# NM_080425.4(GNAS):c.1323C>T (p.Pro441=)

https://sugi.bio/variant/gnas-p-pro441

## Summary

**GNAS p.Pro441= (c.1323C>T)** is classified **Uncertain significance** in GNAS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-16). Very rare (popmax 0.00189%, amr); Associated with pseudohypoparathyroidism type 1B.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs146744182 · 3 submitters · 8 linked conditions · very rare (popmax 0.00189%, amr)

## For patients & families {#patients}

This is a change in the GNAS gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to pseudohypoparathyroidism type 1B.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Not applicable |
| Age of onset (of this condition) | Adolescent, Childhood, Infancy, Neonatal |
| Diagnostic panels | GNAS is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Pseudohypoparathyroidism type 1B** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Pseudohypoparathyroidism — Obligate (100%)
- Hypocalcemia — Very frequent (99-80%)
- Hyperphosphatemia — Very frequent (99-80%)
- Elevated circulating parathyroid hormone level — Very frequent (99-80%)
- Low urinary cyclic AMP response to PTH administration — Very frequent (99-80%)
- Full cheeks — Frequent (79-30%)
- Round face — Frequent (79-30%)
- Short neck — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010680/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GNAS](https://sugi.bio/atlas/gene/GNAS/) |
| Protein change (HGVS p.) | p.Pro441= |
| Coding change (HGVS c.) | c.1323C>T |
| MANE Select transcript | [NM_000516](https://www.ncbi.nlm.nih.gov/nuccore/NM_000516) (variant reported on NM_080425) |
| dbSNP | [rs146744182](https://www.ncbi.nlm.nih.gov/snp/rs146744182/) |
| Variant type | single nucleotide variant |
| Location | chr20:58854588-58854588 (GRCh38) |
| ClinVar | [VCV930718](https://www.ncbi.nlm.nih.gov/clinvar/variation/930718/) |

**All HGVS expressions:** `LRG_1051:g.1316G>A`, `NC_000020.10:g.57429643C>T`, `NC_000020.11:g.58854588C>T`, `NG_016194.2:g.19849C>T`, `NG_021433.1:g.1316G>A`, `NG_143671.1:g.98C>T`, `NM_001077490.3:c.1136C>T`, `NM_001309861.2:c.-39+12713C>T`, `NM_001309883.1:c.1136C>T`, `NM_001410912.1:c.43+13702C>T`, `NM_001410913.1:c.1323C>T`, `NM_016592.5:c.*42+13702C>T`, `NM_080425.4:c.1323C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -14.778, GERP -2.58 — fast-evolving / accelerated position
- CADD: **PHRED 0.464**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00189%** (amr) · FAF95 0.00051% · FAF99 0.000373% · 1/52,936 in the highest group · 12/1,550,382 alleles overall — very rare (popmax 0.00189%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00189% | 52,936 |
| European (non-Finnish) | 0.000951% | 105,161 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**GNAS** population constraint: LOEUF 0.302, pLI 0.99999, missense-Z 4.8425; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **441** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 59.47, 4% of residues very-high.

**200 experimental structure(s)** (PDB): [24TB](https://www.rcsb.org/structure/24TB), [24TI](https://www.rcsb.org/structure/24TI), [25NV](https://www.rcsb.org/structure/25NV), [25NX](https://www.rcsb.org/structure/25NX), [5G53](https://www.rcsb.org/structure/5G53), [5UZ7](https://www.rcsb.org/structure/5UZ7) — incl. mutant structure 6AU6.

## What this gene does {#gene-function}

*Describes the biological roles of GNAS (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** GNAS's established molecular role includes G protein activity. p.Pro441= falls in the disordered region. In Reactome, GNAS is annotated in disease pathway(s) including **ADORA2B mediated anti-inflammatory cytokines production**.

**Disease mechanism (Reactome):** GNAS loss or alteration is curated in [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821).

### Pathways affected {#pathways}

GNAS participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821) | electronic |
| [Glucagon signaling in metabolic regulation](https://reactome.org/content/detail/R-HSA-163359) | curated |
| [Glucagon-type ligand receptors](https://reactome.org/content/detail/R-HSA-420092) | curated |
| [Hedgehog 'off' state](https://reactome.org/content/detail/R-HSA-5610787) | curated |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | curated |
| [PKA activation in glucagon signalling](https://reactome.org/content/detail/R-HSA-164378) | curated |
| [Vasopressin regulates renal water homeostasis via Aquaporins](https://reactome.org/content/detail/R-HSA-432040) | curated |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | electronic |
| [G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555) | electronic |
| [G alpha (z) signalling events](https://reactome.org/content/detail/R-HSA-418597) | electronic |
| [GPER1 signaling](https://reactome.org/content/detail/R-HSA-9634597) | electronic |
| [Glucagon-like Peptide-1 (GLP1) regulates insulin secretion](https://reactome.org/content/detail/R-HSA-381676) | electronic |
| [Prostacyclin signalling through prostacyclin receptor](https://reactome.org/content/detail/R-HSA-392851) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** G protein activity, D1 dopamine receptor binding.

**Biological process:** response to parathyroid hormone, intracellular glucose homeostasis, adenylate cyclase-activating G protein-coupled receptor signaling pathway, adenylate cyclase-activating serotonin receptor signaling pathway, regulation of skeletal muscle contraction, response to prostaglandin E.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-16.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2019–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-03-01 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-19 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-16 |

## Associated conditions {#conditions}

[pseudohypoparathyroidism type 1B](https://sugi.bio/atlas/disease/pseudohypoparathyroidism-type-1b/), [pseudohypoparathyroidism type 1A](https://sugi.bio/atlas/disease/pseudohypoparathyroidism-type-1a/), [progressive osseous heteroplasia](https://sugi.bio/atlas/disease/progressive-osseous-heteroplasia/), [pseudohypoparathyroidism type 1C](https://sugi.bio/atlas/disease/pseudohypoparathyroidism-type-1c/), [pseudopseudohypoparathyroidism](https://sugi.bio/atlas/disease/pseudopseudohypoparathyroidism/), [McCune-Albright syndrome](https://sugi.bio/atlas/disease/mccune-albright-syndrome/), [ACTH-independent macronodular adrenal hyperplasia 1](https://sugi.bio/atlas/disease/acth-independent-macronodular-adrenal-hyperplasia-1/), [pituitary adenoma 3, multiple types](https://sugi.bio/atlas/disease/pituitary-adenoma-3-multiple-types/).

**Reported phenotype names (ClinVar):** Pseudohypoparathyroidism type 1B, ACTH-independent macronodular adrenal hyperplasia 1, McCune-Albright syndrome, Pituitary adenoma 3, multiple types, Progressive osseous heteroplasia, Pseudohypoparathyroidism type 1C, Pseudohypoparathyroidism type I A, Pseudopseudohypoparathyroidism, not provided, Pseudohypoparathyroidism Type IB.

## Similar variants {#similar}

Related GNAS variant pages (same residue, condition, or type): [GNAS c.139+1G>C](/variant/gnas-c-139-plus-1g-c), [GNAS c.432+1G>A](/variant/gnas-c-432-plus-1g-a), [GNAS c.433-2A>C](/variant/gnas-c-433-minus-2a-c), [GNAS p.Arg165Cys](/variant/gnas-p-arg165cys), [GNAS p.Arg201Cys](/variant/gnas-p-arg201cys), [GNAS p.Arg201His](/variant/gnas-p-arg201his), [GNAS p.Arg228Cys](/variant/gnas-p-arg228cys), [GNAS p.Arg231Cys](/variant/gnas-p-arg231cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 930718). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*