# NM_000466.3(PEX1):c.147G>A (p.Val49=)

https://sugi.bio/variant/pex1-p-val49

## Summary

**PEX1 p.Val49= (c.147G>A)** is classified **Conflicting classifications of pathogenicity** in PEX1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-05). Ultra-rare (popmax 0.066%, mid); Associated with peroxisome biogenesis disorder 1B.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs202230667 · 8 submitters · 3 linked conditions · ultra-rare (popmax 0.066%, mid)

## For patients & families {#patients}

This is a change in the PEX1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 8 submitters, and is linked to peroxisome biogenesis disorder 1B.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024772/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.Val49= |
| Coding change (HGVS c.) | c.147G>A |
| MANE Select transcript | [NM_000466](https://www.ncbi.nlm.nih.gov/nuccore/NM_000466) |
| dbSNP | [rs202230667](https://www.ncbi.nlm.nih.gov/snp/rs202230667/) |
| Variant type | single nucleotide variant |
| Location | chr7:92522228-92522228 (GRCh38) |
| ClinVar | [VCV729928](https://www.ncbi.nlm.nih.gov/clinvar/variation/729928/) |

**All HGVS expressions:** `NC_000007.13:g.92151542C>T`, `NC_000007.14:g.92522228C>T`, `NG_008341.2:g.11304G>A`, `NM_000466.3:c.147G>A`, `NM_001282677.2:c.147G>A`, `NM_001282678.2:c.-513G>A`

## 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 -0.858, GERP -4.54 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.827**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.066%** (mid) · FAF95 0.0225% · FAF99 0.0135% · 4/6,058 in the highest group · 114/1,614,052 alleles overall — ultra-rare (popmax 0.066%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.066% | 1,514 |
| Remaining individuals (not grpmax-eligible) | 0.0272% | 3,677 |
| African / African-American | 0.012% | 8,338 |
| South Asian | 0.00769% | 13,012 |
| European (non-Finnish) | 0.00627% | 15,946 |
| Admixed American | 0.005% | 20,006 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-05.

**Submitter consensus:** conflicting (5 Uncertain significance, 5 Likely benign).

**Submission history:** 10 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-28 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2018-06-22 |
| Clinical Genetics, Academic Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-06-30 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-05 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-09 |

## Associated conditions {#conditions}

[peroxisome biogenesis disorder 1B](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-1b/), [peroxisome biogenesis disorder 1A (Zellweger)](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-1a-zellweger/), [Zellweger spectrum disorders](https://sugi.bio/atlas/disease/zellweger-spectrum-disorders/).

**Reported phenotype names (ClinVar):** Peroxisome biogenesis disorder 1B, Peroxisome biogenesis disorder 1A (Zellweger), Zellweger spectrum disorders, not provided, Heimler syndrome 1, PEX1-related disorder, not specified, PEX1-related condition, PEROXISOME BIOGENESIS DISORDER (NEONATAL ADRENOLEUKODYSTROPHY/INFANTILE REFSUM DISEASE), INFANTILE PHYTANIC ACID STORAGE DISEASE.

## 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 2026-10-11); 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 729928). 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.*