# NM_005036.6(PPARA):c.1141G>C (p.Ala381Pro)

https://sugi.bio/variant/ppara-p-ala381pro

## Summary

**PPARA p.Ala381Pro (c.1141G>C)** is classified **Uncertain significance** in PPARA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PPARA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [PPARA](https://sugi.bio/atlas/gene/PPARA/) |
| Protein change (HGVS p.) | p.Ala381Pro |
| Coding change (HGVS c.) | c.1141G>C |
| MANE Select transcript | [NM_005036](https://www.ncbi.nlm.nih.gov/nuccore/NM_005036) |
| Variant type | single nucleotide variant |
| Location | chr22:46232221-46232221 (GRCh38) |
| ClinVar | [VCV4570677](https://www.ncbi.nlm.nih.gov/clinvar/variation/4570677/) |

**All HGVS expressions:** `NC_000022.10:g.46628118G>C`, `NC_000022.11:g.46232221G>C`, `NG_012204.2:g.86688G>C`, `NM_001001928.4:c.1141G>C`, `NM_001001929.3:c.1141G>C`, `NM_001362872.2:c.1141G>C`, `NM_001362873.3:c.1141G>C`, `NM_001393941.1:c.1141G>C`, `NM_001393942.1:c.1141G>C`, `NM_001393943.1:c.1141G>C`, `NM_001393944.1:c.1141G>C`, `NM_001393945.1:c.1141G>C`, `NM_001393946.1:c.1126G>C`, `NM_001393947.1:c.509-2912G>C`, `NM_005036.6:c.1141G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9975)
- REVEL 0.621 (indeterminate)
- SaProt LLR -12.109 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 9.893, GERP 2.09, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in PPARA (of 2,774 modeled).
- CADD: **PHRED 29.3**. 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 0.67** across the covering region of the MANE Select transcript (46,215,287–46,235,377), spanning 20,090 bp. Chi-square p 5.8e-13. 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}

**PPARA** population constraint: LOEUF 0.711, pLI 0.0035263, missense-Z 2.5308. *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 **381** lies in the nr lbd domain; an α-helix; the 'required for heterodimerization with rxra' region.

AlphaFold model confidence (whole protein): pLDDT 81.18, 66% of residues very-high.

**79 experimental structure(s)** (PDB): [1I7G](https://www.rcsb.org/structure/1I7G), [1K7L](https://www.rcsb.org/structure/1K7L), [1KKQ](https://www.rcsb.org/structure/1KKQ), [2NPA](https://www.rcsb.org/structure/2NPA), [2P54](https://www.rcsb.org/structure/2P54), [2REW](https://www.rcsb.org/structure/2REW).

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

*Describes the biological roles of PPARA (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:** PPARA's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. p.Ala381Pro falls in the nr lbd domain.


### Pathways affected {#pathways}

PPARA participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of gene expression by SREBF (SREBP)](https://reactome.org/content/detail/R-HSA-2426168) | curated |
| [Cytoprotection by HMOX1](https://reactome.org/content/detail/R-HSA-9707564) | curated |
| [Nuclear Receptor transcription pathway](https://reactome.org/content/detail/R-HSA-383280) | curated |
| [Regulation of lipid metabolism by PPARalpha](https://reactome.org/content/detail/R-HSA-400206) | curated |
| [SUMOylation of intracellular receptors](https://reactome.org/content/detail/R-HSA-4090294) | curated |
| [Transcriptional activation of mitochondrial biogenesis](https://reactome.org/content/detail/R-HSA-2151201) | curated |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | curated |
| [BMAL1:CLOCK,NPAS2 activates circadian expression](https://reactome.org/content/detail/R-HSA-1368108) | electronic |
| [Expression of BMAL (ARNTL), CLOCK, and NPAS2](https://reactome.org/content/detail/R-HSA-9931509) | electronic |
| [Heme signaling](https://reactome.org/content/detail/R-HSA-9707616) | electronic |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | electronic |
| [RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression](https://reactome.org/content/detail/R-HSA-9933387) | electronic |
| [Transcriptional regulation of brown and beige adipocyte differentiation by EBF2](https://reactome.org/content/detail/R-HSA-9844594) | electronic |

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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, DNA-binding transcription repressor activity, RNA polymerase II-specific, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA-binding transcription factor activity, nuclear steroid receptor activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of ketone metabolic process, negative regulation of macrophage derived foam cell differentiation, negative regulation of cholesterol storage, regulation of fatty acid metabolic process, negative regulation of transforming growth factor beta receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-28 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related PPARA variant pages (same residue, condition, or type): [PPARA p.Asn235=](/variant/ppara-p-asn235), [PPARA p.Leu184=](/variant/ppara-p-leu184), [PPARA p.Val227Ala](/variant/ppara-p-val227ala), [PPARA p.Ala186Val](/variant/ppara-p-ala186val), [PPARA p.Ala201Thr](/variant/ppara-p-ala201thr), [PPARA p.Ala225Thr](/variant/ppara-p-ala225thr), [PPARA p.Ala291Thr](/variant/ppara-p-ala291thr), [PPARA p.Arg141His](/variant/ppara-p-arg141his).

### 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 2026-07-14); 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 4570677). 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.*