Pseudohypoparathyroidism: genes and variants
Pseudohypoparathyroidism is linked to 2 analyzed proteins (GNAS and PTH1R). 14 DNA variants are known to cause it; 11 more are uncertain, and 1 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: pseudohypoparathyroidism type 1A; pseudohypoparathyroidism type 1B; pseudohypoparathyroidism type 1C
Genes linked to Pseudohypoparathyroidism
GNAS: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
It produces the stimulatory G-alpha subunit that activates adenylyl cyclase downstream of many hormone receptors, with complex tissue-specific imprinting at the locus. Inactivating variants cause pseudohypoparathyroidism-spectrum disorders, while activating somatic variants cause McCune-Albright syndrome and some endocrine tumors.
13 disease-causing and 11 uncertain variants in GNAS are linked to Pseudohypoparathyroidism.
PTH1R: Parathyroid hormone/parathyroid hormone-related peptide receptor
It responds to parathyroid hormone and PTH-related peptide to coordinate calcium homeostasis and growth-plate development through cyclic-AMP and other pathways. Gain- and loss-of-function variants cause distinct skeletal disorders including Jansen metaphyseal chondrodysplasia and Blomstrand chondrodysplasia.
1 disease-causing and 0 uncertain variants in PTH1R are linked to Pseudohypoparathyroidism.
Known disease-causing variants in Pseudohypoparathyroidism
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| GNAS R201H | 201 | G-alpha | Disease-causing (★★) |
| GNAS R201C | 201 | G-alpha | Disease-causing (★★) |
| GNAS R231C | 231 | G-alpha | Disease-causing (★★) |
| GNAS R232C | 232 | G-alpha | Disease-causing (★★) |
| GNAS P115L | 115 | G-alpha | Disease-causing (★★) |
| GNAS R228C | 228 | G-alpha | Disease-causing (★★) |
| GNAS R336W | 336 | G-alpha | Disease-causing (★★) |
| GNAS M1V | 1 | Disease-causing (★★) | |
| GNAS P116L | 116 | G-alpha | Disease-causing (★★) |
| PTH1R D241E | 241 | Transmembrane | Disease-causing (★) |
| GNAS L99P | 99 | G-alpha | Disease-causing |
| GNAS S250R | 250 | G-alpha | Disease-causing |
| GNAS S251R | 251 | G-alpha | Disease-causing |
| GNAS L388R | 388 | G-alpha | Disease-causing |
Uncertain variants in Pseudohypoparathyroidism that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| GNAS R232H | 232 | G-alpha | Uncertain (★★) | +7: 2 other pathogenic changes within 3 positions; R232C at the same position is pathogenic; seen in 1.4e-06 of gnomAD DNA copies; REVEL 0.826 |
Same protein, different disease
- Pseudohypoparathyroidism type I A is also caused by GNAS variants; they fall mostly in different places as the Pseudohypoparathyroidism variants (29 disease-causing).
- Pseudopseudohypoparathyroidism is also caused by GNAS variants; they fall mostly in different places as the Pseudohypoparathyroidism variants (7 disease-causing).
- McCune-Albright syndrome is also caused by GNAS variants; they fall partly in the same places as the Pseudohypoparathyroidism variants (5 disease-causing).
- Metaphyseal chondrodysplasia, Jansen type is also caused by PTH1R variants; they fall mostly in different places as the Pseudohypoparathyroidism variants (5 disease-causing).
Diseases related to Pseudohypoparathyroidism
- Hereditary spastic paraplegia, also linked to GNAS
- Pseudohypoparathyroidism type I A, also linked to GNAS
- Connective tissue disorder, also linked to PTH1R
- Osteoporosis, also linked to PTH1R
- Pseudopseudohypoparathyroidism, also linked to GNAS
- Metaphyseal chondrodysplasia, Jansen type, also linked to PTH1R
- McCune-Albright syndrome, also linked to GNAS
- Postmenopausal osteoporosis, also linked to PTH1R
- Chondrodysplasia Blomstrand type, also linked to PTH1R
- Pituitary adenoma 3, multiple types, also linked to GNAS
- Primary failure of tooth eruption, also linked to PTH1R
- Eiken syndrome, also linked to PTH1R
Frequently asked questions
Which genes are linked to Pseudohypoparathyroidism?
In CATVariant, Pseudohypoparathyroidism is linked to 2 analyzed proteins: GNAS (Guanine nucleotide-binding protein G(s) subunit alpha isoforms short) and PTH1R (Parathyroid hormone/parathyroid hormone-related peptide receptor).
How many genetic variants are linked to Pseudohypoparathyroidism?
60 variants: 14 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 11 are of uncertain significance or have conflicting reports.
Which uncertain variants in Pseudohypoparathyroidism look disease-causing?
1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example GNAS R232H. These are leads for expert review, not diagnoses.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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