CRHR1

Chr 17

corticotropin releasing hormone receptor 1

Also known as: CRF-R, CRF-R-1, CRF-R1, CRF1, CRFR-1, CRFR1, CRH-R-1, CRH-R1

NCBI Gene: 1394ENSG00000120088UniProt: P34998OMIM: 122561

This gene encodes a G-protein coupled receptor that binds corticotropin-releasing hormone and urocortin to activate adenylyl cyclase and regulate the hypothalamic-pituitary-adrenal axis stress response. Mutations cause isolated ACTH deficiency, an autosomal recessive disorder presenting in infancy with severe hypoglycemia, failure to thrive, and life-threatening adrenal insufficiency due to impaired cortisol production. The gene is not highly constrained against loss-of-function variants, consistent with the recessive inheritance pattern observed clinically.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.71
Clinical Summary— CRHR1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
59 unique Pathogenic / Likely Pathogenic· 53 VUS of 131 total submissions
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Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.71LOEUF
pLI 0.000
Z-score 2.71
OE 0.44 (0.28–0.71)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.73Z-score
OE missense 0.71 (0.63–0.80)
196 obs / 277.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.44 (0.28–0.71)
0≤0.351.4
Missense OE0.71 (0.63–0.80)
0≤0.61.4
Synonymous OE0.91
0≤1.21.6
LoF obs/exp: 12 / 27.2Missense obs/exp: 196 / 277.0Syn Z: 0.76
DN
0.85top 5%
GOF
0.83top 10%
LOF
0.2092th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

131 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55
Likely Pathogenic4
VUS53
Likely Benign8
Benign6
Conflicting1
55
Pathogenic
4
Likely Pathogenic
53
VUS
8
Likely Benign
6
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
55
0
55
Likely Pathogenic
0
0
4
0
4
VUS
0
49
4
0
53
Likely Benign
0
6
0
2
8
Benign
0
2
2
2
6
Conflicting
—1
Total057654127

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CRHR1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Differential genome-wide association analysis of schizophrenia and post-traumatic stress disorder identifies opposing effects at the MAPT/CRHR1 locus.
Cheng ZS.·Front Genet
2026Open Access
Targeting CRHR1 Signaling in Experimental Infantile Epileptic Spasms Syndrome: Evidence for Route-Dependent Efficacy.
Chachua T et al.·Children (Basel)
2026Open Access
CRHR1 Gene Copy Number Variations, Chronic Viral Infections, and Age as Correlates of Cognitive Impairment in Adults After SARS-CoV-2 Infection.
Hovhannisyan Y et al.·Curr Issues Mol Biol
2026Open Access
Asiaticoside ameliorates pyrimethanil-induced autophagy-dependent liver injury by suppressing CRHR1.
Chen R et al.·Ecotoxicol Environ Saf
2025
Reducing stress and alcohol-related behaviors by targeting D1-CRHR1 receptor interactions in the amygdala.
Broccoli L et al.·Front Pharmacol
2025Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients