SERPINA6

Summary

SERPINA6 (serpin family A member 6, HGNC:1540) is a protein-coding gene on chromosome 14q32.13, encoding Corticosteroid-binding globulin (P08185). Major transport protein for glucocorticoids and progestins in the blood of almost all vertebrate species.

This gene encodes an alpha-globulin protein with corticosteroid-binding properties. This is the major transport protein for glucorticoids and progestins in the blood of most vertebrates. The gene localizes to a chromosomal region containing several closely related serine protease inhibitors which may have evolved by duplication events.

Source: NCBI Gene 866 — RefSeq curated summary.

At a glance

• Gene–disease (curated): corticosteroid-binding globulin deficiency (Strong, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 83 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 13
• Druggable target: yes — 16 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001756

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1540
Approved symbol	SERPINA6
Name	serpin family A member 6
Location	14q32.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170099
Ensembl biotype	protein_coding
OMIM	122500
Entrez	866

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 nonsense_mediated_decay

ENST00000341584, ENST00000555056, ENST00000557225, ENST00000874317, ENST00000874318, ENST00000874319, ENST00000874320, ENST00000874321

RefSeq mRNA: 1 — MANE Select: NM_001756 NM_001756

CCDS: CCDS9924

Canonical transcript exons

ENST00000341584 — 5 exons

Exon	Start	End
ENSE00001011206	94304248	94304603
ENSE00001384926	94314036	94314667
ENSE00002502468	94323267	94323336
ENSE00003654268	94306071	94306218
ENSE00003662159	94309736	94310006

Expression profiles

Bgee: expression breadth broad, 61 present calls, max score 98.74.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.9234 / max 1824.3789, expressed in 90 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144688	3.6524	80
207347	0.1296	24
207348	0.1102	22
207349	0.0312	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
liver	UBERON:0002107	98.74	gold quality
right lobe of liver	UBERON:0001114	98.70	gold quality
gall bladder	UBERON:0002110	94.27	gold quality
islet of Langerhans	UBERON:0000006	83.96	gold quality
pancreas	UBERON:0001264	82.04	gold quality
body of pancreas	UBERON:0001150	81.78	gold quality
right uterine tube	UBERON:0001302	80.17	gold quality
adult mammalian kidney	UBERON:0000082	79.20	gold quality
kidney	UBERON:0002113	74.51	gold quality
metanephros cortex	UBERON:0010533	74.26	gold quality
cortex of kidney	UBERON:0001225	69.98	gold quality
fallopian tube	UBERON:0003889	68.21	gold quality
rectum	UBERON:0001052	66.66	gold quality
endocervix	UBERON:0000458	63.90	gold quality
mucosa of transverse colon	UBERON:0004991	61.46	gold quality
transverse colon	UBERON:0001157	59.22	gold quality
colonic epithelium	UBERON:0000397	57.45	gold quality
uterine cervix	UBERON:0000002	57.02	gold quality
ectocervix	UBERON:0012249	52.85	gold quality
endometrium	UBERON:0001295	51.90	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	50.22	gold quality
duodenum	UBERON:0002114	48.11	gold quality
colon	UBERON:0001155	46.26	gold quality
placenta	UBERON:0001987	46.21	gold quality
left uterine tube	UBERON:0001303	45.81	gold quality
adrenal tissue	UBERON:0018303	45.37	gold quality
vagina	UBERON:0000996	43.61	gold quality
bone marrow cell	CL:0002092	43.53	gold quality
intestine	UBERON:0000160	43.10	gold quality
fundus of stomach	UBERON:0001160	40.40	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-98	yes	761.64
E-ANND-3	yes	4.70

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXM1, HNF1A, HNF1B, NR3C1, ONECUT1

miRNA regulators (miRDB)

16 targeting SERPINA6, 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-4713-3P	100.00	65.92	505
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-432-5P	98.00	68.13	989
HSA-MIR-2467-5P	97.36	67.71	991
HSA-MIR-6515-5P	97.08	65.48	1219
HSA-MIR-514A-5P	96.94	65.49	801
HSA-MIR-134-3P	96.83	66.22	1001

Literature-anchored findings (GeneRIF, showing 40)

• findings support the hypothesis that the corticosteroid binding globulin level is an interesting indicator for both insulin resistance and low grade inflammation (PMID:12364459)
• CBG-negative preadipocytes proliferated more rapidly and showed greater peroxisome proliferator-activated receptor-gamma-mediated differentiation than normal preadipocytes. CBG was not expressed in normal human preadipocytes. (PMID:12554596)
• human Fallopian tube cells actively express and secrete a CBG-like progesterone-binding protein, which might play a role in the in vivo modulation of human sperm acrosome reaction (PMID:14871264)
• Homozygosity for the serine allele of the CBG gene may predispose to chronic fatigue syndrome, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions. (PMID:15554358)
• Circulating adiponectin, CBG concentration, and fasting cortisol were significantly interrelated in healthy subjects. A significant sexual dimorphism exists in this association. (PMID:15877287)
• We concluded that CBG gene polymorphisms might modulate the influence of the HPA axis on the fat mass distribution in obese women. (PMID:16222046)
• To the best of our knowledge, this case represents the first de novo mutation reported for corticosteroid-binding globulin deficiency, implicating a pathogenic role of variants of SERPINA6 in some cases of muscle fatigue. (PMID:17245537)
• A mechanism for the effect of CBG mutations on fatigue is not readily apparent because free cortisol levels are normal. (PMID:17547679)
• The crystal structures of cleaved human CBG (cCBG) at 1.8-A resolution and its complex with cortisol at 2.3-A resolution, is reported. (PMID:18513745)
• several substitutions (E334A, V336R, G340S, and T342P) increased the steroid binding affinities of human CBG even before elastase cleavage (PMID:19011238)
• Results describe the expression of corticosteroid-binding globulin (CBG) in the low-grade malignant human astrocytoma cell line 1321N1. (PMID:19172388)
• Effect of mutations of SERPINA6 on cortisol-binding, and thermal and protease sensitivity are reported. (PMID:20226861)
• SHBG, CBG and total cortisol and free plasma cortisol were measured and to investigate whether or not these analytes correlated with the degree of insulin resistance and the presence of the metabolic syndrome. (PMID:20354921)
• Plasma cortisol responses attenuated more rapidly in the able-bodied men, compared to spinal cord-injured subjects, due to significant rise in circulating corticosteroid-binding globulin. (PMID:20839151)
• Allosteric modulation of hormone release from thyroxine and corticosteroid-binding globulins. (PMID:21325280)
• N-glycans are involved in the CBG:receptor interaction and indicates that the modulation is performed by steric and/or electrostatic means through the terminal neuraminic acid residues. (PMID:21558494)
• Data show thatin chronic hepatitis C patients, IL28B polymorphism was associated with serum levels of corticosteroid binding globulin, a major transporter of cortisol. (PMID:21750736)
• CBG influences the endocrine and neurobehavioral response to stress, including the development of pain/fatigue syndromes (PMID:21795453)
• We found that polymorphisms in SLC6A4, TPH2, and SERPINA6 appear to be maternal factors increasing the risk of having a child with facial clefts. (PMID:22072571)
• investigation of physicochemical, electronic, and structural requirements for selective and effective binding of steroids (many are endogenous steroid metabolites) to CBG and SHBG active/ligand-binding sites (PMID:22242800)
• genetic association studies in Chinese populations: Data suggest that SERPINA6 with SNP (A51V) is poorly produced/secreted; plasma corticosteroid-binding globulin levels in heterozygous subjects for this variant are 50% lower than in normal subjects. (PMID:22337907)
• The influence of glucocorticoid receptor and corticosteroid-binding globulin gene polymorphisms in obesity and/or cortisol action in prepubertal obese children. (PMID:22576823)
• three polymorphisms, -26 C/G, -54 C/T, and -144 G/C located close to the putative hepatic nuclear factor (HNF) 1 binding elements, altered the transactivation effect of HNF1beta (PMID:22932886)
• Atomic interactions observed between progesterone and CBG explain the lower affinity of progesterone in comparison to corticosteroids. (PMID:23300763)
• CBG is coexpressed with hypothalamic neuropeptides.CBG may be involved in control of systemic and central stress response. (PMID:24246737)
• genetic variation in the SERPINA6 gene may be associated with altered CBG levels during adolescence. (PMID:24691024)
• Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants (PMID:25010111)
• SERPINA6-rs1998056 regulated by FOXA/ERalpha might be associated with female HCC risk (PMID:25198130)
• Human cardiomyocytes express mineralocorticoid receptors, but are mostly free of nuclear glucocorticoid receptors. CBG is expressed in myocardium and in Purkinje fibers. CBG in heart is colocalized with mineralocorticoid receptor. (PMID:25251318)
• 8 naturally occurring CBG mutants with abnormalities in cortisol-binding affinity, cortisol-binding capacity, production/secretion, sensitivity to proteolytic cleavage of the reactive center loop, or recognition by monoclonal antibodies used for ELISAs were identified (PMID:25322275)
• the results suggest that DEX repression of Corticosteroid-binding globulin involves tethering of the glucocorticoid receptor to C/EBPb. (PMID:25335188)
• The study investigate the half-life of intact and elastase cleaved CBG in the rabbit. The half-lives of intact and cleaved human CBG are 10 h and identical. (PMID:25636722)
• Data indicate there was no significant circadian variation in serum cortisol-binding globulin (CBG) concentration in any of the 4 groups. (PMID:26603673)
• The results suggest reduced CBG cleavage in central obesity, possibly contributing to the characteristic inflammatory phenotype of the central obesity and metabolic syndrome. (PMID:27300474)
• In conclusion, site-specific CBG N-glycosylation regulates the bioavailability of cortisol in inflamed environments by fine-tuning the RCL proteolysis by endogenous and exogenous elastases. (PMID:27339896)
• Corticosteroid-binding globulin cleavage may be pathogen-dependent in bloodstream infection (PMID:27887960)
• Data suggest that some individuals with adrenal insufficiency due to SERPINA6 mutations present with hypotension or nonspecific symptoms such as fatigue, nausea, or chronic pain, but symptomatology varies widely, even between family members with identical mutations. [REVIEW] (PMID:29194043)
• N-glycans at other sites also appear to protect CBG from neutrophil elastase or chymotrypsin. (PMID:29273683)
• We generated weighted polygenic risk score (PRS) based on 6 genome-wide significant SNPs (rs11621961, rs11629171, rs7161521, rs2749527, rs3762132, rs4900229). salivary cortisol increased in the high PRS group. It remained unchanged in low PRS group. These results were mainly driven by minor alleles of rs7161521 (SERPINA6) and rs4900229 (SERPINA1). (PMID:29679879)
• Low circulating haCBG concentrations are associated with mortality in septic shock (PMID:30160799)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Serpina6	ENSMUSG00000060807
rattus_norvegicus	Serpina6	ENSRNOG00000009438

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), SERPINH1 (ENSG00000149257), SERPINI1 (ENSG00000163536), SERPINA12 (ENSG00000165953), SERPINB7 (ENSG00000166396), SERPINB8 (ENSG00000166401), SERPINB12 (ENSG00000166634), SERPINF2 (ENSG00000167711), SERPINA9 (ENSG00000170054), 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

Corticosteroid-binding globulin — P08185 (reviewed: P08185)

Alternative names: Serpin A6, Transcortin

All UniProt accessions (3): P08185, G3V350, G3V4V7

UniProt curated annotations — full annotation on UniProt →

Function. Major transport protein for glucocorticoids and progestins in the blood of almost all vertebrate species.

Subcellular location. Secreted.

Tissue specificity. Plasma; synthesized in liver. Has also been identified in a number of glycocorticoid responsive cells.

Post-translational modifications. N-glycosylated; binds 5 oligosaccharide chains. Glycosylation in position Asn-260 is needed for steroid binding.

Disease relevance. Corticosteroid-binding globulin deficiency (CBG deficiency) [MIM:611489] Extremely rare hereditary disorder characterized by reduced corticosteroid-binding capacity with normal or low plasma corticosteroid-binding globulin concentration, and normal or low basal cortisol levels associated with hypo/hypertension and muscle fatigue. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Proteolytic cleavage leads to an important conformation change. This reduces the affinity for steroids.

Similarity. Belongs to the serpin family.

RefSeq proteins (1): NP_001747* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF00079

UniProt features (51 total): strand 18, helix 12, glycosylation site 6, turn 5, binding site 4, sequence variant 3, signal peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4C41	X-RAY DIFFRACTION	1.8
2VDX	X-RAY DIFFRACTION	1.84
2VDY	X-RAY DIFFRACTION	2.3
4BB2	X-RAY DIFFRACTION	2.48
4C49	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08185-F1	86.77	0.74

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): 250 (conserved cysteine within steroid binding domain)

Ligand- & substrate-binding residues (4): 254; 286; 390; 393

Glycosylation sites (6): 260, 330, 369, 31, 96, 176

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-194002	Glucocorticoid biosynthesis
R-HSA-9757110	Prednisone ADME
R-HSA-1430728	Metabolism
R-HSA-196071	Metabolism of steroid hormones
R-HSA-556833	Metabolism of lipids
R-HSA-8957322	Metabolism of steroids
R-HSA-9748784	Drug ADME

MSigDB gene sets: 141 (showing top): MODULE_52, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_GLUCOCORTICOID_METABOLIC_PROCESS, GNF2_HPN, HNF1_Q6, MODULE_404, LEE_LIVER_CANCER_CIPROFIBRATE_DN, STOSSI_RESPONSE_TO_ESTRADIOL, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, SMID_BREAST_CANCER_LUMINAL_B_UP, HSIAO_LIVER_SPECIFIC_GENES, GOBP_STEROID_BIOSYNTHETIC_PROCESS, GOBP_GLUCOCORTICOID_BIOSYNTHETIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GNF2_HPX

GO Biological Process (2): glucocorticoid biosynthetic process (GO:0006704), glucocorticoid metabolic process (GO:0008211)

GO Molecular Function (4): serine-type endopeptidase inhibitor activity (GO:0004867), steroid binding (GO:0005496), molecular carrier activity (GO:0140104), lipid binding (GO:0008289)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Metabolism of steroid hormones	1
Drug ADME	1
Metabolism of steroids	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
glucocorticoid metabolic process	1
steroid hormone biosynthetic process	1
steroid metabolic process	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
lipid binding	1
molecular_function	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

1052 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SERPINA6	SHBG	P04278	952
SERPINA6	ALB	P02768	825
SERPINA6	NR3C1	P04150	725
SERPINA6	TRPV1	Q8NER1	721
SERPINA6	POMC	P01189	720
SERPINA6	GPR55	Q9Y2T6	705
SERPINA6	CNR1	P21554	696
SERPINA6	TRPV2	Q9Y5S1	684
SERPINA6	HSD11B2	P80365	654
SERPINA6	NR2F1	P10589	648
SERPINA6	NR3C2	P08235	638
SERPINA6	HTR1A	P08908	613
SERPINA6	TTR	P02766	609
SERPINA6	CRH	P06850	601
SERPINA6	HSD11B1	P28845	593

IntAct

7 interactions, top by confidence:

A	B	Type	Score
SERPINA6	COCH	psi-mi:“MI:0914”(association)	0.530
IPO5	SLC27A2	psi-mi:“MI:0914”(association)	0.530
SERPINA6	METRN	psi-mi:“MI:0915”(physical association)	0.400
UBE2U	IGLL5	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): P3H4 (Affinity Capture-MS), COCH (Affinity Capture-MS), PAM (Affinity Capture-MS), COL4A2 (Affinity Capture-MS), SERPINF1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), WRB (Affinity Capture-MS), HLA-DPB1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), COCH (Affinity Capture-MS), PAM (Affinity Capture-MS), PAM (Affinity Capture-MS), SERPINF1 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), COCH (Affinity Capture-MS)

ESM2 similar proteins: A2I7M9, A2I7N0, A2I7N1, A2I7N2, A2I7N3, A6QPQ2, B2D1U1, E1BF81, O54762, P01011, P05154, P05544, P05545, P07759, P08185, P09006, P22323, P22324, P22325, P22599, P26595, P29621, P29622, P31211, P50451, P70458, Q00896, Q00897, Q00898, Q03044, Q03734, Q3ZEJ6, Q5I2A0, Q5R536, Q5R9E3, Q5RCR2, Q60396, Q63556, Q63969, Q64118

Diamond homologs: A0A090BX51, A0A0K8RCY5, A0A0K8RJ89, A0A0K8RJV9, A2I7M9, A2I7N0, A2I7N1, A2I7N2, A2I7N3, A5PJK0, A6QPQ2, A9RA96, B0CMB0, B1MTC3, B2KI30, B3RFC3, B4USX2, O02739, O08800, O35684, O54757, O54758, O54759, O54760, O73790, O75830, P01008, P01011, P05120, P05154, P05544, P05545, P05619, P07759, P08185, P09006, P23775, P29508, P29524, P29621

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	68
Likely benign	4
Benign	5

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
16976	NM_001756.4(SERPINA6):c.32G>A (p.Trp11Ter)	Pathogenic
1077111	NM_001756.4(SERPINA6):c.164_165del (p.Val55fs)	Likely pathogenic

SpliceAI

768 predictions. Top by Δscore:

Variant	Effect	Δscore
14:94306066:TTTAC:T	donor_loss	1.0000
14:94306067:TTA:T	donor_loss	1.0000
14:94306068:TAC:T	donor_loss	1.0000
14:94306069:ACC:A	donor_loss	1.0000
14:94306070:C:A	donor_loss	1.0000
14:94306215:CTGG:C	acceptor_gain	1.0000
14:94306216:TGG:T	acceptor_gain	1.0000
14:94309732:TTA:T	donor_loss	1.0000
14:94309734:A:AC	donor_gain	1.0000
14:94309735:C:CC	donor_gain	1.0000
14:94309735:C:CG	donor_loss	1.0000
14:94309735:CCTG:C	donor_gain	1.0000
14:94304600:CCAC:C	acceptor_gain	0.9900
14:94304601:CAC:C	acceptor_gain	0.9900
14:94304601:CACC:C	acceptor_gain	0.9900
14:94304603:CCTG:C	acceptor_loss	0.9900
14:94304604:CT:C	acceptor_loss	0.9900
14:94304605:T:A	acceptor_loss	0.9900
14:94304607:T:TC	acceptor_gain	0.9900
14:94306069:A:AC	donor_gain	0.9900
14:94306070:C:CC	donor_gain	0.9900
14:94306216:TGGC:T	acceptor_loss	0.9900
14:94306217:GG:G	acceptor_gain	0.9900
14:94306219:C:CC	acceptor_gain	0.9900
14:94306219:C:G	acceptor_loss	0.9900
14:94306220:T:G	acceptor_loss	0.9900
14:94306224:C:CT	acceptor_gain	0.9900
14:94309734:AC:A	donor_gain	0.9900
14:94309734:ACCTG:A	donor_gain	0.9900
14:94309735:CC:C	donor_gain	0.9900

AlphaMissense

2690 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:94309957:G:C	F221L	0.979
14:94309957:G:T	F221L	0.979
14:94309959:A:G	F221L	0.979
14:94309758:A:G	W288R	0.975
14:94309758:A:T	W288R	0.975
14:94304487:G:C	F383L	0.974
14:94304487:G:T	F383L	0.974
14:94304489:A:G	F383L	0.974
14:94309987:A:C	F211L	0.958
14:94309987:A:T	F211L	0.958
14:94309989:A:G	F211L	0.958
14:94314442:G:C	S69R	0.956
14:94314442:G:T	S69R	0.956
14:94314444:T:G	S69R	0.956
14:94309958:A:G	F221S	0.949
14:94309872:A:G	C250R	0.946
14:94310001:A:G	W207R	0.946
14:94310001:A:T	W207R	0.946
14:94309756:C:A	W288C	0.941
14:94309756:C:G	W288C	0.941
14:94314220:G:C	F143L	0.936
14:94314220:G:T	F143L	0.936
14:94314222:A:G	F143L	0.936
14:94309870:G:C	C250W	0.932
14:94314322:G:C	F109L	0.931
14:94314322:G:T	F109L	0.931
14:94314324:A:G	F109L	0.931
14:94309865:A:G	L252P	0.929
14:94306198:G:T	P302Q	0.927
14:94314463:G:C	N62K	0.925

dbSNP variants (sampled 300 via entrez): RS1000167474 (14:94312501 C>T), RS1000197946 (14:94312308 T>C), RS1000199167 (14:94320341 G>A), RS1000254371 (14:94319074 T>A), RS1000501346 (14:94311363 A>G), RS1000778367 (14:94305010 T>G), RS1000804773 (14:94318768 T>C,G), RS1000833631 (14:94323189 A>C), RS1000847583 (14:94306491 G>T), RS1000992420 (14:94317441 T>G), RS1001031150 (14:94323424 T>C,G), RS1001170135 (14:94322143 A>G), RS1001369447 (14:94322339 T>G), RS1001407354 (14:94305948 C>G,T), RS1001798556 (14:94315482 A>G)

Disease associations

OMIM: gene MIM:122500 | disease phenotypes: MIM:611489

GenCC curated gene-disease

Disease	Classification	Inheritance
corticosteroid-binding globulin deficiency	Strong	Autosomal recessive

Mondo (1): corticosteroid-binding globulin deficiency (MONDO:0012675)

Orphanet (1): Corticosteroid-binding globulin deficiency (Orphanet:199247)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000822	Hypertension
HP:0001903	Anemia
HP:0002615	Hypotension
HP:0002900	Hypokalemia
HP:0003581	Adult onset
HP:0003750	Increased muscle fatiguability
HP:0008163	Decreased circulating cortisol level
HP:0012364	Decreased urinary potassium
HP:0012378	Fatigue
HP:0025406	Asthenia
HP:6000243	Reduced circulating corticosteroid-binding globulin concentration

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001585_36	Breast size	8.000000e-07
GCST002932_11	Manganese levels	6.000000e-06
GCST007615_38	C-reactive protein levels	1.000000e-09
GCST010243_19	Apolipoprotein B levels	4.000000e-13
GCST010245_127	LDL cholesterol levels	4.000000e-12
GCST90011898_37	Alanine aminotransferase levels	5.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2421 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

16 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,111,404 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL103	PROGESTERONE	4	162,141
CHEMBL1091	HYDROCORTISONE ACETATE	4	45,061
CHEMBL131	PREDNISOLONE	4	140,604
CHEMBL135	ESTRADIOL	4	123,080
CHEMBL1405	ESTRONE	4	36,722
CHEMBL193482	ESTRIOL	4	21,295
CHEMBL386630	TESTOSTERONE	4	129,997
CHEMBL389621	HYDROCORTISONE	4	207,645
CHEMBL90593	PRASTERONE	4	23,422
CHEMBL110739	CORTICOSTERONE	3	28,274
CHEMBL1499	CORTISONE	3	79,011
CHEMBL757	NANDROLONE	3	9,485
CHEMBL253144	CORTODOXONE	2	10,892
CHEMBL273453	ALDOSTERONE	2	50,544
CHEMBL27769	STANOLONE	2	34,222
CHEMBL253363	PREGNENOLONE	1	9,009

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10144771	SERPINA6		0.00	0

ChEMBL bioactivities

31 potent at pChembl≥5 of 31 total, top 31 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.88	Ki	13.18	nM	CORTICOSTERONE
7.88	Ki	13.18	nM	HYDROCORTISONE
7.88	Ki	13.18	nM	CORTODOXONE
7.74	Ki	18.2	nM	HYDROXYPROGESTERONE
7.69	Ki	20.42	nM	CHEMBL432825
7.65	Ki	22.39	nM	DESOXYCORTICOSTERONE
7.55	Ki	28.18	nM	HYDROCORTISONE ACETATE
7.51	Ki	30.9	nM	PREDNISOLONE
7.38	Ki	41.69	nM	PROGESTERONE
7.20	Ki	63.1	nM	CORTICOSTERONE
7.12	Ki	75.86	nM	CHEMBL433198
6.89	Ki	128.8	nM	CORTISONE
6.82	Ki	151.4	nM	CHEMBL284109
6.78	Ki	166	nM	CHEMBL284253
6.72	Ki	190.6	nM	TESTOSTERONE
6.28	Ki	524.8	nM	ALDOSTERONE
6.25	Ki	562.3	nM	CHEMBL2311120
6.14	Ki	724.4	nM	NANDROLONE
5.92	Ki	1202	nM	STANOLONE
5.80	Ki	1585	nM	CHEMBL93948
5.76	Ki	1738	nM	ANDROSTENEDIONE
5.61	Ki	2455	nM	ANDROSTERONE
5.23	Ki	5888	nM	PREGNENOLONE
5.23	Ki	5888	nM	ETIOCHOLANOLONE
5.00	Ki	1e+04	nM	ANDROSTENEDIOL
5.00	Ki	1e+04	nM	ESTRONE
5.00	Ki	1e+04	nM	ESTRIOL
5.00	Ki	1e+04	nM	HYDROXYPREGNENOLONE
5.00	Ki	1e+04	nM	PRASTERONE
5.00	Ki	1e+04	nM	ANDROSTANEDIOL
5.00	Ki	1e+04	nM	ESTRADIOL

PubChem BioAssay actives

31 with measured affinity, of 274 total; 30 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
(8R,9S,10R,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-3-one	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.0132	uM
(8S,9S,10R,11S,13S,14S,17S)-11-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.0132	uM
hydrocortisone	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.0132	uM
hydroxyprogesterone	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.0182	uM
(8S,9S,10R,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-2,10,13-trimethyl-1,2,6,7,8,9,12,14,15,16-decahydrocyclopenta[a]phenanthrene-3,11-dione	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.0204	uM
desoxycortone	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.0224	uM
Hydrocortisone Acetate	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.0282	uM
Prednisolone	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.0309	uM
Progesterone	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.0417	uM
(6S)-17-acetyl-6,10,13-trimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.0759	uM
Cortisone	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.1288	uM
(8R,9S,10R,13S,14S,17S)-17-acetyl-13-methyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.1514	uM
(8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,6,7,8,9,12,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthrene-3,11-dione	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.1660	uM
Testosterone	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.1905	uM
(8S,9S,10R,11S,13R,14S,17S)-11-hydroxy-17-(2-hydroxyacetyl)-10-methyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthrene-13-carbaldehyde	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.5248	uM
(8R,9S,10R,13S,14S,16R,17S)-17-acetyl-16,17-dihydroxy-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-3-one	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.5623	uM
(8R,9S,10R,13S,14S,17S)-17-hydroxy-13-methyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	0.7244	uM
(5S,8R,9S,10S,13S,14S,17S)-17-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	1.2023	uM
(2R,8S,9R,10S,11S,13S,14S,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-2,10,13-trimethyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	1.5849	uM
(8R,9S,10R,13S,14S)-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17-dione	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	1.7378	uM
(3R,5S,8R,9S,10S,13S,14S)-3-hydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-17-one	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	2.4547	uM
(3R,5R,8R,9S,10S,13S,14S)-3-hydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-17-one	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	5.8884	uM
1-[(3S,8S,9S,10R,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethanone	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	5.8884	uM
1-[(3R,5R,8R,9S,10S,13S,14S,17R)-3,17-dihydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-17-yl]ethanone	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	10.0000	uM
(3S,8R,9S,10R,13S,14S,17S)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3,17-diol	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	10.0000	uM
(3S,5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diol	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	10.0000	uM
Estriol	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	10.0000	uM
Estradiol	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	10.0000	uM
Estrone	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	10.0000	uM
prasterone	51055: Binding affinity to human CBG receptor (corticosteroid-binding globulins)	ki	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	4
Cyclosporine	decreases expression	4
Aflatoxin B1	affects expression, decreases expression, decreases methylation, increases expression	4
Dexamethasone	affects cotreatment, affects binding, increases activity, decreases expression, increases expression	3
bisphenol A	affects expression, decreases methylation	2
Acetaminophen	decreases expression	2
Ethinyl Estradiol	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
withaferin A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
norgestimate	affects cotreatment, increases expression	1
sodium arsenite	decreases expression	1
periodate-oxidized adenosine	affects expression	1
drospirenone	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
2,3-dimethoxy-1,4-naphthoquinone	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	decreases expression	1
Ortho Evra	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	decreases expression	1
Cadmium	decreases expression	1
Caffeine	decreases expression	1
Copper	affects binding	1
Dimethylnitrosamine	decreases expression	1
Estradiol	increases expression, increases reaction	1
Glucocorticoids	increases transport	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL665988	Binding	In silico binding affinity to human corticosteriod binding globulin	Validation of EGSITE2, a mixed integer program for deducing objective site models for experimental binding data. — J Med Chem

Clinical trials (associated diseases)

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