# NM_138711.6(PPARG):c.1124T>C (p.Leu375Pro)

https://sugi.bio/variant/pparg-p-leu375pro

## Summary

**PPARG p.Leu375Pro (c.1124T>C)** is classified **Likely pathogenic** in PPARG (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-15). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with PPARG-related familial partial lipodystrophy.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2125285337 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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 PPARG-related familial partial lipodystrophy.

*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 |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | PPARG is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of PPARG-related familial partial lipodystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypertension — Obligate (100%)
- Insulin resistance — Obligate (100%)
- Lipoatrophy — Obligate (100%)
- Diabetes mellitus — Very frequent (99-80%)
- Insulin-resistant diabetes mellitus — Very frequent (99-80%)
- Xanthomatosis — Very frequent (99-80%)
- Hypertriglyceridemia — Very frequent (99-80%)
- Hepatomegaly — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012600/index) · [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.Leu375Pro |
| Coding change (HGVS c.) | c.1124T>C |
| MANE Select transcript | [NM_138711](https://www.ncbi.nlm.nih.gov/nuccore/NM_138711) |
| dbSNP | [rs2125285337](https://www.ncbi.nlm.nih.gov/snp/rs2125285337/) |
| Variant type | single nucleotide variant |
| Location | chr3:12417098-12417098 (GRCh38) |
| ClinVar | [VCV1341578](https://www.ncbi.nlm.nih.gov/clinvar/variation/1341578/) |

**All HGVS expressions:** `NC_000003.11:g.12458597T>C`, `NC_000003.12:g.12417098T>C`, `NG_011749.1:g.134249T>C`, `NM_001330615.4:c.729+11017T>C`, `NM_001354666.3:c.1124T>C`, `NM_001354667.3:c.1124T>C`, `NM_001354669.2:c.497T>C`, `NM_001374261.3:c.729+11017T>C`, `NM_001374262.3:c.729+11017T>C`, `NM_001374263.2:c.1124T>C`, `NM_001374264.2:c.1124T>C`, `NM_001374265.1:c.819+11017T>C`, `NM_001374266.1:c.653+11099T>C`, `NM_005037.7:c.1124T>C`, `NM_015869.5:c.1214T>C`, `NM_138711.6:c.1124T>C`, `NM_138712.5:c.1124T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9994) — concordant with the pathogenic call
- REVEL 0.917 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.905 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.875, GERP 2.28, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **L405P** vs ClinVar **L375P**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in PPARG (of 3,016 modeled).
- CADD: **PHRED 31.0**. 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 0.60** across the covering region of the MANE Select transcript (12,381,424–12,434,142), spanning 52,718 bp. Chi-square p 1.2e-17. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for PPARG (928 scored positions, the nearest 24 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- 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}

Residue **405** lies in the nr lbd domain.

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. p.Leu375Pro falls in the nr lbd domain.


### 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 2021-01-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-01-15 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** PPARG-related familial partial lipodystrophy, 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 2026-10-15); 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 1341578). 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.*