# NM_138711.6(PPARG):c.275T>C (p.Leu92Pro)

https://sugi.bio/variant/pparg-p-leu92pro

## Summary

**PPARG p.Leu92Pro (c.275T>C)** is classified **Conflicting classifications of pathogenicity** in PPARG (ClinVar, No assertion criteria, 2 submitters; last evaluated 2024-06-14). AlphaMissense: likely benign (0.0738); Absent from gnomAD v4.1; Associated with PPARG-related disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: No assertion criteria · 2 submitters · 2 linked conditions · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PPARG gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to PPARG-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 | [PPARG](https://sugi.bio/atlas/gene/PPARG/) |
| Protein change (HGVS p.) | p.Leu92Pro |
| Coding change (HGVS c.) | c.275T>C |
| MANE Select transcript | [NM_138711](https://www.ncbi.nlm.nih.gov/nuccore/NM_138711) |
| Variant type | single nucleotide variant |
| Location | chr3:12381376-12381376 (GRCh38) |
| ClinVar | [VCV3345678](https://www.ncbi.nlm.nih.gov/clinvar/variation/3345678/) |

**All HGVS expressions:** `NC_000003.11:g.12422875T>C`, `NC_000003.12:g.12381376T>C`, `NG_011749.1:g.98527T>C`, `NM_001330615.4:c.275T>C`, `NM_001354666.3:c.275T>C`, `NM_001354667.3:c.275T>C`, `NM_001354668.2:c.365T>C`, `NM_001354669.2:c.-153T>C`, `NM_001354670.2:c.281T>C`, `NM_001374261.3:c.275T>C`, `NM_001374262.3:c.275T>C`, `NM_001374263.2:c.275T>C`, `NM_001374264.2:c.275T>C`, `NM_001374265.1:c.365T>C`, `NM_001374266.1:c.281T>C`, `NM_005037.7:c.275T>C`, `NM_015869.5:c.365T>C`, `NM_138711.6:c.275T>C`, `NM_138712.5:c.275T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0738)
- REVEL 0.437 (indeterminate)
- SaProt LLR -6.581 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 7.848, GERP 1.89, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **L122P** vs ClinVar **L92P**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 22.5**. 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 1.02** across the covering region of the MANE Select transcript (12,379,712–12,381,423), spanning 1,711 bp. Chi-square p 0.78. 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}

**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}

**Conflicting classifications of pathogenicity** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-06-14.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Pathogenic).

**Submission history:** 2 submissions (2020–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-06-14 |
| Centro De Biociências, Universidade Federal do Rio Grande do Norte | Pathogenic | no assertion criteria provided | clinical testing | 2020-03-23 |

## Associated conditions {#conditions}

[PPARG-related disorder](https://sugi.bio/atlas/disease/pparg-related-disorder/), [PPARG-related familial partial lipodystrophy](https://sugi.bio/atlas/disease/pparg-related-familial-partial-lipodystrophy/).

**Reported phenotype names (ClinVar):** PPARG-related disorder, PPARG-related familial partial lipodystrophy, PPARG-related condition, PPARG-related disorders, LIPODYSTROPHY, FAMILIAL PARTIAL, ASSOCIATED WITH PPARG MUTATIONS.

## Similar variants {#similar}

Related PPARG variant pages (same residue, condition, or type): [PPARG p.Arg164Gln](/variant/pparg-p-arg164gln), [PPARG p.Arg395Cys](/variant/pparg-p-arg395cys), [PPARG p.Arg395His](/variant/pparg-p-arg395his), [PPARG p.Pro465Leu](/variant/pparg-p-pro465leu), [PPARG p.Tyr121Cys](/variant/pparg-p-tyr121cys), [PPARG p.Asp144Gly](/variant/pparg-p-asp144gly), [PPARG p.Met105Ile](/variant/pparg-p-met105ile), [PPARG p.Pro83Gln](/variant/pparg-p-pro83gln).

### 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 3345678). 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.*