PTH1R
Chr 3ARADparathyroid hormone 1 receptor
Also known as: EKNS, PFE, PTHR, PTHR1
The protein is a G-protein coupled receptor for parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHLH) that activates adenylyl cyclase and calcium signaling pathways essential for bone and mineral metabolism. Mutations cause skeletal dysplasias including Blomstrand chondrodysplasia, Eiken syndrome, Jansen metaphyseal chondrodysplasia, and primary failure of tooth eruption, with both autosomal dominant and autosomal recessive inheritance patterns. The gene is highly constrained against loss-of-function variants, reflecting its critical role in skeletal development and calcium homeostasis.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
480 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 10 | 9 | 10 | 0 | 29 |
Likely Pathogenic | 5 | 6 | 1 | 0 | 12 |
VUS | 2 | 223 | 20 | 8 | 253 |
Likely Benign | 0 | 6 | 58 | 62 | 126 |
Benign | 0 | 0 | 14 | 3 | 17 |
Conflicting | — | 34 | |||
| Total | 17 | 244 | 103 | 73 | 471 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
PTH1R · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
External Resources
Links to major genomics databases and tools