# NM_000318.3(PEX2):c.159_160delinsAT (p.Pro54Ser)

https://sugi.bio/variant/pex2-p-pro54ser

## Summary

**PEX2 p.Pro54Ser (c.159_160delinsAT)** is classified **Uncertain significance** in PEX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-20). No gnomAD frequency available for this variant; Associated with peroxisome biogenesis disorder 5A (Zellweger).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2487453391 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PEX2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to peroxisome biogenesis disorder 5A (Zellweger).

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015861/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PEX2](https://sugi.bio/atlas/gene/PEX2/) |
| Protein change (HGVS p.) | p.Pro54Ser |
| Coding change (HGVS c.) | c.159_160delinsAT |
| MANE Select transcript | [NM_000318](https://www.ncbi.nlm.nih.gov/nuccore/NM_000318) |
| dbSNP | [rs2487453391](https://www.ncbi.nlm.nih.gov/snp/rs2487453391/) |
| Variant type | Indel |
| Location | chr8:76984019-76984020 (GRCh38) |
| ClinVar | [VCV2050712](https://www.ncbi.nlm.nih.gov/clinvar/variation/2050712/) |

**All HGVS expressions:** `NC_000008.10:g.77896255_77896256delinsAT`, `NC_000008.11:g.76984019_76984020delinsAT`, `NG_008371.1:g.21269_21270delinsAT`, `NG_008371.2:g.22024_22025delinsAT`, `NM_000318.3:c.159_160delinsAT`, `NM_001079867.2:c.159_160delinsAT`, `NM_001172086.2:c.159_160delinsAT`, `NM_001172087.2:c.159_160delinsAT`

## 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 9.852, GERP 2.44, phastCons 1 — highly conserved position (PP3-type support)
- Regional missense constraint: **o/e 0.99** across the covering region of the MANE Select transcript (76,983,264–76,984,178), spanning 914 bp. Chi-square p 0.85. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel 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}

**PEX2** population constraint: LOEUF 1.057, pLI 1.7994e-05, missense-Z 0.43329. *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):

- **peroxisome biogenesis disorder** — Definitive (AR)

## Protein context {#protein}

Residue **54** lies in a UniProt-annotated variant site (in pbd5a).

AlphaFold model confidence (whole protein): pLDDT 81.17, 40% of residues very-high.

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

*Describes the biological roles of PEX2 (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:** PEX2's established molecular role includes ubiquitin protein ligase activity.


### Pathways affected {#pathways}

PEX2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Class I peroxisomal membrane protein import](https://reactome.org/content/detail/R-HSA-9603798) | other |
| [E3 ubiquitin ligases ubiquitinate target proteins](https://reactome.org/content/detail/R-HSA-8866654) | other |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | other |

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

**Molecular function:** ubiquitin protein ligase activity.

**Biological process:** very long-chain fatty acid metabolic process, pexophagy, protein monoubiquitination, fatty acid beta-oxidation, peroxisome organization, protein import into peroxisome matrix.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-20.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-20 |

## Associated conditions {#conditions}

[peroxisome biogenesis disorder 5A (Zellweger)](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-5a-zellweger/).

**Reported phenotype names (ClinVar):** Peroxisome biogenesis disorder 5A (Zellweger).

## Similar variants {#similar}

Related PEX2 variant pages (same residue, condition, or type): [PEX2 p.Pro54=](/variant/pex2-p-pro54), [PEX2 p.Tyr277Ter](/variant/pex2-p-tyr277ter), [PEX2 p.Cys184Leu](/variant/pex2-p-cys184leu), [PEX2 c.-17-2A>G](/variant/pex2-c-minus-17-minus-2a-g), [PEX2 p.Ala58fs](/variant/pex2-p-ala58fs), [PEX2 p.Arg119fs](/variant/pex2-p-arg119fs), [PEX2 p.Arg119Ter](/variant/pex2-p-arg119ter), [PEX2 p.Arg125Ter](/variant/pex2-p-arg125ter).

### 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 2050712). 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.*