# NM_000466.3(PEX1):c.657_660del (p.Ser220fs)

https://sugi.bio/variant/pex1-p-ser220fs

## Summary

**PEX1 p.Ser220fs (c.657_660del)** is classified **Pathogenic/Likely pathogenic** in PEX1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-17). No gnomAD frequency available for this variant; Associated with Zellweger spectrum disorders.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs786205656 · 3 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PEX1 gene that is considered likely disease-causing, submitted by 3 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 | PEX1 is a diagnostic-grade gene on 20 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 | [PEX1](https://sugi.bio/atlas/gene/PEX1/) |
| Protein change (HGVS p.) | p.Ser220fs |
| Coding change (HGVS c.) | c.657_660del |
| MANE Select transcript | [NM_000466](https://www.ncbi.nlm.nih.gov/nuccore/NM_000466) |
| dbSNP | [rs786205656](https://www.ncbi.nlm.nih.gov/snp/rs786205656/) |
| Variant type | Deletion |
| Location | chr7:92517855-92517858 (GRCh38) |
| ClinVar | [VCV191337](https://www.ncbi.nlm.nih.gov/clinvar/variation/191337/) |

**All HGVS expressions:** `NC_000007.13:g.92147172_92147175del`, `NC_000007.14:g.92517858_92517861del`, `NG_008341.2:g.15674_15677del`, `NM_000466.3:c.657_660del`, `NM_001282677.2:c.657_660del`, `NM_001282678.2:c.33_36del`

## 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 -0.969, GERP -0.599 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.746, pLI 3.6437e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 24**, so the transcript is predicted to undergo NMD.
- 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: **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}

**PEX1** population constraint: LOEUF 0.746, pLI 3.6437e-11, missense-Z 1.6893. *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 due to PEX1 defect** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 67.19, 8% of residues very-high.

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

*Describes the biological roles of PEX1 (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:** PEX1's established molecular role includes ATP binding.


### Pathways affected {#pathways}

PEX1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |

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

**Molecular function:** ATP binding, ATP hydrolysis activity, protein-containing complex binding, ubiquitin-modified protein reader activity, protein transporter activity.

**Biological process:** protein targeting to peroxisome, peroxisome organization, protein import into peroxisome matrix, protein import into peroxisome matrix, receptor recycling, protein unfolding, microtubule-based peroxisome localization.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-02-17.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2020–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | research |  |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-11-26 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Zellweger spectrum disorders, not provided, Heimler syndrome 1, Zellweger Spectrum Disorder, Zellweger Spectrum, Zellweger syndrome, Zellweger Spectrum Disorder (ZSD), PEROXISOME BIOGENESIS DISORDER 1C, none provided.

## Same-residue context {#hotspot}

Residue **220** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PEX1 p.Ser220Ter](/variant/pex1-p-ser220ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PEX1 variant pages (same residue, condition, or type): [PEX1 p.Ser220Leu](/variant/pex1-p-ser220leu), [PEX1 p.Ser220=](/variant/pex1-p-ser220), [PEX1 c.2072-42_2085del](/variant/pex1-c-2072-minus-42-2085del), [PEX1 p.Ala15fs](/variant/pex1-p-ala15fs), [PEX1 p.Ala921fs](/variant/pex1-p-ala921fs), [PEX1 p.Arg1208fs](/variant/pex1-p-arg1208fs), [PEX1 p.Arg827fs](/variant/pex1-p-arg827fs), [PEX1 p.Asn1088fs](/variant/pex1-p-asn1088fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 191337). 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.*