Pseudohypoparathyroidism type I A: genes and variants
Pseudohypoparathyroidism type I A is linked to 1 analyzed protein (GNAS). 29 DNA variants are known to cause it; 13 more are uncertain, and 1 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Pseudohypoparathyroidism type I A
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.
29 disease-causing and 13 uncertain variants in GNAS are linked to Pseudohypoparathyroidism type I A.
Where Pseudohypoparathyroidism type I A variants cluster
- GNAS G2 motif (positions 196–204): 4 of 29 disease-causing changes, 6.0× more than its size predicts.
- GNAS G1 motif (positions 42–55): 3 of 29 disease-causing changes, 2.9× more than its size predicts.
Known disease-causing variants in Pseudohypoparathyroidism type I A
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| GNAS R201H | 201 | G-alpha | Disease-causing (★★) |
| GNAS R231H | 231 | G-alpha | Disease-causing (★★) |
| GNAS R265H | 265 | G-alpha | Disease-causing (★★) |
| GNAS R165C | 165 | G-alpha | Disease-causing (★★) |
| GNAS R232H | 232 | G-alpha | Disease-causing (★★) |
| GNAS R265C | 265 | G-alpha | Disease-causing (★★) |
| GNAS I103T | 103 | G-alpha | Disease-causing (★★) |
| GNAS R228C | 228 | G-alpha | Disease-causing (★★) |
| GNAS R336W | 336 | G-alpha | Disease-causing (★★) |
| GNAS G353R | 353 | G-alpha | Disease-causing (★★) |
| GNAS E392K | 392 | G-alpha | Disease-causing (★★) |
| GNAS R199C | 199 | G-alpha | Disease-causing (★) |
| GNAS R199P | 199 | G-alpha | Disease-causing (★) |
| GNAS R199L | 199 | G-alpha | Disease-causing (★) |
| GNAS R258L | 258 | G-alpha | Disease-causing (★) |
| GNAS R42S | 42 | G-alpha | Disease-causing (★) |
| GNAS G52S | 52 | G-alpha | Disease-causing (★) |
| GNAS R258P | 258 | G-alpha | Disease-causing (★) |
| GNAS L282R | 282 | G-alpha | Disease-causing (★) |
| GNAS S306L | 306 | G-alpha | Disease-causing (★) |
| GNAS R342Q | 342 | G-alpha | Disease-causing (★) |
| GNAS R356H | 356 | G-alpha | Disease-causing (★) |
| GNAS I372T | 372 | G-alpha | Disease-causing (★) |
| GNAS Q384E | 384 | G-alpha | Disease-causing (★) |
| GNAS M1I | 1 | Disease-causing (★) | |
| GNAS L43V | 43 | G-alpha | Disease-causing (★) |
| GNAS R160G | 160 | G-alpha | Disease-causing (★) |
| GNAS K293R | 293 | G-alpha | Disease-causing (★) |
| GNAS R347T | 347 | G-alpha | Disease-causing (★) |
Uncertain variants in Pseudohypoparathyroidism type I A that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| GNAS R228H | 228 | G-alpha | Uncertain (★★) | +7: 2 other pathogenic changes within 3 positions; R228C at the same position is pathogenic; seen in 6.6e-06 of gnomAD DNA copies; REVEL 0.803 |
Same protein, different disease
- Pseudohypoparathyroidism is also caused by GNAS variants; they fall partly in the same places as the Pseudohypoparathyroidism type I A variants (13 disease-causing).
- Pseudopseudohypoparathyroidism is also caused by GNAS variants; they fall partly in the same places as the Pseudohypoparathyroidism type I A variants (7 disease-causing).
- McCune-Albright syndrome is also caused by GNAS variants; they fall in the same places as the Pseudohypoparathyroidism type I A variants (5 disease-causing).
Diseases related to Pseudohypoparathyroidism type I A
- Hereditary spastic paraplegia, also linked to GNAS
- Pseudohypoparathyroidism, also linked to GNAS
- Pseudopseudohypoparathyroidism, also linked to GNAS
- McCune-Albright syndrome, also linked to GNAS
- Pituitary adenoma 3, multiple types, also linked to GNAS
- Progressive osseous heteroplasia, also linked to GNAS
Frequently asked questions
Which genes are linked to Pseudohypoparathyroidism type I A?
In CATVariant, Pseudohypoparathyroidism type I A is linked to 1 analyzed protein: GNAS (Guanine nucleotide-binding protein G(s) subunit alpha isoforms short).
How many genetic variants are linked to Pseudohypoparathyroidism type I A?
42 variants: 29 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 13 are of uncertain significance or have conflicting reports.
Which uncertain variants in Pseudohypoparathyroidism type I A look disease-causing?
1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example GNAS R228H. 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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