# NM_000287.4(PEX6):c.406delinsAT (p.Pro136fs)

https://sugi.bio/variant/pex6-p-pro136fs

## Summary

**PEX6 p.Pro136fs (c.406delinsAT)** is classified **Likely pathogenic** in PEX6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-17). No gnomAD frequency available for this variant; Associated with Zellweger spectrum disorders.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs1554128488 · 3 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PEX6 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 | PEX6 is a diagnostic-grade gene on 24 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 | [PEX6](https://sugi.bio/atlas/gene/PEX6/) |
| Protein change (HGVS p.) | p.Pro136fs |
| Coding change (HGVS c.) | c.406delinsAT |
| MANE Select transcript | [NM_000287](https://www.ncbi.nlm.nih.gov/nuccore/NM_000287) |
| dbSNP | [rs1554128488](https://www.ncbi.nlm.nih.gov/snp/rs1554128488/) |
| Variant type | Indel |
| Location | chr6:42978745-42978745 (GRCh38) |
| ClinVar | [VCV557579](https://www.ncbi.nlm.nih.gov/clinvar/variation/557579/) |

**All HGVS expressions:** `NC_000006.11:g.42946483delinsAT`, `NC_000006.12:g.42978745delinsAT`, `NG_008370.1:g.5499delinsAT`, `NM_000287.4:c.406delinsAT`, `NM_001316313.2:c.406delinsAT`, `NR_133009.2:n.437delinsAT`

## 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 7.259, GERP 0.507, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.799, pLI 1.1594e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 17**, so the transcript is predicted to undergo NMD.
- 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}

**PEX6** population constraint: LOEUF 0.799, pLI 1.1594e-11, missense-Z 1.3471. *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}


AlphaFold model confidence (whole protein): pLDDT 69.87, 1% of residues very-high.

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

*Describes the biological roles of PEX6 (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:** PEX6's established molecular role includes ATP binding.


### Pathways affected {#pathways}

PEX6 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, translocation, protein import into peroxisome matrix, receptor recycling, protein unfolding, protein stabilization.

## Clinical significance {#significance}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-17.

**Submitter consensus:** unanimous (3/3 Likely pathogenic).

**Submission history:** 3 submissions (2018–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2018-04-04 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-07-09 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-17 |

## Associated conditions {#conditions}

[Zellweger spectrum disorders](https://sugi.bio/atlas/disease/zellweger-spectrum-disorders/), [peroxisome biogenesis disorder 4A (Zellweger)](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-4a-zellweger/), [peroxisome biogenesis disorder 4B](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-4b/).

**Reported phenotype names (ClinVar):** Zellweger spectrum disorders, Peroxisome biogenesis disorder 4A (Zellweger), Peroxisome biogenesis disorder 4B, Heimler syndrome 2, Zellweger Spectrum Disorder, Zellweger Spectrum, Zellweger syndrome, Zellweger Spectrum Disorder (ZSD), PEROXISOME BIOGENESIS DISORDER 4C, Zellweger syndrome spectrum (PEX6-related).

## Similar variants {#similar}

Related PEX6 variant pages (same residue, condition, or type): [PEX6 p.Pro136Gln](/variant/pex6-p-pro136gln), [PEX6 p.Ala4fs](/variant/pex6-p-ala4fs), [PEX6 p.Ile800fs](/variant/pex6-p-ile800fs), [PEX6 p.Ala656fs](/variant/pex6-p-ala656fs), [PEX6 p.Glu772fs](/variant/pex6-p-glu772fs), [PEX6 p.Gly470fs](/variant/pex6-p-gly470fs), [PEX6 p.Leu266fs](/variant/pex6-p-leu266fs), [PEX6 p.Leu674fs](/variant/pex6-p-leu674fs).

### 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 557579). 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.*