# NM_002618.4(PEX13):c.201dup (p.Val68fs)

https://sugi.bio/variant/pex13-p-val68fs

## Summary

**PEX13 p.Val68fs (c.201dup)** is classified **Pathogenic** in PEX13 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-14). Very rare (popmax 0.00167%, amr); Associated with peroxisome biogenesis disorder 11A (Zellweger).

**At a glance:** Pathogenic · review: Single submitter · rsID rs1288976071 · 1 submitter · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the PEX13 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to peroxisome biogenesis disorder 11A (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/0015874/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PEX13](https://sugi.bio/atlas/gene/PEX13/) |
| Protein change (HGVS p.) | p.Val68fs |
| Coding change (HGVS c.) | c.201dup |
| MANE Select transcript | [NM_002618](https://www.ncbi.nlm.nih.gov/nuccore/NM_002618) |
| dbSNP | [rs1288976071](https://www.ncbi.nlm.nih.gov/snp/rs1288976071/) |
| Variant type | Duplication |
| Location | chr2:61031526-61031527 (GRCh38) |
| ClinVar | [VCV1426245](https://www.ncbi.nlm.nih.gov/clinvar/variation/1426245/) |

**All HGVS expressions:** `NC_000002.11:g.61258662dup`, `NC_000002.12:g.61031527dup`, `NG_008665.1:g.18851dup`, `NM_002618.4:c.201dup`

## 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 -1.108, GERP -3.32 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.159, pLI 2.8784e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 4**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 21.2**. 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: **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 (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/59,996 in the highest group · 1/1,614,042 alleles overall — very rare (popmax 0.00167%, amr).

*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}

**PEX13** population constraint: LOEUF 1.159, pLI 2.8784e-07, missense-Z -0.75296. *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 **68** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 65.62, 16% of residues very-high.

**3 experimental structure(s)** (PDB): [7Z0I](https://www.rcsb.org/structure/7Z0I), [7Z0J](https://www.rcsb.org/structure/7Z0J), [7Z0K](https://www.rcsb.org/structure/7Z0K).

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

*Describes the biological roles of PEX13 (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:** PEX13's established molecular role includes transmembrane protein transporter activity. p.Val68fs falls in the disordered region.


### Pathways affected {#pathways}

PEX13 participates in **3 Reactome pathways** (⚕ = disease pathway):

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

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

**Molecular function:** transmembrane protein transporter activity.

**Biological process:** protein import into peroxisome matrix, docking, protein import into peroxisome matrix, translocation, cellular response to reactive oxygen species.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-14.

**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 | 2024-02-14 |

## Associated conditions {#conditions}

[peroxisome biogenesis disorder 11A (Zellweger)](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-11a-zellweger/).

**Reported phenotype names (ClinVar):** Peroxisome biogenesis disorder 11A (Zellweger), Peroxisome biogenesis disorder 11A.

## Similar variants {#similar}

Related PEX13 variant pages (same residue, condition, or type): [PEX13 p.Val68Met](/variant/pex13-p-val68met), [PEX13 p.Val68=](/variant/pex13-p-val68), [PEX13 p.Ala277fs](/variant/pex13-p-ala277fs), [PEX13 p.Pro8fs](/variant/pex13-p-pro8fs), [PEX13 p.Thr49fs](/variant/pex13-p-thr49fs), [PEX13 c.914-8dup](/variant/pex13-c-914-minus-8dup), [PEX13 c.93-3dup](/variant/pex13-c-93-minus-3dup), [PEX13 p.Arg16Ter](/variant/pex13-p-arg16ter).

### 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 1426245). 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.*