# NM_000466.3(PEX1):c.840T>C (p.Val280=)

https://sugi.bio/variant/pex1-p-val280

## Summary

**PEX1 p.Val280= (c.840T>C)** is classified **Likely benign** in PEX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-05). Very rare (popmax 0.00167%, amr); Associated with Zellweger spectrum disorders.

**At a glance:** Likely benign · review: Single submitter · rsID rs1353988386 · 1 submitter · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the PEX1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Val280= |
| Coding change (HGVS c.) | c.840T>C |
| MANE Select transcript | [NM_000466](https://www.ncbi.nlm.nih.gov/nuccore/NM_000466) |
| dbSNP | [rs1353988386](https://www.ncbi.nlm.nih.gov/snp/rs1353988386/) |
| Variant type | single nucleotide variant |
| Location | chr7:92517675-92517675 (GRCh38) |
| ClinVar | [VCV1942018](https://www.ncbi.nlm.nih.gov/clinvar/variation/1942018/) |

**All HGVS expressions:** `NC_000007.13:g.92146989A>G`, `NC_000007.14:g.92517675A>G`, `NG_008341.2:g.15857T>C`, `NM_000466.3:c.840T>C`, `NM_001282677.2:c.840T>C`, `NM_001282678.2:c.216T>C`

## 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 -0.044, GERP -4.24 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.698**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.20 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/60,024 in the highest group · 1/1,613,940 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}

**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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-05 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Zellweger spectrum disorders, Zellweger Spectrum Disorder, Zellweger Spectrum, Zellweger Spectrum Disorder (ZSD), Zellweger syndrome.

## Similar variants {#similar}

Related PEX1 variant pages (same residue, condition, or type): [PEX1 c.1239+1G>T](/variant/pex1-c-1239-plus-1g-t), [PEX1 c.130-1G>T](/variant/pex1-c-130-minus-1g-t), [PEX1 c.130-2A>G](/variant/pex1-c-130-minus-2a-g), [PEX1 c.130-2A>T](/variant/pex1-c-130-minus-2a-t), [PEX1 c.1483+1G>A](/variant/pex1-c-1483-plus-1g-a), [PEX1 c.1587+1G>A](/variant/pex1-c-1587-plus-1g-a), [PEX1 c.1670+1G>A](/variant/pex1-c-1670-plus-1g-a), [PEX1 c.1670+1G>T](/variant/pex1-c-1670-plus-1g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1942018). 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.*