# NM_000516.7(GNAS):c.343C>T (p.Pro115Ser)

https://sugi.bio/variant/gnas-p-pro115ser

## Summary

**GNAS p.Pro115Ser (c.343C>T)** is classified **Pathogenic** in GNAS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-11). AlphaMissense: likely pathogenic (0.9646); Absent from gnomAD v4.1; Associated with GNAS-related disorder.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs2146182909 · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GNAS gene that is considered disease-causing, submitted by 3 submitters, and is linked to GNAS-related disorder.

*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.*

**Support & next steps:** [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.Pro115Ser |
| Coding change (HGVS c.) | c.343C>T |
| MANE Select transcript | [NM_000516](https://www.ncbi.nlm.nih.gov/nuccore/NM_000516) |
| dbSNP | [rs2146182909](https://www.ncbi.nlm.nih.gov/snp/rs2146182909/) |
| Variant type | single nucleotide variant |
| Location | chr20:58903702-58903702 (GRCh38) |
| ClinVar | [VCV1459427](https://www.ncbi.nlm.nih.gov/clinvar/variation/1459427/) |

**All HGVS expressions:** `NC_000020.10:g.57478757C>T`, `NC_000020.11:g.58903702C>T`, `NG_016194.2:g.68963C>T`, `NM_000516.7:c.343C>T`, `NM_001077488.5:c.346C>T`, `NM_001077489.4:c.298C>T`, `NM_001077490.3:c.*204C>T`, `NM_001309840.2:c.166C>T`, `NM_001309861.2:c.166C>T`, `NM_016592.5:c.*249C>T`, `NM_080425.4:c.2272C>T`, `NM_080426.4:c.301C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9646) — concordant with the pathogenic call
- REVEL 0.855 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.71 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 5.184, GERP 1.88, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P758S** vs ClinVar **P115S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 27.1**. 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.*
- Regional missense constraint: **o/e 0.31** across the covering region of the MANE Select transcript (58,891,863–58,909,556), spanning 17,693 bp — the region is depleted of missense variation. Chi-square p 9.1e-28. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **758** lies in the g-alpha domain.

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.Pro115Ser falls in the g-alpha domain. 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-11.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-11 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-01 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-02-02 |

## Associated conditions {#conditions}

[GNAS-related disorder](https://sugi.bio/atlas/disease/gnas-related-disorder/).

**Reported phenotype names (ClinVar):** GNAS-related disorder, not provided, none provided.

## Same-residue context {#hotspot}

Residue **115** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [GNAS p.Pro115Leu](/variant/gnas-p-pro115leu), [GNAS p.Pro115Arg](/variant/gnas-p-pro115arg). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GNAS variant pages (same residue, condition, or type): [GNAS p.Pro115Leu](/variant/gnas-p-pro115leu), [GNAS p.Trp115Ter](/variant/gnas-p-trp115ter), [GNAS p.Pro115Arg](/variant/gnas-p-pro115arg), [GNAS p.Pro115=](/variant/gnas-p-pro115), [GNAS p.Ala102Val](/variant/gnas-p-ala102val), [GNAS p.Arg165His](/variant/gnas-p-arg165his), [GNAS p.Arg201Cys](/variant/gnas-p-arg201cys), [GNAS p.Arg258Gln](/variant/gnas-p-arg258gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1459427). 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.*