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: 1394 ENSG00000120088 UniProt: P34998 OMIM: 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.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a G-protein coupled receptor that binds neuropeptides of the corticotropin releasing hormone family that are major regulators of the hypothalamic-pituitary-adrenal pathway. The encoded protein is essential for the activation of signal transduction pathways that regulate diverse physiological processes including stress, reproduction, immune response and obesity. Alternative splicing results in multiple transcript variants. Naturally-occurring readthrough transcription between this gene and upstream GeneID:147081 results in transcripts that encode isoforms that share similarity with the products of this gene. [provided by RefSeq, Aug 2016]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.71

LOEUF

Multiple*

Mechanism· predicted

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 OE?0.44 (0.28–0.71)

0≤0.351.4

Missense OE?0.71 (0.63–0.80)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 12 / 27.2Missense obs/exp: 196 / 277.0Syn Z: 0.76

Background carrier burden — how many people carry a rare variant somewhere in CRHR1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

514 rare PASS variants

Rare truncating (LoF)

1 in 2,200

76 rare PASS variants

Rare synonymous (reference)

1 in 530

151 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CRHR1. 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 190	1 in 3,200
South Asian	~43k	1 in 190	1 in 1,900
Remaining (unassigned)	~30k	1 in 100	1 in 3,700
European (Finnish)	~27k	1 in 260	≈ 1 in 6,600
Admixed American	~22k	1 in 74	1 in 1,200
African / African American	~21k	1 in 110	1 in 2,000
East Asian	~20k	1 in 90	1 in 420
Ashkenazi Jewish	~13k	1 in 1,000	1 in 1,700
Middle Eastern	~2,884	1 in 140	≈ 1 in 2,900

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 13 coding exons well covered in gnomAD exomes and genomes.? see exons ↓