# NM_138711.6(PPARG):c.46_58del (p.Ser17fs)

https://sugi.bio/variant/pparg-p-ser17fs

## Summary

**PPARG p.Ser17fs (c.46_58del)** is classified **Likely pathogenic** in PPARG (ClinVar, Single submitter, 1 submitter; last evaluated 2016-01-01). No gnomAD frequency available for this variant; Associated with obesity disorder.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2049559215 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PPARG gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to obesity 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.*

|  |  |
| --- | --- |
| Clinical trials | 6100 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PPARG is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PPARG](https://sugi.bio/atlas/gene/PPARG/) |
| Protein change (HGVS p.) | p.Ser17fs |
| Coding change (HGVS c.) | c.46_58del |
| MANE Select transcript | [NM_138711](https://www.ncbi.nlm.nih.gov/nuccore/NM_138711) |
| dbSNP | [rs2049559215](https://www.ncbi.nlm.nih.gov/snp/rs2049559215/) |
| Variant type | Deletion |
| Location | chr3:12379752-12379764 (GRCh38) |
| ClinVar | [VCV930372](https://www.ncbi.nlm.nih.gov/clinvar/variation/930372/) |

**All HGVS expressions:** `NC_000003.11:g.12421256_12421268del`, `NC_000003.12:g.12379757_12379769del`, `NG_011749.1:g.96908_96920del`, `NM_001330615.4:c.46_58del`, `NM_001354666.3:c.46_58del`, `NM_001354667.3:c.46_58del`, `NM_001354668.2:c.136_148del`, `NM_001354669.2:c.-382_-370del`, `NM_001354670.2:c.52_64del`, `NM_001374261.3:c.46_58del`, `NM_001374262.3:c.46_58del`, `NM_001374263.2:c.46_58del`, `NM_001374264.2:c.46_58del`, `NM_001374265.1:c.136_148del`, `NM_001374266.1:c.52_64del`, `NM_005037.7:c.46_58del`, `NM_015869.5:c.136_148del`, `NM_138711.6:c.46_58del`, `NM_138712.5:c.46_58del`

## Computational & population evidence {#evidence}

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

- **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 8.528, GERP 1.74, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.628, pLI 0.21436. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 8**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**PPARG** population constraint: LOEUF 0.628, pLI 0.21436, missense-Z 3.1059. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **lipodystrophy** — Definitive (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 76.11, 55% of residues very-high.

**321 experimental structure(s)** (PDB): [1FM6](https://www.rcsb.org/structure/1FM6), [1FM9](https://www.rcsb.org/structure/1FM9), [1I7I](https://www.rcsb.org/structure/1I7I), [1K74](https://www.rcsb.org/structure/1K74), [1KNU](https://www.rcsb.org/structure/1KNU), [1NYX](https://www.rcsb.org/structure/1NYX) — incl. mutant structure 2ZVT.

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

*Describes the biological roles of PPARG (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:** PPARG's established molecular role includes transcription cis-regulatory region binding.


### Pathways affected {#pathways}

PPARG participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Nuclear Receptor transcription pathway](https://reactome.org/content/detail/R-HSA-383280) | curated |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | curated |
| [MECP2 regulates transcription factors](https://reactome.org/content/detail/R-HSA-9022707) | electronic |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | other |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | electronic |
| [SUMOylation of intracellular receptors](https://reactome.org/content/detail/R-HSA-4090294) | electronic |
| [Transcriptional regulation of brown and beige adipocyte differentiation by EBF2](https://reactome.org/content/detail/R-HSA-9844594) | electronic |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, transcription coregulator binding, DNA-binding transcription activator activity, RNA polymerase II-specific, nucleic acid binding, DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of blood pressure, positive regulation of gene expression, negative regulation of gene expression, negative regulation of macrophage derived foam cell differentiation, positive regulation of cholesterol efflux.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2016-01-01.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-01-01 |

## Associated conditions {#conditions}

[obesity disorder](https://sugi.bio/atlas/disease/obesity-disorder/).

**Reported phenotype names (ClinVar):** Obesity, Obesity disorder.

## Similar variants {#similar}

Related PPARG variant pages (same residue, condition, or type): [PPARG p.Asp144Gly](/variant/pparg-p-asp144gly), [PPARG c.-8-28078C>G](/variant/pparg-c-minus-8-minus-28078c-g), [PPARG p.His447=](/variant/pparg-p-his447), [PPARG p.Ile454=](/variant/pparg-p-ile454), [PPARG p.Ser427=](/variant/pparg-p-ser427), [PPARG c.391-3C>T](/variant/pparg-c-391-minus-3c-t), [PPARG p.Ala116=](/variant/pparg-p-ala116), [PPARG p.Arg210Gln](/variant/pparg-p-arg210gln).

### 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 930372). 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.*