HHIP

Summary

HHIP (hedgehog interacting protein, HGNC:14866) is a protein-coding gene on chromosome 4q31.21, encoding Hedgehog-interacting protein (Q96QV1). Modulates hedgehog signaling in several cell types including brain and lung through direct interaction with members of the hedgehog family.

This gene encodes a member of the hedgehog-interacting protein (HHIP) family. The hedgehog (HH) proteins are evolutionarily conserved protein, which are important morphogens for a wide range of developmental processes, including anteroposterior patterns of limbs and regulation of left-right asymmetry in embryonic development. Multiple cell-surface receptors are responsible for transducing and/or regulating HH signals. The HHIP encoded by this gene is a highly conserved, vertebrate-specific inhibitor of HH signaling. It interacts with all three HH family members, SHH, IHH and DHH. Two single nucleotide polymorphisms (SNPs) near this gene are significantly associated with risk of chronic obstructive pulmonary disease (COPD). A single nucleotide polymorphism in this gene is also strongly associated with human height.

Source: NCBI Gene 64399 — RefSeq curated summary.

At a glance

• GWAS associations: 134
• Clinical variants (ClinVar): 96 total
• MANE Select transcript: NM_022475

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14866
Approved symbol	HHIP
Name	hedgehog interacting protein
Location	4q31.21
Locus type	gene with protein product
Status	Approved
Aliases	HIP, FLJ20992
Ensembl gene	ENSG00000164161
Ensembl biotype	protein_coding
OMIM	606178
Entrez	64399

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 protein_coding, 5 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000296575, ENST00000434550, ENST00000503090, ENST00000505891, ENST00000509630, ENST00000511314, ENST00000512791, ENST00000515080, ENST00000911099, ENST00000911100, ENST00000968631

RefSeq mRNA: 1 — MANE Select: NM_022475 NM_022475

CCDS: CCDS3762

Canonical transcript exons

ENST00000296575 — 13 exons

Exon	Start	End
ENSE00001081949	144706531	144706682
ENSE00001081950	144737764	144745271
ENSE00001081951	144718875	144718956
ENSE00001081952	144734741	144734889
ENSE00001081955	144646156	144646954
ENSE00001081956	144715300	144715430
ENSE00001081959	144708168	144708311
ENSE00001081960	144707087	144707260
ENSE00003486964	144714225	144714348
ENSE00003503461	144652605	144652797
ENSE00003539734	144658790	144658946
ENSE00003645618	144659637	144659838
ENSE00003646016	144711950	144712071

Expression profiles

Bgee: expression breadth ubiquitous, 206 present calls, max score 96.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 51.0296 / max 4348.6951, expressed in 957 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49874	44.0553	878
49882	3.6530	650
49873	0.7616	299
49877	0.6957	218
49878	0.5710	234
49876	0.3371	146
49879	0.2097	107
49875	0.1963	103
49881	0.1745	102
49871	0.1460	81

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	96.43	gold quality
endothelial cell	CL:0000115	93.78	gold quality
globus pallidus	UBERON:0001875	92.32	gold quality
inferior vagus X ganglion	UBERON:0005363	92.18	gold quality
medial globus pallidus	UBERON:0002477	92.13	gold quality
lateral globus pallidus	UBERON:0002476	92.03	gold quality
tibia	UBERON:0000979	91.75	gold quality
subthalamic nucleus	UBERON:0001906	90.52	gold quality
dorsal plus ventral thalamus	UBERON:0001897	90.00	gold quality
synovial joint	UBERON:0002217	89.54	gold quality
colonic epithelium	UBERON:0000397	89.52	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.46	gold quality
postcentral gyrus	UBERON:0002581	89.13	gold quality
visceral pleura	UBERON:0002401	88.70	gold quality
medulla oblongata	UBERON:0001896	88.54	gold quality
superior vestibular nucleus	UBERON:0007227	88.12	gold quality
parietal lobe	UBERON:0001872	87.97	gold quality
Brodmann (1909) area 46	UBERON:0006483	87.54	gold quality
ventral tegmental area	UBERON:0002691	87.40	gold quality
jejunal mucosa	UBERON:0000399	86.70	gold quality
lower lobe of lung	UBERON:0008949	86.70	gold quality
caput epididymis	UBERON:0004358	86.27	gold quality
substantia nigra pars compacta	UBERON:0001965	85.69	gold quality
Ammon’s horn	UBERON:0001954	85.06	gold quality
pons	UBERON:0000988	84.79	gold quality
pylorus	UBERON:0001166	84.28	gold quality
lateral nuclear group of thalamus	UBERON:0002736	83.12	gold quality
lung	UBERON:0002048	83.02	gold quality
entorhinal cortex	UBERON:0002728	82.84	gold quality
midbrain	UBERON:0001891	82.55	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-11	yes	756.70
E-MTAB-6308	yes	448.40
E-HCAD-1	yes	92.42
E-HCAD-35	yes	77.25
E-ANND-3	yes	25.85

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1, GLI2, ID2, LHX2, SHH

miRNA regulators (miRDB)

98 targeting HHIP, 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-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267

Literature-anchored findings (GeneRIF, showing 40)

• These results suggest that reduced expression of HIP, a naturally occurring Hh pathway antagonist, in tumor neo-vasculature may contribute to increased Hh signaling within the tumor and possibly promote angiogenesis. (PMID:15294024)
• The different pattern of expression and abnormal localization in the diseased pancreas suggest that the enhanced activation of hedgehog signaling in in pancreatic cancer and pancreatic duct carcinoma. (PMID:15754313)
• Aberrant methylation of the Human Hedgehog interacting protein is associated with pancreatic neoplasms (PMID:15970691)
• The down-regulation of HHIP transcription is due to DNA hypermethylation and/or loss of heterozygoty in hepatocellular carcinoma. (PMID:18559595)
• Genome-wide significant association of the HHIP locus with lung function. The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. (PMID:19300482)
• Results propose a role for Hedgehog-interacting protein as a structural decoy receptor for vertebrate Hedgehog. (PMID:19561609)
• Results describe a series of crystal structures for the human Hedgehog-interacting protein ectodomain and Desert hedgehog (DHH) in isolation, as well as HHIP in complex with DHH (HHIP-DHH) and Sonic hedgehog (Shh) (HHIP-Shh), with and without Ca2+. (PMID:19561611)
• show in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that RUNX2 potentially mediates this process by regulating ADAMTS5 expression (PMID:19915594)
• Genetic variation near the Hip gene was significantly associated with risk of COPD, depending on the number of pack-years of smoking. (PMID:19996190)
• The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. (PMID:20656943)
• Mutation of the hedgehog signaling patwhway play a key role in the development of basal cell carrcinomas. (PMID:20800318)
• results suggest the possibility of epigenetic regulation of HHIP in medulloblastoma (PMID:20853133)
• the GG genotype of the rs 1489759 HHIP single-nucleotide polymorphism (SNP) and the CC genotype of the rs 2202507 GYPA SNP confers a ‘‘protective’’ effect on COPD (OR 0.59, p50.006 for HHIP and OR50.65, p50.006 for GYPA) and lung cancer. (PMID:21119205)
• We found that HIP, PDGFRalpha, SMO and Su(Fu) gene highly expressed in the primary esophageal squamous cell carcinomas (PMID:21210262)
• A subset of normal lung function genes, including HHIP, FAM13A, and PTCH1, together predict lung function abnormalities, a measure of severity in white and African American subjects with asthma. (PMID:21397937)
• Low HHIP expression is associated with chronic obstructive pulmonary disease. (PMID:22140090)
• Resveratrol inhibits proliferation and induces apoptosis through the hedgehog signaling pathway in pancreatic cancer cells.( (PMID:22301921)
• no correlation between hedgehog activity and SHH, Gli1 and Patched1 mRNA levels was observed. other mechanisms aside from transcriptional regulation of these factors are responsible for hedgehog activity in tumor cells derived from GBM. (PMID:22406999)
• GDC-0449 treatment is pharmacodynamically effective as evidenced by paracrine Hedgehog signaling inhibition and results in prostate cancer cell proliferation reduction. (PMID:22457212)
• Results suggest involvement of the Hedgehog pathway in CPHD and that both SHH and HHIP are investigated as a second screening in CPHD, after mutations in the classical CPHD genes have been ruled out. (PMID:22897141)
• The data demonstrated that loss of expression of HHIP and PTCH is associated with the methylation of gene promoters (PMID:23440386)
• HHIP, HDAC4, NCR3 and RARB polymorphisms may have a role in impaired lung function that begins in early life (PMID:23456936)
• Identification of potential HHIP targets of gene expression regulation in chronic obstructive pulmonary disease. (PMID:23459001)
• Genetic variants in HHIP are associated with FEV1 in subjects with chronic obstructive pulmonary disease. (PMID:23731023)
• These data suggest that activated Hedgehog signalling contributes to the biology of human fetal rhabdomyomas. (PMID:23780909)
• Data indicate that the Shh signaling transduction is facilitated by binding of Shh to its receptor protein, Ptch, and show the complex structure of Shh-Hhip. (PMID:23935859)
• our study suggests that the HHIP gene may be involved in COPD susceptibility in Chinese Han population. (PMID:23994291)
• We show that GPC3, an hepatocellular carcinoma biomarker and Hh mediator, regulates human stellate cell viability by regulating Hh signaling. (PMID:24439425)
• HHIP is located within genes previously associated with chronic obstructive pulmonary disease susceptibility. (PMID:25006744)
• Shh-mediated degradation of Hhip allows cell autonomous and non-cell autonomous Shh signaling. (PMID:25215859)
• HHIP might be a diagnostic or prognostic marker in glioma and help to the detection of these tumors in early stages of disease. (PMID:25416442)
• HHIP expression and Gli1 expression were independent prognostic factors in glioblastoma. (PMID:26482617)
• HHIP - candidate gene for Chronic Obstructive Pulmonary Disease identified by Genome-wide association studies. (PMID:26527870)
• This work supports a feasible vicious cycle in which EMPs generated during endothelial injury, in turn, aggravate endothelial damage by carrying HHIP into target ECs, contributing to the continuously deteriorating endothelial damage in the development of aGVHD. EMPs harboring HHIP would represent a potential therapeutic target for aGVHD. (PMID:27009877)
• HHIP underexpression is associated with lung adenocarcinoma. (PMID:27015549)
• The rate of methylation of ZIC1, ZIC4, HHIP, and DACT2 in tumors was very high, while methylation of CXXC4 was low to moderate in OSCC and LSCC. (PMID:27553089)
• this study shows that HHIP confers a risk for airway obstruction in general that is not driven exclusively by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease (PMID:27612410)
• HHIP plays a role in lung branching development, and reduced levels of HHIP ultimately result in lung hypoplasia. (PMID:27845578)
• Results showed that smoking and HHIP variant rs7654947 were associated with chronic obstructive pulmonary disease (COPD)development and lung function decline. Moreover, we found that cigarette smoking and gene susceptibility have cooperative effects on COPD risk and lung function decline (PMID:28640141)
• loss of AT2 R is associated with podocyte loss/dysfunction and is mediated, at least in part, via augmented ectopic hedgehog interacting protein expression in podocytes (PMID:28722118)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hhip	ENSDARG00000060397
mus_musculus	Hhip	ENSMUSG00000064325
rattus_norvegicus	Hhip	ENSRNOG00000018268

Paralogs (2): HHIPL2 (ENSG00000143512), HHIPL1 (ENSG00000182218)

Protein

Protein identifiers

Hedgehog-interacting protein — Q96QV1 (reviewed: Q96QV1)

All UniProt accessions (1): Q96QV1

UniProt curated annotations — full annotation on UniProt →

Function. Modulates hedgehog signaling in several cell types including brain and lung through direct interaction with members of the hedgehog family.

Subunit / interactions. Interacts with all three hedgehog family members, SHH, IHH and DHH.

Subcellular location. Cell membrane. Secreted Cytoplasm.

Tissue specificity. Widely expressed in fetal and adult tissues. Highest expression in adult heart, liver and pancreas, and in fetal kidney.

Domain organisation. A flexible loop interacts with the SHH zinc binding site and contributes to zinc binding.

Polymorphism. Genetic variations in HHIP define the stature quantitative trait locus 12 (STQTL12) [MIM:612224]. Adult height is an easily observable and highly heritable complex continuous trait. Because of this, it is a model trait for studying genetic influence on quantitative traits.

Miscellaneous. Potentially soluble form.

Similarity. Belongs to the HHIP family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96QV1-1	1	yes
Q96QV1-2	2

RefSeq proteins (1): NP_071920* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR011041	Quinoprot_gluc/sorb_DH_b-prop	Homologous_superfamily
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR012938	Glc/Sorbosone_DH	Domain
IPR013111	EGF_extracell	Domain
IPR018143	Folate_rcpt-like	Domain

Pfam: PF03024, PF07974, PF07995

UniProt features (98 total): strand 47, helix 13, disulfide bond 11, turn 7, mutagenesis site 4, glycosylation site 4, sequence conflict 3, domain 2, splice variant 2, signal peptide 1, chain 1, sequence variant 1, region of interest 1, binding site 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
7PGN	X-RAY DIFFRACTION	2.4
2WG3	X-RAY DIFFRACTION	2.6
7PGL	X-RAY DIFFRACTION	2.63
7PGM	X-RAY DIFFRACTION	2.7
7PGK	X-RAY DIFFRACTION	2.75
2WFT	X-RAY DIFFRACTION	2.8
3HO3	X-RAY DIFFRACTION	2.9
3HO5	X-RAY DIFFRACTION	3.01
3HO4	X-RAY DIFFRACTION	3.1
2WG4	X-RAY DIFFRACTION	3.15
2WFX	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96QV1-F1	79.77	0.47

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 (1): 383

Disulfide bonds (11): 216–536, 218–543, 402–624, 435–452, 500–594, 608–617, 612–623, 625–634, 639–649, 643–655, 657–666

Glycosylation sites (4): 99, 416, 447, 459

Mutagenesis-validated functional residues (4):

Position	Phenotype
380	abolishes shh binding.
382	abolishes shh binding.
383	abolishes shh binding.
387	abolishes shh binding.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5632681	Ligand-receptor interactions
R-HSA-5635851	GLI proteins bind promoters of Hh responsive genes to promote transcription

MSigDB gene sets: 206 (showing top): ATF_B, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RRAGTTGT_UNKNOWN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, BENPORATH_ES_WITH_H3K27ME3, KEGG_HEDGEHOG_SIGNALING_PATHWAY, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, NKX25_02, GOBP_EPITHELIAL_TUBE_BRANCHING_INVOLVED_IN_LUNG_MORPHOGENESIS, GOBP_LUNG_MORPHOGENESIS, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS, CREBP1_Q2

GO Biological Process (9): signal transduction (GO:0007165), neuroblast proliferation (GO:0007405), dorsal/ventral pattern formation (GO:0009953), negative regulation of signal transduction (GO:0009968), regulation of fibroblast growth factor receptor signaling pathway (GO:0040036), negative regulation of smoothened signaling pathway (GO:0045879), skeletal system morphogenesis (GO:0048705), epithelial tube branching involved in lung morphogenesis (GO:0060441), animal organ morphogenesis (GO:0009887)

GO Molecular Function (4): zinc ion binding (GO:0008270), hedgehog family protein binding (GO:0097108), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (6): extracellular region (GO:0005576), cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell surface (GO:0009986), ciliary membrane (GO:0060170), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Hedgehog ‘on’ state	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of signal transduction	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
generation of neurons	1
neural precursor cell proliferation	1
regionalization	1
signal transduction	1
negative regulation of cell communication	1
negative regulation of signaling	1
negative regulation of response to stimulus	1
fibroblast growth factor receptor signaling pathway	1
regulation of cellular response to growth factor stimulus	1
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1
negative regulation of signal transduction	1
skeletal system development	1
animal organ morphogenesis	1
branching morphogenesis of an epithelial tube	1
lung morphogenesis	1
anatomical structure morphogenesis	1
animal organ development	1
transition metal ion binding	1
protein binding	1
binding	1
cation binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
cilium	1
cell projection membrane	1
bounding membrane of organelle	1

Protein interactions and networks

STRING

1580 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HHIP	SHH	Q15465	986
HHIP	IHH	Q14623	984
HHIP	DHH	O43323	965
HHIP	PTCH1	Q13635	954
HHIP	GLI1	P08151	898
HHIP	FAM13A	O94988	851
HHIP	SMO	Q99835	844
HHIP	GLI2	P10070	820
HHIP	GLI3	P10071	790
HHIP	GAS1	P54826	737
HHIP	PTCH2	Q9Y6C5	691
HHIP	IREB2	P48200	687
HHIP	SUFU	Q9UMX1	673
HHIP	CHRNA3	P32297	664
HHIP	KIF7	Q2M1P5	642

IntAct

17 interactions, top by confidence:

A	B	Type	Score
HHIP	SHH	psi-mi:“MI:0407”(direct interaction)	0.690
SHH	HHIP	psi-mi:“MI:0407”(direct interaction)	0.690
HHIP	SHH	psi-mi:“MI:0915”(physical association)	0.690
	SHH	psi-mi:“MI:0407”(direct interaction)	0.440
HHIP	PTCH1	psi-mi:“MI:0915”(physical association)	0.400
HHIP	DHH	psi-mi:“MI:0915”(physical association)	0.400
HHIP	IHH	psi-mi:“MI:0915”(physical association)	0.400
HHIP	APPBP2	psi-mi:“MI:0915”(physical association)	0.400
	CCN1	psi-mi:“MI:0914”(association)	0.350
HDAC11	AGPS	psi-mi:“MI:0914”(association)	0.350
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
CDH5	MYO1C	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (8): HHIP (Affinity Capture-RNA), APPBP2 (Affinity Capture-MS), HHIP (Affinity Capture-MS), HHIP (Affinity Capture-MS), HHIP (Cross-Linking-MS (XL-MS)), RPL18A (Cross-Linking-MS (XL-MS)), HHIP (Affinity Capture-MS), HHIP (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3NFE2, A0JM59, A2RT67, A5PK16, A5PN09, A7Z056, D3YZI9, D7PF45, F1QGZ6, O14757, O15357, O35710, O81360, P36195, P41002, P51944, Q0JCU7, Q32NJ2, Q32NM1, Q5E9N5, Q5F3G0, Q5R5Z6, Q5T447, Q5XGG5, Q6DI92, Q6P549, Q6ZN16, Q7T0L6, Q7TN16, Q7ZUM8, Q80TA6, Q80WG7, Q8AYC9, Q8BRH3, Q8C6M1, Q8K4F8, Q8N414, Q8N6K7, Q8W519, Q94K49

Diamond homologs: A1L0T3, A1L1V4, A1L4H1, A5PJQ2, A6H737, A7E3W2, B4F6N6, B5DF27, B8A4W9, E1C3U7, F1QQC3, F1RD85, F7J220, G3V801, M9NDE3, O08762, O43866, O70513, P16264, P21757, P21758, P30203, P30204, P30205, P56730, P58022, P58215, P70117, P85521, Q05585, Q07797, Q08380, Q08B63, Q14DK5, Q24JV9, Q2VL90, Q2VLG4, Q2VLG6, Q2VLH6, Q4A3R3

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
GLI1	“up-regulates quantity by expression”	HHIP	“transcriptional regulation”
GLI2	“up-regulates quantity by expression”	HHIP	“transcriptional regulation”
HHIP	“down-regulates activity”	IHH	binding
HHIP	“down-regulates activity”	SHH	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2273 predictions. Top by Δscore:

Variant	Effect	Δscore
4:144646951:TAAGG:T	donor_loss	1.0000
4:144646952:AAGG:A	donor_loss	1.0000
4:144646953:AGGTA:A	donor_loss	1.0000
4:144646955:G:GA	donor_loss	1.0000
4:144646956:T:A	donor_loss	1.0000
4:144658786:AAAG:A	acceptor_gain	1.0000
4:144658915:G:GT	donor_gain	1.0000
4:144658931:TGG:T	donor_gain	1.0000
4:144658933:G:GT	donor_gain	1.0000
4:144658939:A:G	donor_gain	1.0000
4:144658956:GA:G	donor_gain	1.0000
4:144659822:TTCA:T	donor_gain	1.0000
4:144659834:TAAAG:T	donor_loss	1.0000
4:144659835:AAAG:A	donor_loss	1.0000
4:144659836:AAG:A	donor_loss	1.0000
4:144659837:AGG:A	donor_loss	1.0000
4:144659838:GGTTG:G	donor_loss	1.0000
4:144659839:G:C	donor_loss	1.0000
4:144659840:T:A	donor_loss	1.0000
4:144706590:A:T	donor_gain	1.0000
4:144711948:A:AG	acceptor_gain	1.0000
4:144711949:G:GG	acceptor_gain	1.0000
4:144711949:GAT:G	acceptor_gain	1.0000
4:144714219:TTCCA:T	acceptor_loss	1.0000
4:144714220:TCCA:T	acceptor_loss	1.0000
4:144714221:CCA:C	acceptor_loss	1.0000
4:144714222:CA:C	acceptor_loss	1.0000
4:144714223:A:AG	acceptor_gain	1.0000
4:144714223:A:AT	acceptor_loss	1.0000
4:144714224:G:GG	acceptor_gain	1.0000

AlphaMissense

4602 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:144646790:T:A	C39S	0.999
4:144646791:G:C	C39S	0.999
4:144652632:T:A	C103S	0.999
4:144652633:G:C	C103S	0.999
4:144652779:T:C	C152R	0.999
4:144652780:G:A	C152Y	0.999
4:144652781:C:G	C152W	0.999
4:144659752:G:C	G249R	0.999
4:144659822:T:A	V272D	0.999
4:144706545:A:C	R282S	0.999
4:144706545:A:T	R282S	0.999
4:144706597:T:G	Y300D	0.999
4:144706606:T:G	Y303D	0.999
4:144737850:T:A	C666S	0.999
4:144737851:G:C	C666S	0.999
4:144646790:T:C	C39R	0.998
4:144652632:T:C	C103R	0.998
4:144652759:G:A	C145Y	0.998
4:144652760:C:G	C145W	0.998
4:144652779:T:A	C152S	0.998
4:144652780:G:C	C152S	0.998
4:144658852:T:C	C179R	0.998
4:144658856:T:G	F180C	0.998
4:144659753:G:A	G249D	0.998
4:144706544:G:C	R282T	0.998
4:144706546:G:A	G283R	0.998
4:144706546:G:C	G283R	0.998
4:144706655:T:C	L319P	0.998
4:144706661:T:A	V321D	0.998
4:144707217:G:T	G372W	0.998

dbSNP variants (sampled 300 via entrez): RS1000084423 (4:144715859 T>A), RS1000107109 (4:144722708 G>T), RS1000164242 (4:144729068 T>C), RS1000184775 (4:144737222 A>C), RS1000188175 (4:144709013 A>C), RS1000189613 (4:144732401 G>A,T), RS1000198062 (4:144708612 A>C), RS1000199621 (4:144677608 T>C), RS1000250092 (4:144676212 A>C), RS1000316930 (4:144671323 T>G), RS1000331601 (4:144701724 A>G,T), RS1000366587 (4:144743433 G>A), RS1000415544 (4:144690182 T>C), RS1000419966 (4:144649696 C>A,T), RS1000456359 (4:144694879 C>T)

Disease associations

OMIM: gene MIM:606178 | disease phenotypes: MIM:606963

GenCC curated gene-disease

Mondo (1): chronic obstructive pulmonary disease (MONDO:0005002)

Orphanet (0):

HPO phenotypes

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

GWAS associations

134 associations (top):

Study	Trait	p-value
GCST000174_16	Height	2.000000e-09
GCST000175_33	Height	1.000000e-11
GCST000176_7	Height	1.000000e-11
GCST000359_2	Chronic obstructive pulmonary disease	1.000000e-07
GCST000362_1	Pulmonary function	8.000000e-11
GCST000372_6	Height	4.000000e-06
GCST000542_1	Pulmonary function	3.000000e-20
GCST000544_4	Pulmonary function	6.000000e-13
GCST000603_2	Chronic obstructive pulmonary disease	5.000000e-07
GCST000644_1	Height	1.000000e-09
GCST000817_33	Height	2.000000e-09
GCST000817_64	Height	6.000000e-51
GCST001321_3	Chronic obstructive pulmonary disease	3.000000e-07
GCST001784_50	Pulmonary function (smoking interaction)	5.000000e-18
GCST001956_9	Height	4.000000e-21
GCST002350_3	Chronic obstructive pulmonary disease (severe)	4.000000e-15
GCST002351_3	Chronic obstructive pulmonary disease (moderate to severe)	2.000000e-12
GCST002525_16	Local histogram emphysema pattern	1.000000e-08
GCST002525_2	Local histogram emphysema pattern	2.000000e-09
GCST002646_4	Infant length	2.000000e-09
GCST002647_72	Height	2.000000e-86
GCST002702_51	Height	4.000000e-14
GCST002783_453	Body mass index	6.000000e-09
GCST002783_489	Body mass index	3.000000e-08
GCST002783_91	Body mass index	1.000000e-06
GCST002795_5	Chronic obstructive pulmonary disease	1.000000e-07
GCST002945_46	Emphysema imaging phenotypes	2.000000e-12
GCST002945_52	Emphysema imaging phenotypes	8.000000e-10
GCST003267_10	Pre bronchodilator FEV1/FVC ratio	2.000000e-08
GCST003267_11	Pre bronchodilator FEV1/FVC ratio	3.000000e-08

EFO canonical traits (22, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:0005850	emphysema pattern measurement
EFO:0006785	infant body height
EFO:0004340	body mass index
EFO:0007626	emphysema imaging measurement
EFO:0007828	daytime rest measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference
EFO:0004314	forced expiratory volume
EFO:0004318	smoking behavior
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008002	physical activity measurement
EFO:0004344	birth weight
EFO:0007785	femoral neck bone mineral density
EFO:0009959	diverticular disease
EFO:0009270	heel bone mineral density
EFO:0004341	body fat distribution
EFO:0005939	parental genotype effect measurement
EFO:0004346	neuroimaging measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004980	appendicular lean mass

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D029424	Pulmonary Disease, Chronic Obstructive	C08.381.495.389; C23.550.291.500.875

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
trichostatin A	affects cotreatment, increases expression	3
bisphenol A	affects expression, decreases expression	2
mono-(2-ethylhexyl)phthalate	increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Resveratrol	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Doxorubicin	increases expression	2
Ethinyl Estradiol	affects expression, decreases expression	2
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
terbufos	increases methylation	1
cobaltous chloride	decreases expression	1
methaneselenol	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	increases expression, decreases reaction	1
deguelin	increases 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
thifluzamide	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
(+)-JQ1 compound	decreases expression	1
Decitabine	affects expression, affects methylation	1
Vorinostat	increases expression	1
Panobinostat	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120978	PHASE4	UNKNOWN	Can Advair and Flovent Reduce Systemic Inflammation Related to Chronic Obstructive Pulmonary Disease (COPD)? A Multi-Center Randomized Controlled Trial
NCT00134979	PHASE4	COMPLETED	Formoterol Certihaler, Tiotropium HandiHaler and Tiotropium HandiHaler in Combination With Formoterol Certihaler in Patients With Stable Chronic Obstructive Pulmonary Disease
NCT00158847	PHASE4	TERMINATED	Modification Of Disease Outcome In COPD
NCT00170222	PHASE4	COMPLETED	Placebo Versus Antibiotics in Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)
NCT00175565	PHASE4	COMPLETED	Inhaled Steroid Reduces Systemic Inflammation in COPD
NCT00181207	PHASE4	COMPLETED	Airway Clearance for Prevention of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
NCT00186706	PHASE4	COMPLETED	Selenium Supplementation in Chronic Obstructive Pulmonary Disease (COPD) Patients
NCT00190437	PHASE4	COMPLETED	ANTEAB: a Study of Early Antibiotherapy in the ICU Management of Acute Exacerbations of COPD
NCT00202176	PHASE4	COMPLETED	Effects of Bronchodilators in Mild Chronic Obstructive Pulmonary Disease (COPD)
NCT00202189	PHASE4	COMPLETED	Effects of Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease (COPD)
NCT00232674	PHASE4	COMPLETED	Efficacy Study of the Effect of Budesonide on Emphysema
NCT00288548	PHASE4	UNKNOWN	Metoprolol and Formoterol in Chronic Obstructive Pulmonary Disease (COPD)
NCT00291408	PHASE4	WITHDRAWN	Effect of Symbicort on HAT and HDAC in Sputum Macrophages of COPD
NCT00291460	PHASE4	UNKNOWN	Inspiratory Muscle Training in Hypercapnic COPD
NCT00292838	PHASE4	COMPLETED	Relative Potency of Inhaled Corticosteroids
NCT00311961	PHASE4	COMPLETED	Intravenous Versus Oral Administration of Prednisolone in Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)
NCT00316992	PHASE4	COMPLETED	Safety of Ramelteon in Subjects With Chronic Obstructive Pulmonary Disease
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00335621	PHASE4	WITHDRAWN	Replacement of Nebulised Ipratropium With Inhaled Tiotropium in Stable Chronic Obstructive Pulmonary Disease (COPD)
NCT00354354	PHASE4	COMPLETED	Bronchodilators and Oxygen Kinetics With Exercise in Chronic Obstructive Pulmonary Disease (COPD) Patients
NCT00379028	PHASE4	COMPLETED	Airway Clearance Study
NCT00405236	PHASE4	COMPLETED	Effect of Tiotropium on Inflammation and Exacerbations in COPD
NCT00412204	PHASE4	COMPLETED	Study to Evaluate the Effects of Tiotropium Bromide on Chronic Obstructive Pulmonary Disease (COPD) During Exercise
NCT00424528	PHASE4	COMPLETED	Efficacy Safety Study of Arformoterol/Tiotropium Combination Versus Either Therapy Alone in Chronic Obstructive Pulmonary Disease (COPD)
NCT00440245	PHASE4	COMPLETED	Bronchoprotection of Salbutamol in Asthma and Chronic Obstructive Pulmonary Disease
NCT00440687	PHASE4	COMPLETED	Withdrawal of Inhaled Corticosteroids in Patients With COPD in Primary Care
NCT00489853	PHASE4	COMPLETED	Evaluation of Efficacy on Exercise Tolerance of Symbicort (Budesonide/Formoterol) Compared to Placebo and Oxis in Patients With Severe COPD
NCT00491803	PHASE4	COMPLETED	Sildenafil Effects on Pulmonary Haemodynamics and Gas Exchange in Chronic Obstructive Pulmonary Disease (COPD)
NCT00495586	PHASE4	COMPLETED	Effectiveness of Antibiotic Therapy for Exacerbations of Chronic Obstructive Pulmonary Disease
NCT00525564	PHASE4	COMPLETED	Effects of Salmeterol on Walking Capacity in Patients With COPD
NCT00532584	PHASE4	WITHDRAWN	Effect of Steroids on Gene Expression in the Healthy Smokers Lungs
NCT00542880	PHASE4	COMPLETED	Evaluation of Onset of Effect in Patients With Severe Chronic Obstructive Pulmonary Disease (COPD) Treated With Symbicort® Compared to Seretide®
NCT00561886	PHASE4	COMPLETED	Change of Inspiratory Peak Flow in COPD
NCT00569270	PHASE4	COMPLETED	Dynamic Hyperinflation and Tiotropium
NCT00571428	PHASE4	COMPLETED	Efficacy Safety Study of Arformoterol QD Dosing Versus BID Dosing in COPD
NCT00578968	PHASE4	COMPLETED	Cardiac Limitations in Chronic Obstructive Pulmonary Disease: Benefits of Bronchodilation
NCT00592033	PHASE4	COMPLETED	Effect of Oxygen in Normoxaemic COPD Patients Who Desaturate During Exercise
NCT00628225	PHASE4	COMPLETED	Smoking Cessation in Patients With COPD (SMOCC) in General Practice
NCT00633776	PHASE4	WITHDRAWN	Perforomist Versus Foradil Evaluated by Inspiratory Capacity and High Resolution Computed Tomography (HRCT)
NCT00639236	PHASE4	COMPLETED	Effectiveness and Safety of Inhaling Hypertonic Saline in Patients With Chronic Obstructive Pulmonary Disease