# NM_000318.3(PEX2):c.789_790del (p.Phe263fs)

https://sugi.bio/variant/pex2-p-phe263fs

## Summary

**PEX2 p.Phe263fs (c.789_790del)** is classified **Likely pathogenic** in PEX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-20). Very rare (popmax 8.47e-05%, nfe); Associated with Zellweger spectrum disorders.

**At a glance:** Likely pathogenic · review: Multiple submitters · 2 submitters · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the PEX2 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to Zellweger spectrum disorders.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Neonatal |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PEX2 is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of Zellweger syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal pinna morphology — Very frequent (99-80%)
- Death in infancy — Very frequent (99-80%)
- Respiratory insufficiency — Very frequent (99-80%)
- Hepatomegaly — Very frequent (99-80%)
- EEG abnormality — Very frequent (99-80%)
- Skeletal dysplasia — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)
- Depressed nasal bridge — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007917/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.Phe263fs |
| Coding change (HGVS c.) | c.789_790del |
| MANE Select transcript | [NM_000318](https://www.ncbi.nlm.nih.gov/nuccore/NM_000318) |
| Variant type | Deletion |
| Location | chr8:76983389-76983390 (GRCh38) |
| ClinVar | [VCV4818162](https://www.ncbi.nlm.nih.gov/clinvar/variation/4818162/) |

**All HGVS expressions:** `NC_000008.10:g.77895626_77895627del`, `NC_000008.11:g.76983390_76983391del`, `NG_008371.1:g.21899_21900del`, `NG_008371.2:g.22654_22655del`, `NM_000318.3:c.789_790del`, `NM_001079867.2:c.789_790del`, `NM_001172086.2:c.789_790del`, `NM_001172087.2:c.789_790del`

## 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 7.709, GERP 2.44, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.057, pLI 1.7994e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (4 of 4)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 32.0**. 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 deletion 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 **8.47e-05%** (nfe) · 1/1,180,038 in the highest group · 1/1,613,958 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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 **263** lies in a UniProt-annotated variant site (in pbd5a); a UniProt-annotated variant site (in pbd5b and pbd5a); a UniProt-annotated variant site (in pbd5b).

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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-20.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2019–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-09-20 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-09-06 |

## Associated conditions {#conditions}

[Zellweger spectrum disorders](https://sugi.bio/atlas/disease/zellweger-spectrum-disorders/).

**Reported phenotype names (ClinVar):** Zellweger spectrum disorders, PEX2-related disorder, Zellweger syndrome, Zellweger Spectrum Disorder, Zellweger Spectrum, Zellweger Spectrum Disorder (ZSD), PEX2-related condition.

## Similar variants {#similar}

Related PEX2 variant pages (same residue, condition, or type): [PEX2 p.Arg94fs](/variant/pex2-p-arg94fs), [PEX2 p.Glu118fs](/variant/pex2-p-glu118fs), [PEX2 p.Gly113_Arg114insTer](/variant/pex2-p-gly113-arg114inster), [PEX2 p.Leu204fs](/variant/pex2-p-leu204fs), [PEX2 p.Cys283fs](/variant/pex2-p-cys283fs), [PEX2 p.Gly149fs](/variant/pex2-p-gly149fs), [PEX2 p.Leu166fs](/variant/pex2-p-leu166fs), [PEX2 p.Lys136fs](/variant/pex2-p-lys136fs).

### 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 4818162). 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.*