SERPINH1

Summary

SERPINH1 (serpin family H member 1, HGNC:1546) is a protein-coding gene on chromosome 11q13.5, encoding Serpin H1 (P50454). Binds specifically to collagen.

This gene encodes a member of the serpin superfamily of serine proteinase inhibitors. The encoded protein is localized to the endoplasmic reticulum and plays a role in collagen biosynthesis as a collagen-specific molecular chaperone. Autoantibodies to the encoded protein have been found in patients with rheumatoid arthritis. Expression of this gene may be a marker for cancer, and nucleotide polymorphisms in this gene may be associated with preterm birth caused by preterm premature rupture of membranes. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9.

Source: NCBI Gene 871 — RefSeq curated summary.

At a glance

• Gene–disease (curated): osteogenesis imperfecta type 10 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 30
• Clinical variants (ClinVar): 297 total — 10 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 48
• Druggable target: yes
• MANE Select transcript: NM_001235

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1546
Approved symbol	SERPINH1
Name	serpin family H member 1
Location	11q13.5
Locus type	gene with protein product
Status	Approved
Aliases	HSP47
Ensembl gene	ENSG00000149257
Ensembl biotype	protein_coding
OMIM	600943
Entrez	871

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 30 protein_coding, 2 nonsense_mediated_decay

ENST00000358171, ENST00000524558, ENST00000525492, ENST00000525611, ENST00000525876, ENST00000526242, ENST00000526397, ENST00000526638, ENST00000528760, ENST00000528990, ENST00000529643, ENST00000530284, ENST00000532356, ENST00000533449, ENST00000533603, ENST00000649490, ENST00000872810, ENST00000872811, ENST00000872812, ENST00000872813, ENST00000922053, ENST00000922054, ENST00000922055, ENST00000922056, ENST00000922057, ENST00000922058, ENST00000922059, ENST00000922060, ENST00000922061, ENST00000947468, ENST00000947469, ENST00000947470

RefSeq mRNA: 2 — MANE Select: NM_001235 NM_001207014, NM_001235

CCDS: CCDS8239

Canonical transcript exons

ENST00000358171 — 5 exons

Exon	Start	End
ENSE00000989624	75568731	75568829
ENSE00000989625	75568939	75569171
ENSE00001412921	75566316	75566971
ENSE00002152080	75571781	75572783
ENSE00003899828	75562253	75562319

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 99.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 96.7626 / max 827.0920, expressed in 1740 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115906	80.6433	1612
115905	16.0470	1675
115907	0.0723	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.63	gold quality
endometrium epithelium	UBERON:0004811	98.52	gold quality
smooth muscle tissue	UBERON:0001135	98.49	gold quality
omental fat pad	UBERON:0010414	98.23	gold quality
peritoneum	UBERON:0002358	98.22	gold quality
pericardium	UBERON:0002407	98.07	gold quality
right coronary artery	UBERON:0001625	98.01	gold quality
ascending aorta	UBERON:0001496	97.93	gold quality
thoracic aorta	UBERON:0001515	97.88	gold quality
left uterine tube	UBERON:0001303	97.87	gold quality
cartilage tissue	UBERON:0002418	97.83	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.67	gold quality
body of uterus	UBERON:0009853	97.65	gold quality
right ovary	UBERON:0002118	97.54	gold quality
upper lobe of left lung	UBERON:0008952	97.35	gold quality
coronary artery	UBERON:0001621	97.20	gold quality
myometrium	UBERON:0001296	97.19	gold quality
left coronary artery	UBERON:0001626	97.17	gold quality
descending thoracic aorta	UBERON:0002345	97.15	gold quality
upper lobe of lung	UBERON:0008948	97.11	gold quality
endocervix	UBERON:0000458	97.07	gold quality
vena cava	UBERON:0004087	97.06	gold quality
gall bladder	UBERON:0002110	97.05	gold quality
left ovary	UBERON:0002119	96.82	gold quality
colonic epithelium	UBERON:0000397	96.79	gold quality
right adrenal gland	UBERON:0001233	96.58	gold quality
aorta	UBERON:0000947	96.48	gold quality
periodontal ligament	UBERON:0008266	96.31	gold quality
placenta	UBERON:0001987	96.29	gold quality
left adrenal gland	UBERON:0001234	96.28	gold quality

Single-cell (SCXA)

Detected in 26 experiment(s), a significant marker in 23.

Experiment	Marker?	Max mean expression
E-HCAD-24	yes	2241.99
E-MTAB-6701	yes	2065.21
E-CURD-112	yes	1450.59
E-MTAB-10485	yes	1359.06
E-MTAB-5061	yes	1094.04
E-HCAD-13	yes	1030.72
E-MTAB-9154	yes	802.82
E-MTAB-10287	yes	120.51
E-HCAD-1	yes	89.46
E-HCAD-10	yes	57.35
E-MTAB-8410	yes	42.19
E-HCAD-5	yes	40.04
E-HCAD-31	yes	26.04
E-ANND-3	yes	18.06
E-GEOD-93593	yes	16.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA3, GATA4, HSF1, KLF2, MAF, SP1, SP3, TP53

Literature-anchored findings (GeneRIF, showing 40)

• The enhancement of HSP47 expression by TGF-beta and IL-1 beta has been confirmed in embryonic lung fibroblasts. (PMID:11994473)
• induced in cicatricial pemphigoid: possible role(s) in dermal fibrosis (PMID:12061838)
• Results indicate a novel means by which type I collagen production is regulated by the endoplasmic reticulum constituent, Hsp47. (PMID:12163502)
• Modulates the production of the endostatin precursor collagen XVIII in head and neck carcinomas (PMID:12174873)
• levels of HSP47 protein and autoantibodies to HSP47 in the sera of patients with rheumatic autoimmune diseases (PMID:12659832)
• gene expression profiling in epidermolysis bullosa acquisita (PMID:12824005)
• high levels of expression of Hsp47 and adult and oncofetal fibronectin in Dupuytren’s contracture suggests that cell-mediated alterations in the extracellular environment may play an important role in the disease process (PMID:15047128)
• HSP47 has a role in aging and photoaging in human fibroblasts (PMID:15247019)
• The surface-exposed RA-A47 may induce autoantibodies and inflammatory reactions in autoimmune disease situations such as rheumatoid arthritis. (PMID:15389525)
• HSP47 is constitutively expressed in human hepatic stellate cells and may be a target for antifibrotic therapy. (PMID:15806139)
• Our results suggest the existence of different fibrotic pathways among these groups involved in the expression of HSP47 and type I procollagen. (PMID:15955241)
• results suggest nitric oxide has dual effects on collagen synthesis by fibroblasts: the direct stimulation of collagen synthesis due to the up-regulation of procollagen alphaI(1) mRNA, and an indirect effect through the increase of HSP47 mRNA expression (PMID:16171977)
• analysis of the client recognition mechanism of HSP47 (PMID:16326708)
• analysis of recognition of the collagen triple helix by chaperone HSP47 (PMID:16484215)
• A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans. (PMID:16938879)
• The anti-fibrotic effect of pirfenidone may be mediated through direct inhibition of collagen type I expression and inhibition of HSP47 expression in lung fibroblasts. (PMID:18093617)
• HSP47-positive fibroblasts were main constituent cell of dermatofibroma. (PMID:18095990)
• These studies define a new haplotype in the SERPINH1 gene that modifies risk of an adverse obstetrical outcome. (PMID:18205191)
• During keratin preparation from cultured human tumor cell lines, Hsps might be associated with keratin expression in tumor cells (PMID:18293509)
• We conclude that colligin 2 is expressed in all cellular components of glioma blood vessels and may serve as a general marker for active angiogenesis (PMID:19067716)
• Hsp47 was exposed on surface of GPVI-activated platelets; inhibition of Hsp47 abolished platelet aggregation in response to collagen, but partially reduced aggregation in response to other agonists; propose Hsp47 may play a role in hemostasis & thrombosis (PMID:19341245)
• overexpression of HSP47 is a unique characteristic of ulcerative colitis-associated carcinoma related to type I collagen synthesis, with possible clinical applications. (PMID:19603022)
• down-regulated KLF4, CHGA, GPX3, SST and LIPF, together with up-regulated SERPINH1, THY1 and INHBA is an 8-gene signature for gastric cancer (PMID:20043075)
• Increased heat shock protein 47 expression is associated with esophageal squamous cell carcinoma. (PMID:20112500)
• HSP47 and fascin expression may play role in the pathogenesis of invasive ductal carcinoma of the breast and prostatic adenocarcinoma because their expression is significantly higher than their normal counterpart. (PMID:20701077)
• Overexpression of HSP47 decreased the secretion of heterotrimers containing the mutant collagen alpha5(IV) chain. (PMID:21187648)
• Hsp47 recognizes the triple-helix form of procollagen in vitro and in vivo. (PMID:22235129)
• Hsp47 may be related to the TGF-beta1-induced transdifferentiation of human Tenon’s fibroblasts to myofibroblasts. (PMID:22967132)
• NMR and mutational identification of the collagen-binding site of the chaperone Hsp47 (PMID:23049894)
• Correlative Hsp47 expression in fibroblasts with bFGF in inflammatory cells may contribute to stromal fibrosis and obstruction in colorectal carcinoma (PMID:23265436)
• TRAIL induced HSF1 inactivation leads to the suppression of Hsp47-dependent collagen production in activated human hepatic stellate cells. (PMID:23587601)
• silencing of the HSP47 gene significantly inhibited cell migration and invasion in cancer cells and the expression of HSP47 was upregulated in cancer tissues and cervical intraepithelial neoplasia, as demonstrated by immunostaining. (PMID:24141696)
• IL-17A-induced HSP47 expression is involved in collagen I expression in intestinal subepithelial myofibroblasts, which might contribute to intestinal fibrosis in Crohn’s disease. (PMID:24534724)
• HSP47 is a novel glioma-associated antigen (PMID:24623841)
• miR-29b down-regulates HSP47 and LOX expression. (PMID:24650661)
• In patients with schistosomiasis japonica, TGF-beta1 participates not only in the inflammatory process, but also in the fibrotic process in which Hsp47 and CTGF probably play a key role. (PMID:25111595)
• Mutations in the HSP47 and FKBP65 produce a moderately severe form of Osteogenesis imperfect. (PMID:25510505)
• Hsp47 expression promotes cancer progression in part by enhancing deposition of extracellular matrix proteins. (PMID:25744716)
• The present study demonstrates that HSP47 promotes glioma angiogenesis and highlights the importance of HSP47 as an attractive therapeutic target of GBM. (PMID:25758142)
• Overexpression of HSP47 is associated with poor prognosis in patients with esophageal squamous cell carcinoma and this is consistent with the function of HSP47 in terms of increased cell proliferation and colony formation. (PMID:25953518)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	serpinh1b	ENSDARG00000019949
danio_rerio	serpinh1a	ENSDARG00000075954
mus_musculus	Serpinh1	ENSMUSG00000070436
rattus_norvegicus	Serpinh1	ENSRNOG00000016831

Paralogs (36): SERPINB1 (ENSG00000021355), SERPINB3 (ENSG00000057149), SERPIND1 (ENSG00000099937), SERPINA4 (ENSG00000100665), SERPINE1 (ENSG00000106366), SERPINI2 (ENSG00000114204), SERPINC1 (ENSG00000117601), SERPINA7 (ENSG00000123561), SERPINB6 (ENSG00000124570), SERPINF1 (ENSG00000132386), AGT (ENSG00000135744), SERPINE2 (ENSG00000135919), SERPINA10 (ENSG00000140093), SERPING1 (ENSG00000149131), SERPINI1 (ENSG00000163536), SERPINA12 (ENSG00000165953), SERPINB7 (ENSG00000166396), SERPINB8 (ENSG00000166401), SERPINB12 (ENSG00000166634), SERPINF2 (ENSG00000167711), SERPINA9 (ENSG00000170054), SERPINA6 (ENSG00000170099), SERPINB9 (ENSG00000170542), SERPINA11 (ENSG00000186910), SERPINA5 (ENSG00000188488), SERPINA3 (ENSG00000196136), SERPINA1 (ENSG00000197249), SERPINB2 (ENSG00000197632), SERPINB13 (ENSG00000197641), SERPINB11 (ENSG00000206072), SERPINB4 (ENSG00000206073), SERPINB5 (ENSG00000206075), HMSD (ENSG00000221887), SERPINB10 (ENSG00000242550), SERPINE3 (ENSG00000253309), SERPINA2 (ENSG00000258597)

Protein

Protein identifiers

Serpin H1 — P50454 (reviewed: P50454)

Alternative names: 47 kDa heat shock protein, Arsenic-transactivated protein 3, Cell proliferation-inducing gene 14 protein, Collagen-binding protein, Rheumatoid arthritis-related antigen RA-A47

All UniProt accessions (13): P50454, E9PIG2, E9PJH8, E9PK86, E9PKH2, E9PLA6, E9PMI5, E9PNX1, E9PPV6, E9PQ34, E9PR70, E9PRS3, H0YEP8

UniProt curated annotations — full annotation on UniProt →

Function. Binds specifically to collagen. Could be involved as a chaperone in the biosynthetic pathway of collagen.

Subcellular location. Endoplasmic reticulum lumen.

Disease relevance. Osteogenesis imperfecta 10 (OI10) [MIM:613848] A form of osteogenesis imperfecta, a disorder of bone formation characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI10 is an autosomal recessive form characterized by multiple bone deformities and fractures, generalized osteopenia, dentinogenesis imperfecta, and blue sclerae. The disease is caused by variants affecting the gene represented in this entry.

Induction. By heat shock.

Polymorphism. A functional SNP in the promoter of SERPINH1 is associated in African Americans with an increased risk for preterm premature rupture of membranes (PPROM) [MIM:610504]. PPROM is defined as rupture of the membranes before 37 weeks of gestation. SERPINH1 with the -656 T allele displays significantly reduced promoter activity compared to the major -656 C allele. Prematurity is correlated with an increased frequency of the -656 T allele.

Similarity. Belongs to the serpin family.

RefSeq proteins (2): NP_001193943, NP_001226* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000215	Serpin_fam	Family
IPR023795	Serpin_CS	Conserved_site
IPR023796	Serpin_dom	Domain
IPR033830	Serpin_H1_serpin_dom	Domain
IPR036186	Serpin_sf	Homologous_superfamily
IPR042178	Serpin_sf_1	Homologous_superfamily
IPR042185	Serpin_sf_2	Homologous_superfamily

Pfam: PF00079

UniProt features (25 total): sequence conflict 12, modified residue 5, glycosylation site 2, sequence variant 2, signal peptide 1, chain 1, short sequence motif 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50454-F1	91.71	0.87

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): 377–378 (reactive bond homolog)

Post-translational modifications (5): 94, 141, 207, 296, 319

Glycosylation sites (2): 125, 120

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-3371511	HSF1 activation
R-HSA-3371568	Attenuation phase
R-HSA-3371571	HSF1-dependent transactivation
R-HSA-1474244	Extracellular matrix organization
R-HSA-1474290	Collagen formation

MSigDB gene sets: 404 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, SHEPARD_CRASH_AND_BURN_MUTANT_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GNF2_PTX3, DARWICHE_PAPILLOMA_PROGRESSION_RISK, GOBP_CHONDROCYTE_DEVELOPMENT, chr11q13, BROWNE_HCMV_INFECTION_48HR_DN, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP

GO Biological Process (5): chondrocyte development involved in endochondral bone morphogenesis (GO:0003433), response to unfolded protein (GO:0006986), collagen fibril organization (GO:0030199), collagen biosynthetic process (GO:0032964), protein maturation (GO:0051604)

GO Molecular Function (5): RNA binding (GO:0003723), serine-type endopeptidase inhibitor activity (GO:0004867), collagen binding (GO:0005518), obsolete unfolded protein binding (GO:0051082), protein binding (GO:0005515)

GO Cellular Component (7): obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), extracellular matrix (GO:0031012), membrane raft (GO:0045121), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Cellular response to heat stress	3
Collagen formation	1
HSF1-dependent transactivation	1
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
intracellular membrane-bounded organelle	2
chondrocyte development	1
chondrocyte differentiation involved in endochondral bone morphogenesis	1
endochondral bone morphogenesis	1
response to topologically incorrect protein	1
extracellular matrix organization	1
biosynthetic process	1
collagen metabolic process	1
gene expression	1
protein metabolic process	1
nucleic acid binding	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
protein-containing complex binding	1
binding	1
endomembrane system	1
endoplasmic reticulum	1
intracellular organelle lumen	1
external encapsulating structure	1
membrane microdomain	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

317 interactions, top by confidence:

A	B	Type	Score
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SH3KBP1	USP27X	psi-mi:“MI:0914”(association)	0.640
PSMD2	SERPINH1	psi-mi:“MI:0915”(physical association)	0.610
SERPINH1	AK2	psi-mi:“MI:0915”(physical association)	0.560
SERPINH1	CDH1	psi-mi:“MI:0915”(physical association)	0.560
SERPINH1	CSNK1D	psi-mi:“MI:0915”(physical association)	0.560
DNASE1L1	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
ETS2	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
SERPINH1	IDH1	psi-mi:“MI:0915”(physical association)	0.560
SERPINH1	ITGAV	psi-mi:“MI:0915”(physical association)	0.560
KEL	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
SERPINH1	PTN	psi-mi:“MI:0915”(physical association)	0.560
RAPSN	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
RPL37A	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
SERPINH1	SGCA	psi-mi:“MI:0915”(physical association)	0.560
SUV39H1	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
YY1	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
PCSK7	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
SIGMAR1	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
SNRNP35	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
KLK8	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
BAHD1	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
SERBP1	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560
ARFGAP3	SERPINH1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (388): SERPINH1 (Affinity Capture-MS), SERPINH1 (Affinity Capture-MS), SERPINH1 (Affinity Capture-MS), SERPINH1 (Affinity Capture-MS), SERPINH1 (Affinity Capture-MS), SERPINH1 (Affinity Capture-MS), CFL1 (Co-fractionation), SERPINH1 (Co-fractionation), SERPINH1 (Co-fractionation), SERPINH1 (Co-fractionation), SERPINH1 (Co-fractionation), SERPINH1 (Co-fractionation), SERPINH1 (Co-fractionation), SERPINH1 (Affinity Capture-MS), SERPINH1 (Affinity Capture-MS)

ESM2 similar proteins: A0A090BX51, A0A0K8RCY5, A0A0K8RJ89, A0A0K8RJV9, A0A7H0DNF9, O75635, P01008, P07092, P07093, P07385, P0DSW3, P0DSW4, P12393, P13731, P13909, P14754, P15059, P20961, P22777, P22922, P29457, P32261, P32262, P41361, P42926, P50449, P50454, P68565, P68566, P79335, P80034, Q00387, Q03383, Q06B72, Q06B74, Q06B75, Q07235, Q0E8C8, Q27085, Q27086

Diamond homologs: A9RA96, B3RFC3, O00394, O02739, O08800, P01010, P01013, P05154, P05619, P12725, P13731, P19324, P29457, P30740, P34955, P35237, P38029, P48594, P50452, P50453, P50454, P80229, Q1JPB0, Q2KJH6, Q4G075, Q4R3G2, Q52L45, Q5BIR5, Q5I0S8, Q5R899, Q5RBS3, Q5RCW5, Q5SV42, Q60854, Q64118, Q8VHP7, Q9D154, A5PJK0, Q7XMK0, B0CMB0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 138 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
Defective CFTR causes cystic fibrosis	6	13.1×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
tricarboxylic acid cycle	5	21.1×	2e-03
ERAD pathway	8	12.0×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	1
Uncertain significance	153
Likely benign	82
Benign	18

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
2755357	NM_001235.5(SERPINH1):c.184C>T (p.Gln62Ter)	Pathogenic
2867184	NM_001235.5(SERPINH1):c.974del (p.Gly325fs)	Pathogenic
30141	NM_001235.5(SERPINH1):c.233T>C (p.Leu78Pro)	Pathogenic
3681612	NM_001235.5(SERPINH1):c.954+1G>T	Pathogenic
3710879	NM_001235.5(SERPINH1):c.866del (p.Gln289fs)	Pathogenic
4711331	NM_001235.5(SERPINH1):c.321_340del (p.His108fs)	Pathogenic
4714363	NM_001235.5(SERPINH1):c.454C>T (p.Gln152Ter)	Pathogenic
4727844	NM_001235.5(SERPINH1):c.405C>G (p.Tyr135Ter)	Pathogenic
599349	NM_001235.5(SERPINH1):c.1233dup (p.Asp412Ter)	Pathogenic
8664	NC_000011.10:g.75561608C>T	Pathogenic
591550	NM_001235.5(SERPINH1):c.436T>C (p.Phe146Leu)	Likely pathogenic

SpliceAI

862 predictions. Top by Δscore:

Variant	Effect	Δscore
11:75566920:G:GT	donor_gain	1.0000
11:75566967:CAAGC:C	donor_gain	1.0000
11:75566968:AAGC:A	donor_gain	1.0000
11:75566969:AGC:A	donor_gain	1.0000
11:75566970:GC:G	donor_gain	1.0000
11:75566970:GCG:G	donor_gain	1.0000
11:75566972:G:GG	donor_gain	1.0000
11:75568723:A:AG	acceptor_gain	1.0000
11:75568724:A:G	acceptor_gain	1.0000
11:75568727:A:AG	acceptor_gain	1.0000
11:75568728:C:G	acceptor_gain	1.0000
11:75568728:CA:C	acceptor_loss	1.0000
11:75568729:A:AG	acceptor_gain	1.0000
11:75568730:G:GT	acceptor_gain	1.0000
11:75568730:GC:G	acceptor_gain	1.0000
11:75568730:GCA:G	acceptor_gain	1.0000
11:75568730:GCAC:G	acceptor_gain	1.0000
11:75568730:GCACA:G	acceptor_gain	1.0000
11:75568825:GACAG:G	donor_gain	1.0000
11:75568828:AGG:A	donor_loss	1.0000
11:75568830:G:GG	donor_gain	1.0000
11:75568830:GT:G	donor_loss	1.0000
11:75568831:T:G	donor_loss	1.0000
11:75568937:A:AC	acceptor_loss	1.0000
11:75568937:A:AG	acceptor_gain	1.0000
11:75568937:AG:A	acceptor_gain	1.0000
11:75568938:G:GT	acceptor_gain	1.0000
11:75568938:GG:G	acceptor_gain	1.0000
11:75568938:GGC:G	acceptor_gain	1.0000
11:75568938:GGCC:G	acceptor_gain	1.0000

AlphaMissense

2736 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:75568736:T:A	W210R	0.999
11:75568736:T:C	W210R	0.999
11:75568748:T:C	F214L	0.999
11:75568749:T:C	F214S	0.999
11:75568750:C:A	F214L	0.999
11:75568750:C:G	F214L	0.999
11:75568778:T:C	F224L	0.999
11:75568780:C:A	F224L	0.999
11:75568780:C:G	F224L	0.999
11:75568824:G:C	R239P	0.999
11:75568738:G:C	W210C	0.998
11:75568738:G:T	W210C	0.998
11:75568749:T:G	F214C	0.998
11:75568779:T:C	F224S	0.998
11:75569122:T:A	V302D	0.998
11:75569130:T:C	S305P	0.998
11:75569017:T:C	L267P	0.997
11:75572040:G:C	R405P	0.997
11:75569128:T:A	I304N	0.996
11:75566747:G:C	R133P	0.995
11:75566877:G:C	W176C	0.995
11:75566877:G:T	W176C	0.995
11:75568779:T:G	F224C	0.995
11:75568820:C:G	H238D	0.995
11:75571971:T:C	F382S	0.995
11:75571982:C:G	H386D	0.995
11:75571988:T:C	F388L	0.995
11:75571990:C:A	F388L	0.995
11:75571990:C:G	F388L	0.995
11:75572036:G:T	G404W	0.995

dbSNP variants (sampled 300 via entrez): RS1000791255 (11:75564977 A>T), RS1001116629 (11:75570643 G>A), RS1002002727 (11:75562548 C>T), RS1002597677 (11:75567285 C>T), RS1002676364 (11:75561828 A>G), RS1002749484 (11:75573106 T>C), RS1002804662 (11:75567714 G>A), RS1002934246 (11:75567052 C>T), RS1002995931 (11:75561643 C>A,T), RS1003110123 (11:75561972 G>A,T), RS1003811995 (11:75571618 G>C), RS1003999483 (11:75560340 G>A), RS1004009425 (11:75566057 A>G), RS1004083264 (11:75563205 G>A), RS1004546231 (11:75564481 A>T)

Disease associations

OMIM: gene MIM:600943 | disease phenotypes: MIM:613848, MIM:166200, MIM:610504

GenCC curated gene-disease

Disease	Classification	Inheritance
osteogenesis imperfecta type 10	Strong	Autosomal recessive
osteogenesis imperfecta type 3	Supportive	Autosomal dominant

Mondo (4): osteogenesis imperfecta type 10 (MONDO:0013459), osteogenesis imperfecta (MONDO:0019019), preterm premature rupture of the membranes (MONDO:0012511), osteogenesis imperfecta type 3 (MONDO:0009804)

Orphanet (1): Osteogenesis imperfecta (Orphanet:666)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000272	Malar flattening
HP:0000325	Triangular face
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000586	Shallow orbits
HP:0000592	Blue sclerae
HP:0000703	Dentinogenesis imperfecta
HP:0000774	Narrow chest
HP:0000787	Nephrolithiasis
HP:0000883	Thin ribs
HP:0000885	Broad ribs
HP:0000926	Platyspondyly
HP:0000938	Osteopenia
HP:0001290	Generalized hypotonia
HP:0001382	Joint hypermobility
HP:0001620	Abnormally high-pitched voice
HP:0001788	Premature rupture of membranes
HP:0002021	Pyloric stenosis
HP:0002098	Respiratory distress
HP:0002650	Scoliosis
HP:0002753	Thin bony cortex
HP:0002761	Generalized joint hypermobility
HP:0002857	Genu valgum
HP:0002943	Thoracic scoliosis
HP:0002953	Vertebral compression fracture
HP:0002982	Tibial bowing
HP:0002983	Micromelia

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST000817_191	Height	4.000000e-13
GCST001290_5	Height	2.000000e-09
GCST002647_43	Height	2.000000e-23
GCST002702_63	Height	1.000000e-16
GCST004067_93	Hip circumference adjusted for BMI	1.000000e-08
GCST004212_27	Height	2.000000e-08
GCST004562_242	Waist circumference adjusted for body mass index	2.000000e-06
GCST004562_39	Waist circumference adjusted for body mass index	6.000000e-09
GCST004563_125	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	1.000000e-08
GCST004563_204	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	2.000000e-06
GCST004564_136	Waist circumference adjusted for BMI in active individuals	1.000000e-06
GCST004564_137	Waist circumference adjusted for BMI in active individuals	3.000000e-08
GCST005194_156	Coronary artery disease	4.000000e-09
GCST005195_6	Coronary artery disease	5.000000e-11
GCST005196_52	Coronary artery disease	2.000000e-10
GCST008163_543	Height	3.000000e-10
GCST008839_426	Height	2.000000e-08
GCST008839_480	Height	1.000000e-29
GCST010866_83	Coronary artery disease	3.000000e-12
GCST011365_105	Myocardial infarction	1.000000e-07
GCST012226_306	Waist circumference adjusted for body mass index	2.000000e-15
GCST012227_678	Hip circumference adjusted for BMI	1.000000e-08
GCST012227_679	Hip circumference adjusted for BMI	3.000000e-17
GCST90013466_11	Height	3.000000e-34
GCST90013466_46	Height	4.000000e-15
GCST90013467_17	Height	2.000000e-06
GCST90013468_10	Height	2.000000e-10
GCST90020024_417	A body shape index	2.000000e-09
GCST90020028_1898	Hip circumference adjusted for BMI	3.000000e-14
GCST90020029_242	Waist circumference adjusted for body mass index	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference
EFO:0008002	physical activity measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D010013	Osteogenesis Imperfecta	C05.116.099.708.685; C16.320.737; C17.300.200.540
C536044	Osteogenesis imperfecta, type 3 (supp.)
C563032	Preterm Premature Rupture of the Membranes (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5286 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.51	IC50	3100	nM	CHEMBL371508
5.20	IC50	6300	nM	CHEMBL195530

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
methyl (2R)-6-chloro-2-oxo-3H-1,2lambda4,3-benzodithiazole-4-carboxylate	241840: Inhibitory concentration against Hsp47 collagen chaperone in turbidity assay	ic50	3.1000	uM
2-[2-(4-chloro-3-methylphenyl)-2-oxoethyl]sulfanyl-6-oxo-4-thiophen-2-yl-1H-pyrimidine-5-carbonitrile	241840: Inhibitory concentration against Hsp47 collagen chaperone in turbidity assay	ic50	6.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	7
sodium arsenite	affects cotreatment, increases expression	4
bisphenol A	decreases expression, increases expression	3
cobaltous chloride	increases expression, decreases expression, decreases reaction, increases chemical synthesis	3
Tobacco Smoke Pollution	increases expression, affects expression	3
Cyclosporine	decreases expression, increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	2
Resveratrol	affects secretion, decreases expression	2
Zoledronic Acid	increases expression	2
Carbon Tetrachloride	increases expression	2
Doxorubicin	increases expression	2
Nickel	increases expression	2
Oxygen	decreases reaction, increases expression	2
Silver	increases expression	2
Tretinoin	affects cotreatment, increases expression, decreases expression	2
Zinc	decreases expression, affects cotreatment, increases expression	2
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
lead acetate	affects cotreatment, increases expression	1
sodium arsenate	decreases expression	1
titanium dioxide	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
nickel sulfate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
SB 203580	decreases reaction, increases expression, decreases expression	1
chloropicrin	increases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL833481	Binding	Inhibitory concentration against Hsp47 collagen chaperone in turbidity assay	Identification of small molecule chemical inhibitors of the collagen-specific chaperone Hsp47. — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1YX	Abcam A-549 SERPINH1 KO	Cancer cell line	Male
CVCL_D2CY	Abcam HCT 116 SERPINH1 KO	Cancer cell line	Male
CVCL_TK66	HAP1 SERPINH1 (-) 1	Cancer cell line	Male
CVCL_XS59	HAP1 SERPINH1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00131469	PHASE4	COMPLETED	Study of Teriparatide (FORTEO) to Treat Adults With Osteogenesis Imperfecta
NCT00159419	PHASE4	COMPLETED	Bisphosphonate Therapy for Osteogenesis Imperfecta
NCT01713231	PHASE4	COMPLETED	Effect of High-Dose Vitamin D on Bone Density in Osteogenesis Imperfecta
NCT02303873	PHASE4	COMPLETED	Efficacy and Safety of Alendronate in Chinese Children or Adolescents With Osteogenesis Imperfecta
NCT03735537	PHASE4	COMPLETED	Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
NCT04152551	PHASE4	RECRUITING	Effects of Bisphosphonates on OI-Related Hearing Loss
NCT05322252	PHASE4	COMPLETED	Simultaneous Mifepristone and Misoprostol Versus Misoprostol Alone for Induction of Labor of Nonviable Second Trimester Pregnancy: a Pilot Randomized Controlled Trial
NCT00001305	PHASE3	COMPLETED	Growth Hormone Therapy in Osteogenesis Imperfecta
NCT00005901	PHASE3	COMPLETED	Pamidronate to Treat Osteogenesis Imperfecta in Children
NCT00106028	PHASE3	COMPLETED	Safety and Efficacy of Risedronate in the Treatment of Osteogenesis Imperfecta in Children
NCT00982124	PHASE3	COMPLETED	An Efficacy and Safety Trial of Intravenous Zoledronic Acid in Infants Less Than One Year of Age, With Severe Osteogenesis Imperfecta
NCT02352753	PHASE3	TERMINATED	Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI
NCT03638128	PHASE3	TERMINATED	Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta
NCT05768854	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab vs Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta
NCT05972551	PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate Efficacy and Safety of Romosozumab Compared With Bisphosphonates in Children and Adolescents With Osteogenesis Imperfecta
NCT06636071	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab in Pediatric Japanese Subjects With Osteogenesis Imperfecta
NCT07366086	PHASE3	RECRUITING	Pediatric Safety Follow-up Study of Prior Treatment With Romosozumab for Osteogenesis Imperfecta
NCT01401179	PHASE3	COMPLETED	Antibiotics Study in Preterm Premature Rupture of the Membranes
NCT03118570	PHASE2	COMPLETED	A Study in Adult Patients With Type I, III or IV Osteogenesis Imperfecta Treated With BPS804
NCT00063479	PHASE2	COMPLETED	Bisphosphonate Treatment of Osteogenesis Imperfecta
NCT00131118	PHASE2	COMPLETED	Zoledronic Acid in Children (1 -17 Years) With Severe Osteogenesis Imperfecta
NCT01417091	PHASE2	COMPLETED	Safety, Pharmacokinetics and Pharmacodynamics of BPS804 in Osteogenesis Imperfecta
NCT01679080	PHASE2	TERMINATED	The Effect of Treatment With Teriparatide and Zoledronic Acid in Patients With Osteogenesis Imperfecta
NCT01799798	PHASE2	COMPLETED	Translational Therapy in Patients With Osteogenesis Imperfecta - A Pilot Trial on Treatment With the Rankl-Antibody Denosumab
NCT03208582	PHASE2	COMPLETED	Do Bisphosphonates Alter the Skeletal Response to Mechanical Stimulation in Children With Osteogenesis Imperfecta?
NCT03216486	PHASE2	WITHDRAWN	An Exploratory Study of BPS804 Treatment in Adult Patients With Type I, III or IV Osteogenesis Imperfecta
NCT05312697	PHASE2	TERMINATED	Long-term Extension Study of Setrusumab in Adults With Type I, III, or IV Osteogenesis Imperfecta
NCT07062588	PHASE2	RECRUITING	Osteogenesis Imperfecta Trial of AGA2115 for ADUlts With COL1A1 and/or COL1A2 GeNetic Variations (IDUN)
NCT07557446	PHASE2	NOT_YET_RECRUITING	A Dose REgimen-Finding Study of AGA2115 in Chinese Patients With Osteogenesis ImpeRfecta (EIR)
NCT01061099	PHASE1	COMPLETED	Repeated Infusions of Mesenchymal Stromal Cells in Children With Osteogenesis Imperfecta
NCT00705120	PHASE1	COMPLETED	Treatment of Severe Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation
NCT02172885	PHASE1	COMPLETED	Mesenchymal Stem Cell Based Therapy for the Treatment of Osteogenesis Imperfecta
NCT03064074	PHASE1	COMPLETED	Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta
NCT04545554	PHASE1	COMPLETED	Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta
NCT05231668	PHASE1	TERMINATED	Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI)
NCT06086613	PHASE1	COMPLETED	A First-in-Human Study Evaluating AGA2115 in Adult Healthy Volunteers
NCT05559801	PHASE1/PHASE2	NOT_YET_RECRUITING	Mesenchymal Cell Therapy in Osteogenesis Imperfecta (OI)
NCT05125809	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab vs Placebo for Osteogenesis Imperfecta
NCT03706482	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Boost Brittle Bones Before Birth
NCT04623606	PHASE1/PHASE2	UNKNOWN	Boost to Brittle Bones - Stem Cell Transplantation for Treatment of Brittle Bones