# NM_138711.6(PPARG):c.63C>T (p.Ser21=)

https://sugi.bio/variant/pparg-p-ser21

## Summary

**PPARG p.Ser21= (c.63C>T)** is classified **Likely benign** in PPARG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-17). Rare (popmax 0.1%, amr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs150513215 · 3 submitters · rare (popmax 0.1%, amr)

## For patients & families {#patients}

This is a change in the PPARG gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*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.Ser21= |
| Coding change (HGVS c.) | c.63C>T |
| MANE Select transcript | [NM_138711](https://www.ncbi.nlm.nih.gov/nuccore/NM_138711) |
| dbSNP | [rs150513215](https://www.ncbi.nlm.nih.gov/snp/rs150513215/) |
| Variant type | single nucleotide variant |
| Location | chr3:12379774-12379774 (GRCh38) |
| ClinVar | [VCV720030](https://www.ncbi.nlm.nih.gov/clinvar/variation/720030/) |

**All HGVS expressions:** `NC_000003.11:g.12421273C>T`, `NC_000003.12:g.12379774C>T`, `NG_011749.1:g.96925C>T`, `NM_001330615.4:c.63C>T`, `NM_001354666.3:c.63C>T`, `NM_001354667.3:c.63C>T`, `NM_001354668.2:c.153C>T`, `NM_001354669.2:c.-365C>T`, `NM_001354670.2:c.69C>T`, `NM_001374261.3:c.63C>T`, `NM_001374262.3:c.63C>T`, `NM_001374263.2:c.63C>T`, `NM_001374264.2:c.63C>T`, `NM_001374265.1:c.153C>T`, `NM_001374266.1:c.69C>T`, `NM_005037.7:c.63C>T`, `NM_015869.5:c.153C>T`, `NM_138711.6:c.63C>T`, `NM_138712.5:c.63C>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 -4.942, GERP -3.47 — fast-evolving / accelerated position
- CADD: **PHRED 3.58**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.26 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.1%** (amr) · FAF95 0.0798% · FAF99 0.0724% · 60/59,990 in the highest group · 192/1,614,024 alleles overall — rare (popmax 0.1%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.152% | 658 |
| Admixed American (grpmax) | 0.1% | 1,000 |
| Middle Eastern | 0.0495% | 2,020 |
| Remaining individuals (not grpmax-eligible) | 0.0416% | 2,404 |
| African / African-American | 0.00666% | 15,009 |
| South Asian | 0.00439% | 22,770 |
| European (non-Finnish) | 0.00407% | 24,582 |
| East Asian | 0.00223% | 44,858 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-17.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-07-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-17 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-04 |

**Reported phenotype names (ClinVar):** not provided, PPARG-related disorder, not specified, none provided, PPARG-related disorders, PPARG-related condition, AllHighlyPenetrant.

## 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 c.-8A>G](/variant/pparg-c-minus-8a-g), [PPARG p.Arg110His](/variant/pparg-p-arg110his), [PPARG p.Arg151Gln](/variant/pparg-p-arg151gln).

### 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 720030). 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.*