# NM_003630.3(PEX3):c.473C>G (p.Pro158Arg)

https://sugi.bio/variant/pex3-p-pro158arg

## Summary

**PEX3 p.Pro158Arg (c.473C>G)** is classified **Conflicting classifications of pathogenicity** in PEX3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.2879); Rare (popmax 0.21%, eas); Associated with peroxisome biogenesis disorder 10A (Zellweger).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs199781957 · 5 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.21%, eas)

## For patients & families {#patients}

This is a change in the PEX3 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to peroxisome biogenesis disorder 10A (Zellweger).

*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/0015873/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PEX3](https://sugi.bio/atlas/gene/PEX3/) |
| Protein change (HGVS p.) | p.Pro158Arg |
| Coding change (HGVS c.) | c.473C>G |
| MANE Select transcript | [NM_003630](https://www.ncbi.nlm.nih.gov/nuccore/NM_003630) |
| dbSNP | [rs199781957](https://www.ncbi.nlm.nih.gov/snp/rs199781957/) |
| Variant type | single nucleotide variant |
| Location | chr6:143471399-143471399 (GRCh38) |
| ClinVar | [VCV291279](https://www.ncbi.nlm.nih.gov/clinvar/variation/291279/) |

**All HGVS expressions:** `NC_000006.11:g.143792536C>G`, `NC_000006.12:g.143471399C>G`, `NG_008459.1:g.25619C>G`, `NM_003630.3:c.473C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2879)
- REVEL 0.202 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.744 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.662, GERP 1.12, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.6**. 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.*
- Regional missense constraint: **o/e 0.81** across the covering region of the MANE Select transcript (143,451,043–143,489,223), spanning 38,180 bp. Chi-square p 8.4e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.21 acceptor 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 **0.21%** (eas) · FAF95 0.176% · FAF99 0.163% · 94/44,736 in the highest group · 230/1,606,602 alleles overall — rare (popmax 0.21%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.21% | 476 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.166% | 602 |
| Remaining individuals (not grpmax-eligible) | 0.0257% | 3,888 |
| Middle Eastern | 0.0165% | 6,044 |
| South Asian | 0.00992% | 10,082 |
| European (non-Finnish) | 0.00503% | 19,891 |
| Admixed American | 0.00333% | 30,010 |

*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}

**PEX3** population constraint: LOEUF 0.972, pLI 0.11603, missense-Z 1.0392. *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}

Residue **158** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 88.94, 75% of residues very-high.

**2 experimental structure(s)** (PDB): [3AJB](https://www.rcsb.org/structure/3AJB), [3MK4](https://www.rcsb.org/structure/3MK4).

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

*Describes the biological roles of PEX3 (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:** PEX3's established molecular role includes lipid binding.


### Pathways affected {#pathways}

PEX3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ABC transporters in lipid homeostasis](https://reactome.org/content/detail/R-HSA-1369062) | curated |
| [Class I peroxisomal membrane protein import](https://reactome.org/content/detail/R-HSA-9603798) | electronic |

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

**Molecular function:** lipid binding.

**Biological process:** peroxisome organization, protein import into peroxisome membrane.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-28.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Likely benign, 1 Benign).

**Submission history:** 5 submissions (2016–2026); 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 | 2018-01-13 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-07 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-08-19 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-09-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |

## Associated conditions {#conditions}

[peroxisome biogenesis disorder 10A (Zellweger)](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-10a-zellweger/).

**Reported phenotype names (ClinVar):** Peroxisome biogenesis disorder 10A (Zellweger), not provided, PEX3-related disorder, not specified, PEX3-related condition, AllHighlyPenetrant, Peroxisome biogenesis disorder 10A, none provided.

## Same-residue context {#hotspot}

Residue **158** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PEX3 p.Pro158fs](/variant/pex3-p-pro158fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PEX3 variant pages (same residue, condition, or type): [PEX3 p.Pro158Ala](/variant/pex3-p-pro158ala), [PEX3 p.Pro158Ser](/variant/pex3-p-pro158ser), [PEX3 c.288-1G>A](/variant/pex3-c-288-minus-1g-a), [PEX3 c.-96G>T](/variant/pex3-c-minus-96g-t), [PEX3 p.Arg300Gln](/variant/pex3-p-arg300gln), [PEX3 p.Asp305Glu](/variant/pex3-p-asp305glu), [PEX3 p.Glu266Asp](/variant/pex3-p-glu266asp), [PEX3 p.Met270Ile](/variant/pex3-p-met270ile).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 291279). 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.*