NR3C1

Chr 5AD

nuclear receptor subfamily 3 group C member 1

ENSG00000113580 UniProt: P04150 OMIM: 138040

The glucocorticoid receptor functions as a transcription factor that binds to glucocorticoid response elements to regulate gene expression and modulates other transcription factors, affecting inflammatory responses, cellular proliferation, and differentiation. Mutations cause glucocorticoid resistance with autosomal dominant inheritance. This gene is highly constrained against loss-of-function variants, indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Receptor for glucocorticoids (GC) (PubMed:27120390, PubMed:37478846). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors (PubMed:28139699). Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Involved in chromatin remodeling (PubMed:9590696). Plays a role in rapid mRNA degradation by binding to the 5' UTR of target mRNAs and interacting with PNRC2 in a ligand-dependent manner which recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay (PubMed:25775514). Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth (By similarity)

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Glucocorticoid resistanceMIM #615962

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Glucocorticoid resistance; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

307

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.32

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.970

Z-score 4.50

OE 0.15 (0.08–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.84Z-score

OE missense 0.74 (0.67–0.81)

293 obs / 396.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.08–0.32)

0≤0.351.4

Missense OE?0.74 (0.67–0.81)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 5 / 32.9Missense obs/exp: 293 / 396.1Syn Z: -0.17

Background carrier burden — how many people carry a rare variant somewhere in NR3C1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

759 rare PASS variants

Rare truncating (LoF)

1 in 3,100

61 rare PASS variants

Rare synonymous (reference)

1 in 130

334 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NR3C1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 200	1 in 3,200
South Asian	~43k	1 in 100	1 in 1,100
Remaining (unassigned)	~30k	1 in 120	1 in 5,000
European (Finnish)	~27k	1 in 540	1 in 3,800
Admixed American	~22k	1 in 120	1 in 2,700
African / African American	~21k	1 in 100	1 in 3,700
East Asian	~20k	1 in 110	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 1,200	≈ 1 in 6,300
Middle Eastern	~2,884	1 in 100	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓