# NM_001351132.2(PEX5):c.54_69dup (p.Phe24fs)

https://sugi.bio/variant/pex5-p-phe24fs

## Summary

**PEX5 p.Phe24fs (c.54_69dup)** is classified **Pathogenic** in PEX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-14). No gnomAD frequency available for this variant; Associated with peroxisome biogenesis disorder 2B.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2539798184 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PEX5 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to peroxisome biogenesis disorder 2B.

*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/0015134/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PEX5](https://sugi.bio/atlas/gene/PEX5/) |
| Protein change (HGVS p.) | p.Phe24fs |
| Coding change (HGVS c.) | c.54_69dup |
| MANE Select transcript | [NM_001351132](https://www.ncbi.nlm.nih.gov/nuccore/NM_001351132) |
| dbSNP | [rs2539798184](https://www.ncbi.nlm.nih.gov/snp/rs2539798184/) |
| Variant type | Duplication |
| Location | chr12:7190430-7190431 (GRCh38) |
| ClinVar | [VCV2082711](https://www.ncbi.nlm.nih.gov/clinvar/variation/2082711/) |

**All HGVS expressions:** `NC_000012.11:g.7343027_7343042dup`, `NC_000012.12:g.7190431_7190446dup`, `NG_008448.1:g.6269_6284dup`, `NG_125086.1:g.272_287dup`, `NM_000319.5:c.54_69dup`, `NM_001131023.2:c.54_69dup`, `NM_001131024.2:c.54_69dup`, `NM_001131025.2:c.54_69dup`, `NM_001131026.2:c.54_69dup`, `NM_001300789.3:c.54_69dup`, `NM_001351124.3:c.54_69dup`, `NM_001351126.2:c.54_69dup`, `NM_001351127.2:c.54_69dup`, `NM_001351128.2:c.54_69dup`, `NM_001351130.3:c.54_69dup`, `NM_001351131.2:c.54_69dup`, `NM_001351132.2:c.54_69dup`, `NM_001351133.2:c.54_69dup`, `NM_001351134.2:c.54_69dup`, `NM_001351135.3:c.54_69dup`, `NM_001351136.2:c.54_69dup`, `NM_001351137.3:c.54_69dup`, `NM_001351138.2:c.54_69dup`, `NM_001351139.2:c.54_69dup`, `NM_001351140.2:c.54_69dup`, `NM_001374645.1:c.54_69dup`, `NM_001374646.1:c.54_69dup`, `NM_001374647.2:c.54_69dup`, `NM_001374648.2:c.54_69dup`, `NM_001374649.2:c.54_69dup`

## Computational & population evidence {#evidence}

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

- **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 7.725, GERP 1.34, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.768, pLI 2.1956e-09. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**PEX5** population constraint: LOEUF 0.768, pLI 2.1956e-09, missense-Z 1.8256. *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 **24** lies in the 'amphipathic helix 1 (ah1)' region.

AlphaFold model confidence (whole protein): pLDDT 70.28, 41% of residues very-high.

**11 experimental structure(s)** (PDB): [1FCH](https://www.rcsb.org/structure/1FCH), [2C0L](https://www.rcsb.org/structure/2C0L), [2C0M](https://www.rcsb.org/structure/2C0M), [2J9Q](https://www.rcsb.org/structure/2J9Q), [2W84](https://www.rcsb.org/structure/2W84), [3R9A](https://www.rcsb.org/structure/3R9A) — incl. mutant structure 4KXK.

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

*Describes the biological roles of PEX5 (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:** PEX5's established molecular role includes peroxisome signal sequence receptor activity. p.Phe24fs falls in the amphipathic helix 1 (ah1) region.


### Pathways affected {#pathways}

PEX5 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Pexophagy](https://reactome.org/content/detail/R-HSA-9664873) | curated |
| [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:** peroxisome signal sequence receptor activity, obsolete peroxisome matrix targeting signal-1 binding, enzyme binding, small GTPase binding, obsolete peroxisome membrane targeting sequence binding, protein carrier activity.

**Biological process:** pexophagy, protein targeting to peroxisome, protein import into peroxisome matrix, protein import into peroxisome matrix, docking, protein import into peroxisome matrix, translocation, protein import into peroxisome matrix, receptor recycling.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-14.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-14 |

## Associated conditions {#conditions}

[peroxisome biogenesis disorder 2B](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-2b/).

**Reported phenotype names (ClinVar):** Peroxisome biogenesis disorder 2B.

## Similar variants {#similar}

Related PEX5 variant pages (same residue, condition, or type): [PEX5 p.Ser235fs](/variant/pex5-p-ser235fs), [PEX5 p.Thr316fs](/variant/pex5-p-thr316fs), [PEX5 c.967-3dup](/variant/pex5-c-967-minus-3dup), [PEX5 c.1718+11_1718+14dup](/variant/pex5-c-1718-plus-11-1718-plus-14dup), [PEX5 p.Ala422fs](/variant/pex5-p-ala422fs), [PEX5 p.Arg427fs](/variant/pex5-p-arg427fs), [PEX5 p.Leu270fs](/variant/pex5-p-leu270fs), [PEX5 p.Thr179fs](/variant/pex5-p-thr179fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2082711). 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.*