Glucocorticoid resistance

Summary

Glucocorticoid resistance (MONDO:0014421) is a disease caused by NR3C1 (GenCC Strong), with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include budesonide.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: NR3C1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 194
• Phenotypes (HPO): 21
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0001007	Hirsutism	Very frequent (80-99%)
HP:0003154	Increased circulating ACTH level	Very frequent (80-99%)
HP:0004319	Decreased circulating aldosterone level	Very frequent (80-99%)
HP:0012030	Increased urinary cortisol level	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0000876	Oligomenorrhea	Frequent (30-79%)
HP:0001061	Acne	Frequent (30-79%)
HP:0002900	Hypokalemia	Frequent (30-79%)
HP:0008221	Adrenal hyperplasia	Frequent (30-79%)
HP:0030087	Abnormal testosterone level	Frequent (30-79%)
HP:0200114	Metabolic alkalosis	Frequent (30-79%)
HP:0000062	Ambiguous genitalia	Occasional (5-29%)
HP:0000789	Infertility	Occasional (5-29%)
HP:0000798	Oligozoospermia	Occasional (5-29%)
HP:0000826	Precocious puberty	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0002292	Frontal balding	Occasional (5-29%)
HP:0003118	Increased circulating cortisol level	Occasional (5-29%)
HP:0010458	Female pseudohermaphroditism	Occasional (5-29%)
HP:0001297	Stroke	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glucocorticoid resistance
Mondo ID	MONDO:0014421
MeSH	C564221
OMIM	615962
Orphanet	786
ICD-11	125216923
UMLS	C1841972
MedGen	333960
GARD	0002499
Is cancer (heuristic)	no

Also known as: GCCR · glucocorticoid resistance, generalised · glucocorticoid resistance, generalized

Data availability: 194 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › glucocorticoid resistance

Related subtypes (28): cortisone reductase deficiency, familial hyperlipidemia, hypolipoproteinemia, steroid inherited metabolic disorder, corticosterone methyloxidase type 1 deficiency, lipoid proteinosis, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, vitamin D hydroxylation-deficient rickets, type 1B, mitochondrial trifunctional protein deficiency, pancreatic triacylglycerol lipase deficiency, syndromic dyslipidemia, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of plasmalogens biosynthesis, disorder of phospholipids, sphingolipids and fatty acids biosynthesis, inborn disorder of ketolysis, lysosomal lipid storage disorder, sterol metabolism disorder, disorder of sphingolipid biosynthesis, glycosylphosphatidylinositol biosynthesis defect 18, neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 55, inherited fatty acid metabolism disorder, glycosylphosphatidylinositol biosynthesis defect 16, glycosylphosphatidylinositol biosynthesis defect 15, glycosylphosphatidylinositol biosynthesis defect 17, CYP7B1-related disorder of oxysterol accumulation

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

194 retrieved; paginated sample, class counts are floors:

147 uncertain significance, 11 likely benign, 10 benign/likely benign, 8 pathogenic, 7 benign, 6 conflicting classifications of pathogenicity, 4 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
16147	NM_000176.3(NR3C1):c.1922A>T (p.Asp641Val)	NR3C1	Pathogenic	no assertion criteria provided
16148	NM_000176.3(NR3C1):c.1891_1892+2del	NR3C1	Pathogenic	no assertion criteria provided
16151	NM_000176.3(NR3C1):c.1676T>A (p.Ile559Asn)	NR3C1	Pathogenic	no assertion criteria provided
16152	NM_000176.3(NR3C1):c.2241T>G (p.Ile747Met)	NR3C1	Pathogenic	no assertion criteria provided
16155	NM_000176.3(NR3C1):c.2318T>C (p.Leu773Pro)	NR3C1	Pathogenic	no assertion criteria provided
16158	NM_000176.3(NR3C1):c.2209T>C (p.Phe737Leu)	NR3C1	Pathogenic	no assertion criteria provided
3591808	NM_000176.3(NR3C1):c.1835del (p.Ser612fs)	NR3C1	Pathogenic	criteria provided, single submitter
3591819	NM_000176.3(NR3C1):c.1405C>T (p.Arg469Ter)	NR3C1	Pathogenic	criteria provided, single submitter
2432327	NM_000176.3(NR3C1):c.1185-2A>G	NR3C1	Likely pathogenic	criteria provided, single submitter
3591801	NM_000176.3(NR3C1):c.2186T>C (p.Val729Ala)	NR3C1	Likely pathogenic	criteria provided, single submitter
3591834	NM_000176.3(NR3C1):c.678_679delinsA (p.Pro227fs)	NR3C1	Likely pathogenic	criteria provided, single submitter
4278220	NM_000176.3(NR3C1):c.2182-1G>A	NR3C1	Likely pathogenic	criteria provided, single submitter
2901555	NM_000176.3(NR3C1):c.266A>G (p.Tyr89Cys)	LOC129994918	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1143297	NM_000176.3(NR3C1):c.1082C>T (p.Ser361Phe)	NR3C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2504939	NM_000176.3(NR3C1):c.2185G>A (p.Val729Ile)	NR3C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3591814	NM_000176.3(NR3C1):c.1596G>C (p.Leu532=)	NR3C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713699	NM_000176.3(NR3C1):c.685G>A (p.Ala229Thr)	NR3C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
760048	NM_000176.3(NR3C1):c.88T>C (p.Tyr30His)	NR3C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2912076	NM_000176.3(NR3C1):c.192T>G (p.Asp64Glu)	LOC129994918	Uncertain significance	criteria provided, multiple submitters, no conflicts
351376	NM_000176.3(NR3C1):c.289G>A (p.Val97Met)	LOC129994918	Uncertain significance	criteria provided, single submitter
3591850	NM_000176.3(NR3C1):c.292A>G (p.Met98Val)	LOC129994918	Uncertain significance	criteria provided, single submitter
3591851	NM_000176.3(NR3C1):c.236C>T (p.Ser79Phe)	LOC129994918	Uncertain significance	criteria provided, single submitter
3591852	NM_000176.3(NR3C1):c.222G>T (p.Gln74His)	LOC129994918	Uncertain significance	criteria provided, single submitter
3591853	NM_000176.3(NR3C1):c.208G>C (p.Val70Leu)	LOC129994918	Uncertain significance	criteria provided, single submitter
906660	NM_001018077.1(NR3C1):c.-745C>T	LOC129994924	Uncertain significance	criteria provided, single submitter
906661	NM_001018077.1(NR3C1):c.-753G>A	LOC129994924	Uncertain significance	criteria provided, single submitter
906662	NM_001018077.1(NR3C1):c.-782G>T	LOC129994924	Uncertain significance	criteria provided, single submitter
906663	NM_001018077.1(NR3C1):c.-894T>C	LOC129994924	Uncertain significance	criteria provided, single submitter
906664	NM_001018077.1(NR3C1):c.-896A>C	LOC129994924	Uncertain significance	criteria provided, single submitter
906665	NM_001018077.1(NR3C1):c.-904G>A	LOC129994924	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NR3C1	Strong	Autosomal dominant	glucocorticoid resistance	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NR3C1	Orphanet:786	Generalized glucocorticoid resistance syndrome
NR3C1	Orphanet:96253	Cushing disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NR3C1	HGNC:7978	ENSG00000113580	P04150	Glucocorticoid receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NR3C1	Glucocorticoid receptor	Receptor for glucocorticoids (GC).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	1	385.9×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NR3C1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Glcrtcd_rcpt, Znf_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
endothelial cell	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NR3C1	302	ubiquitous	marker	endothelial cell, tibia, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NR3C1	7,511

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NR3C1	P04150	58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of NPAS4 gene transcription	1	2284.0×	0.002	NR3C1
PTK6 Expression	1	1903.3×	0.002	NR3C1
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	380.7×	0.006	NR3C1
SUMOylation of intracellular receptors	1	335.9×	0.006	NR3C1
Nuclear Receptor transcription pathway	1	200.3×	0.006	NR3C1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	193.6×	0.006	NR3C1
Regulation of RUNX2 expression and activity	1	181.3×	0.006	NR3C1
Potential therapeutics for SARS	1	114.2×	0.009	NR3C1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of glucocorticoid biosynthetic process	1	16852.0×	0.002	NR3C1
glucocorticoid metabolic process	1	2808.7×	0.003	NR3C1
mammary gland duct morphogenesis	1	2407.4×	0.003	NR3C1
nuclear receptor-mediated steroid hormone signaling pathway	1	2106.5×	0.003	NR3C1
response to cortisol	1	1685.2×	0.003	NR3C1
microglia differentiation	1	1532.0×	0.003	NR3C1
neuroinflammatory response	1	1532.0×	0.003	NR3C1
regulation of gluconeogenesis	1	1123.5×	0.003	NR3C1
maternal behavior	1	1123.5×	0.003	NR3C1
cellular response to steroid hormone stimulus	1	1053.2×	0.003	NR3C1
astrocyte differentiation	1	766.0×	0.004	NR3C1
adrenal gland development	1	674.1×	0.004	NR3C1
cellular response to glucocorticoid stimulus	1	624.1×	0.004	NR3C1
cellular response to dexamethasone stimulus	1	581.1×	0.004	NR3C1
motor behavior	1	561.7×	0.004	NR3C1
synaptic transmission, glutamatergic	1	358.6×	0.005	NR3C1
positive regulation of miRNA transcription	1	290.6×	0.006	NR3C1
cellular response to transforming growth factor beta stimulus	1	276.3×	0.006	NR3C1
positive regulation of neuron apoptotic process	1	271.8×	0.006	NR3C1
response to wounding	1	221.7×	0.007	NR3C1
chromosome segregation	1	173.7×	0.008	NR3C1
chromatin organization	1	99.1×	0.014	NR3C1
gene expression	1	79.9×	0.017	NR3C1
cell division	1	46.2×	0.028	NR3C1
regulation of DNA-templated transcription	1	31.6×	0.038	NR3C1
negative regulation of DNA-templated transcription	1	31.6×	0.038	NR3C1
apoptotic process	1	28.7×	0.040	NR3C1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.062	NR3C1
signal transduction	1	16.1×	0.067	NR3C1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.069	NR3C1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NR3C1	CANDESARTAN CILEXETIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR3C1	162	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANDESARTAN CILEXETIL	4	NR3C1
DIENESTROL	4	NR3C1
PROGESTERONE	4	NR3C1
CLOTRIMAZOLE	4	NR3C1
SIMVASTATIN	4	NR3C1
ENZALUTAMIDE	4	NR3C1
EPLERENONE	4	NR3C1
CHLORMADINONE ACETATE	4	NR3C1
IDARUBICIN	4	NR3C1
CLOBETASOL PROPIONATE	4	NR3C1
MOMETASONE FUROATE	4	NR3C1
NORETHINDRONE	4	NR3C1
TESTOSTERONE PROPIONATE	4	NR3C1
PONATINIB	4	NR3C1
EXEMESTANE	4	NR3C1
BETAMETHASONE DIPROPIONATE	4	NR3C1
PREDNICARBATE	4	NR3C1
TIOCONAZOLE	4	NR3C1
BECLOMETHASONE DIPROPIONATE	4	NR3C1
DIFLORASONE DIACETATE	4	NR3C1
OXYMETHOLONE	4	NR3C1
DESOXYCORTICOSTERONE PIVALATE	4	NR3C1
FLUOROMETHOLONE	4	NR3C1
RIMEXOLONE	4	NR3C1
AMCINONIDE	4	NR3C1
HALCINONIDE	4	NR3C1
HYDROXYPROGESTERONE CAPROATE	4	NR3C1
LOTEPREDNOL ETABONATE	4	NR3C1
NORGESTIMATE	4	NR3C1
ALCLOMETASONE DIPROPIONATE	4	NR3C1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NR3C1	1,158	Binding:865, Functional:263, ADMET:28, Toxicity:2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
NR3C1	1,158

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CANDESARTAN CILEXETIL	4	NR3C1
DIENESTROL	4	NR3C1
PROGESTERONE	4	NR3C1
CLOTRIMAZOLE	4	NR3C1
SIMVASTATIN	4	NR3C1
ENZALUTAMIDE	4	NR3C1
EPLERENONE	4	NR3C1
CHLORMADINONE ACETATE	4	NR3C1
IDARUBICIN	4	NR3C1
CLOBETASOL PROPIONATE	4	NR3C1
MOMETASONE FUROATE	4	NR3C1
NORETHINDRONE	4	NR3C1
TESTOSTERONE PROPIONATE	4	NR3C1
PONATINIB	4	NR3C1
EXEMESTANE	4	NR3C1
BETAMETHASONE DIPROPIONATE	4	NR3C1
PREDNICARBATE	4	NR3C1
TIOCONAZOLE	4	NR3C1
BECLOMETHASONE DIPROPIONATE	4	NR3C1
DIFLORASONE DIACETATE	4	NR3C1
OXYMETHOLONE	4	NR3C1
DESOXYCORTICOSTERONE PIVALATE	4	NR3C1
FLUOROMETHOLONE	4	NR3C1
RIMEXOLONE	4	NR3C1
AMCINONIDE	4	NR3C1
HALCINONIDE	4	NR3C1
HYDROXYPROGESTERONE CAPROATE	4	NR3C1
LOTEPREDNOL ETABONATE	4	NR3C1
NORGESTIMATE	4	NR3C1
ALCLOMETASONE DIPROPIONATE	4	NR3C1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NR3C1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03615742	PHASE4	RECRUITING	Diesel Exhaust Induces Glucocorticoid Resistance
NCT04601142	Not specified	UNKNOWN	Association Between the Effect of Glucocorticoid Pulse Therapy on Neuromyelitis Optica (NMO) and Gene Polymorphism

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BUDESONIDE	4	1
CHEMBL249466	0	1