# NM_000287.4(PEX6):c.2414_2417dup (p.Ser807fs)

https://sugi.bio/variant/pex6-p-ser807fs

## Summary

**PEX6 p.Ser807fs (c.2414_2417dup)** is classified **Likely pathogenic** in PEX6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-23). No gnomAD frequency available for this variant; Associated with Heimler syndrome 2.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2481202967 · 1 submitter · 1 linked condition · 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 1 submitter, and is linked to Heimler syndrome 2.

*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:** [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.Ser807fs |
| Coding change (HGVS c.) | c.2414_2417dup |
| MANE Select transcript | [NM_000287](https://www.ncbi.nlm.nih.gov/nuccore/NM_000287) |
| dbSNP | [rs2481202967](https://www.ncbi.nlm.nih.gov/snp/rs2481202967/) |
| Variant type | Duplication |
| Location | chr6:42965734-42965735 (GRCh38) |
| ClinVar | [VCV2677723](https://www.ncbi.nlm.nih.gov/clinvar/variation/2677723/) |

**All HGVS expressions:** `NC_000006.11:g.42933473_42933476dup`, `NC_000006.12:g.42965735_42965738dup`, `NG_008370.1:g.18506_18509dup`, `NG_008396.1:g.9974_9977dup`, `NM_000287.4:c.2414_2417dup`, `NM_001316313.2:c.2150_2153dup`, `NR_133009.2:n.2198_2201dup`

## 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 2.007, GERP -3.36, 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 13 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 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}

**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 Single submitter *(criteria provided, single submitter)*, last evaluated 2021-12-23.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-12-23 |

## Associated conditions {#conditions}

[Heimler syndrome 2](https://sugi.bio/atlas/disease/heimler-syndrome-2/).

**Reported phenotype names (ClinVar):** Heimler syndrome 2, PEROXISOME BIOGENESIS DISORDER 4C.

## Similar variants {#similar}

Related PEX6 variant pages (same residue, condition, or type): [PEX6 p.Pro100fs](/variant/pex6-p-pro100fs), [PEX6 p.Ser443fs](/variant/pex6-p-ser443fs), [PEX6 c.1369_1370dup](/variant/pex6-c-1369-1370dup), [PEX6 p.Ala645fs](/variant/pex6-p-ala645fs), [PEX6 p.Arg814fs](/variant/pex6-p-arg814fs), [PEX6 p.Asn280Ter](/variant/pex6-p-asn280ter), [PEX6 p.Glu15fs](/variant/pex6-p-glu15fs), [PEX6 p.Leu854fs](/variant/pex6-p-leu854fs).

### 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 2677723). 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.*