# NM_003630.3(PEX3):c.856C>A (p.Arg286=)

https://sugi.bio/variant/pex3-p-arg286

## Summary

**PEX3 p.Arg286= (c.856C>A)** is classified **Benign/Likely benign** in PEX3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). Rare (popmax 0.407%, afr).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs147556993 · 3 submitters · rare (popmax 0.407%, afr)

## For patients & families {#patients}

This is a change in the PEX3 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [PEX3](https://sugi.bio/atlas/gene/PEX3/) |
| Protein change (HGVS p.) | p.Arg286= |
| Coding change (HGVS c.) | c.856C>A |
| MANE Select transcript | [NM_003630](https://www.ncbi.nlm.nih.gov/nuccore/NM_003630) |
| dbSNP | [rs147556993](https://www.ncbi.nlm.nih.gov/snp/rs147556993/) |
| Variant type | single nucleotide variant |
| Location | chr6:143479113-143479113 (GRCh38) |
| ClinVar | [VCV286359](https://www.ncbi.nlm.nih.gov/clinvar/variation/286359/) |

**All HGVS expressions:** `NC_000006.11:g.143800250C>A`, `NC_000006.12:g.143479113C>A`, `NG_008459.1:g.33333C>A`, `NM_003630.3:c.856C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.47) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.695, GERP 1.03, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 2.027**. 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 deltas (raw): acceptor loss **0.47**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 37 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.407%** (afr) · FAF95 0.369% · FAF99 0.355% · 303/74,438 in the highest group · 338/1,589,028 alleles overall — rare (popmax 0.407%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.407% | 246 |
| Remaining individuals (not grpmax-eligible) | 0.0195% | 5,137 |
| Admixed American | 0.0167% | 5,993 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,954 |
| European (non-Finnish) | 0.00104% | 96,462 |

*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 **286** 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-19.

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

**Submission history:** 3 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-11 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2016-02-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-19 |

**Reported phenotype names (ClinVar):** not specified, not provided, none provided, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **286** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PEX3 p.Arg286Ter](/variant/pex3-p-arg286ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PEX3 variant pages (same residue, condition, or type): [PEX3 p.Arg286Ter](/variant/pex3-p-arg286ter), [PEX3 p.Arg286Gln](/variant/pex3-p-arg286gln), [PEX3 c.288-1G>A](/variant/pex3-c-288-minus-1g-a), [PEX3 c.942-1G>T](/variant/pex3-c-942-minus-1g-t), [PEX3 p.Arg256Ter](/variant/pex3-p-arg256ter), [PEX3 p.Trp6Ter](/variant/pex3-p-trp6ter), [PEX3 c.818+3A>G](/variant/pex3-c-818-plus-3a-g), [PEX3 c.-96G>T](/variant/pex3-c-minus-96g-t).

### 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 286359). 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.*