tibialis anterior	UBERON:0001385	83.27	silver quality
kidney epithelium	UBERON:0004819	82.53	gold quality
cardiac muscle of right atrium	UBERON:0003379	82.34	gold quality
ectocervix	UBERON:0012249	82.32	gold quality
blood	UBERON:0000178	82.22	gold quality
left ventricle myocardium	UBERON:0006566	82.21	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.90	gold quality
lower esophagus	UBERON:0013473	81.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	786.01
E-ANND-3	yes	13.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

19 targeting HAPLN3, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-665	97.60	65.64	1781

Literature-anchored findings (GeneRIF, showing 2)

• Elevated CLDN16 gene expression was suggested to be involved in the development of breast cancer and to be a biomarker and target treatment for breast cancer. (PMID:20664984)
• DNA methylation levels at GAS6(growth arrest specific 6)/GSTP1(glutathione S-transferase pi 1)/HAPLN3(hyaluronan and proteoglycan link protein 3) genomic loci showed large differences between cancer and benign samples (PMID:31433512)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hapln3	ENSDARG00000045802
mus_musculus	Hapln3	ENSMUSG00000030606
rattus_norvegicus	Hapln3	ENSRNOG00000022321

Paralogs (7): VCAN (ENSG00000038427), NCAN (ENSG00000130287), BCAN (ENSG00000132692), HAPLN2 (ENSG00000132702), HAPLN1 (ENSG00000145681), ACAN (ENSG00000157766), HAPLN4 (ENSG00000187664)

Protein

Protein identifiers

Hyaluronan and proteoglycan link protein 3 — Q96S86 (reviewed: Q96S86)

All UniProt accessions (4): Q96S86, H3BRY4, H3BT26, H3BTH8

UniProt curated annotations — full annotation on UniProt →

Function. May function in hyaluronic acid binding.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Widely expressed with highest levels in spleen and placenta.

Similarity. Belongs to the HAPLN family.

RefSeq proteins (2): NP_001294881, NP_839946* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000538	Link_dom	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR016186	C-type_lectin-like/link_sf	Homologous_superfamily
IPR016187	CTDL_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050691	Hyaluronan_bind_Proteoglycan	Family

Pfam: PF00193, PF07686

UniProt features (10 total): disulfide bond 5, domain 3, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96S86-F1	87.85	0.78

Functional residue map

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

Disulfide bonds (5): 70–146, 188–259, 212–233, 286–356, 311–332

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 98 (showing top): GOBP_SKELETAL_SYSTEM_DEVELOPMENT, AML_Q6, GOMF_GLYCOSAMINOGLYCAN_BINDING, GOCC_SYNAPSE, GOMF_HYALURONIC_ACID_BINDING, GSE13762_CTRL_VS_125_VITAMIND_DAY5_DC_UP, chr15q26, MIKKELSEN_ES_ICP_WITH_H3K4ME3, BOSCO_TH1_CYTOTOXIC_MODULE, LIM_MAMMARY_LUMINAL_PROGENITOR_UP, GOCC_EXTERNAL_ENCAPSULATING_STRUCTURE, ZFP91_TARGET_GENES, MIR33A_3P, MIR29B_3P_MIR29C_3P, MIR29A_3P

GO Biological Process (3): skeletal system development (GO:0001501), cell adhesion (GO:0007155), central nervous system development (GO:0007417)

GO Molecular Function (1): hyaluronic acid binding (GO:0005540)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), synapse (GO:0045202), perineuronal net (GO:0072534), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	2
cellular process	1
nervous system development	1
carboxylic acid binding	1
cell junction	1
perisynaptic extracellular matrix	1
cellular anatomical structure	1

Protein interactions and networks

STRING

774 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HAPLN3	CCDC181	Q5TID7	699
HAPLN3	ZNF660	Q6AZW8	544
HAPLN3	MFGE8	Q08431	489
HAPLN3	EDIL3	O43854	410
HAPLN3	ST6GALNAC3	Q8NDV1	396
HAPLN3	WARS1	P23381	396
HAPLN3	NUCB2	P80303	381
HAPLN3	MYH10	P35580	378
HAPLN3	UBASH3B	Q8TF42	376
HAPLN3	MOB3B	Q86TA1	375
HAPLN3	AOX1	Q06278	371
HAPLN3	HAS1	Q92839	362
HAPLN3	C5orf34	Q96MH7	353
HAPLN3	MCAM	P43121	349
HAPLN3	ITGBL1	O95965	342

IntAct

53 interactions, top by confidence:

A	B	Type	Score
LSM5	LSM1	psi-mi:“MI:0914”(association)	0.640
MGAT4C	GXYLT2	psi-mi:“MI:0914”(association)	0.530
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530
FUT3	C1QL1	psi-mi:“MI:0914”(association)	0.530
HAPLN3	HSPA5	psi-mi:“MI:0914”(association)	0.530
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.530
SERTAD2	PPP2R1A	psi-mi:“MI:0914”(association)	0.530
BIRC2	UMAD1	psi-mi:“MI:0914”(association)	0.350
TRADD	HNRNPCL2	psi-mi:“MI:0914”(association)	0.350
TNIP1	COCH	psi-mi:“MI:0914”(association)	0.350
TAZ	MANBA	psi-mi:“MI:0914”(association)	0.350
LSM5	LSM1	psi-mi:“MI:0914”(association)	0.350
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.350
SAXO5	WDR47	psi-mi:“MI:0914”(association)	0.350
A2M	PZP	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
BST1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
SUSD4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
CEACAM8	PRRT4	psi-mi:“MI:0914”(association)	0.350
IGFL3	CBX4	psi-mi:“MI:0914”(association)	0.350
TAFAZZIN	MANBA	psi-mi:“MI:0914”(association)	0.350
TMPRSS13	TOR1A	psi-mi:“MI:0914”(association)	0.350

BioGRID (49): HAPLN3 (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS), CHAC2 (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS), ARMC8 (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS)

ESM2 similar proteins: A1A4K5, A2ARA8, A7XY94, A8MWY0, O08859, O15041, O42237, O54890, O70309, P03994, P05106, P07354, P10859, P10915, P15396, P18084, P21860, P22413, P26009, P35436, P53708, P55252, P70207, P70275, P80747, P98066, Q00959, Q00960, Q01097, Q07441, Q13224, Q13822, Q28381, Q3UZV7, Q5R1P3, Q5RB22, Q61526, Q64610, Q6BEA0, Q6P9A2

Diamond homologs: A0A182C2Z2, C6KFA3, F1RWC3, O08628, O08859, O14594, O14786, O35276, O35375, O43897, O57382, O57460, O60462, O60494, O70244, P03994, P07354, P07897, P07898, P10859, P10915, P13497, P13608, P13611, P14745, P16112, P25723, P28824, P42674, P55066, P55067, P55252, P79795, P97333, P98063, P98065, P98066, P98068, P98069, P98070

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	98
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1072 predictions. Top by Δscore:

Variant	Effect	Δscore
15:88878252:CCGCC:C	acceptor_gain	1.0000
15:88878253:CGCC:C	acceptor_gain	1.0000
15:88878253:CGCCC:C	acceptor_gain	1.0000
15:88878255:CC:C	acceptor_gain	1.0000
15:88878256:CC:C	acceptor_gain	1.0000
15:88878257:C:T	acceptor_gain	1.0000
15:88878257:CTGGG:C	acceptor_loss	1.0000
15:88878258:T:A	acceptor_loss	1.0000
15:88878962:CTCA:C	donor_loss	1.0000
15:88878963:TCACC:T	donor_loss	1.0000
15:88878964:CAC:C	donor_loss	1.0000
15:88878965:A:AC	donor_gain	1.0000
15:88878965:A:AT	donor_loss	1.0000
15:88878965:AC:A	donor_gain	1.0000
15:88878966:C:CC	donor_gain	1.0000
15:88878966:C:T	donor_loss	1.0000
15:88878966:CC:C	donor_gain	1.0000
15:88879265:CACAC:C	acceptor_gain	1.0000
15:88879266:ACAC:A	acceptor_gain	1.0000
15:88879267:CAC:C	acceptor_gain	1.0000
15:88879267:CACC:C	acceptor_gain	1.0000
15:88879270:C:CA	acceptor_loss	1.0000
15:88879270:C:CC	acceptor_gain	1.0000
15:88881389:T:TA	donor_gain	1.0000
15:88881726:C:CA	acceptor_loss	1.0000
15:88881727:T:C	acceptor_gain	1.0000
15:88881727:T:G	acceptor_loss	1.0000
15:88881727:T:TC	acceptor_gain	1.0000
15:88887170:CCTA:C	donor_loss	1.0000
15:88887171:CTACC:C	donor_loss	1.0000

AlphaMissense

2317 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:88878990:A:C	F258C	0.997
15:88879115:C:A	W216C	0.997
15:88879115:C:G	W216C	0.997
15:88878108:C:A	W315C	0.995
15:88878108:C:G	W315C	0.995
15:88879117:A:G	W216R	0.995
15:88879117:A:T	W216R	0.995
15:88879128:C:G	C212S	0.995
15:88879129:A:T	C212S	0.995
15:88879260:A:C	F168C	0.995
15:88881586:C:A	W88C	0.995
15:88881586:C:G	W88C	0.995
15:88878986:G:C	C259W	0.994
15:88878989:G:C	F258L	0.994
15:88878989:G:T	F258L	0.994
15:88878991:A:G	F258L	0.994
15:88881413:C:G	C146S	0.994
15:88881414:A:T	C146S	0.994
15:88881588:A:G	W88R	0.994
15:88881588:A:T	W88R	0.994
15:88879089:G:T	P225H	0.993
15:88879128:C:A	C212F	0.993
15:88879128:C:T	C212Y	0.993
15:88879148:C:A	W205C	0.993
15:88879148:C:G	W205C	0.993
15:88879259:A:C	F168L	0.993
15:88879259:A:T	F168L	0.993
15:88879261:A:G	F168L	0.993
15:88878144:C:A	W303C	0.992
15:88878144:C:G	W303C	0.992

dbSNP variants (sampled 300 via entrez): RS1000190969 (15:88876859 C>A,T), RS1000360857 (15:88896777 T>C), RS1000364869 (15:88896507 C>A), RS1000429760 (15:88887974 A>C), RS1000577701 (15:88877626 C>A,T), RS1000586800 (15:88882267 G>C), RS1000644152 (15:88878471 C>T), RS1000681585 (15:88881941 G>A,T), RS1000864052 (15:88888274 G>A), RS1000976637 (15:88891924 C>A,G), RS1001002745 (15:88882320 T>C), RS1001016923 (15:88882547 C>T), RS1001184371 (15:88891064 G>A), RS1001320094 (15:88890717 T>C), RS1001712501 (15:88891827 T>C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST004134_4	Multiple keratinocyte cancers	2.000000e-06
GCST004749_46	Lung cancer in ever smokers	6.000000e-06
GCST007293_112	Body fat distribution (arm fat ratio)	8.000000e-07
GCST007293_36	Body fat distribution (arm fat ratio)	2.000000e-09
GCST007293_8	Body fat distribution (arm fat ratio)	4.000000e-12
GCST007294_1	Body fat distribution (trunk fat ratio)	2.000000e-34
GCST007294_122	Body fat distribution (trunk fat ratio)	3.000000e-14
GCST007295_36	Body fat distribution (leg fat ratio)	4.000000e-23
GCST007295_71	Body fat distribution (leg fat ratio)	2.000000e-08
GCST008839_386	Height	4.000000e-12
GCST90000025_235	Appendicular lean mass	2.000000e-12
GCST90000026_7	Appendicular lean mass	9.000000e-07
GCST90000027_32	Appendicular lean mass	4.000000e-07
GCST90020028_1459	Hip circumference adjusted for BMI	1.000000e-09
GCST90020028_1460	Hip circumference adjusted for BMI	3.000000e-13
GCST90020029_771	Waist circumference adjusted for body mass index	6.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0004980	appendicular lean mass
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Doxorubicin	affects expression, increases expression	2
aristolochic acid I	increases expression	1
afuresertib	increases expression	1
TL8-506	affects cotreatment, increases expression	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
terbufos	increases methylation	1
o,p’-DDT	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
pentanal	increases expression	1
ICG 001	decreases expression	1
licochalcone B	increases expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Dasatinib	increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Aldehydes	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
DEET	decreases expression	1
Diethylstilbestrol	decreases expression	1
Fonofos	increases methylation	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1FG	Abcam A-549 HAPLN3 KO 1	Cancer cell line	Male
CVCL_B2N0	Abcam A-549 HAPLN3 KO 2	Cancer cell line	Male

Clinical trials (associated diseases)

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