# NM_004813.4(PEX16):c.859C>T (p.Arg287Cys)

https://sugi.bio/variant/pex16-p-arg287cys

## Summary

**PEX16 p.Arg287Cys (c.859C>T)** is classified **Pathogenic/Likely pathogenic** in PEX16 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.7464); Very rare (popmax 0.0022%, sas); Associated with peroxisome biogenesis disorder 8A (Zellweger).

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs769772100 · 6 submitters · 3 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the PEX16 gene that is considered likely disease-causing, submitted by 6 submitters, and is linked to peroxisome biogenesis disorder 8A (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/0015869/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PEX16](https://sugi.bio/atlas/gene/PEX16/) |
| Protein change (HGVS p.) | p.Arg287Cys |
| Coding change (HGVS c.) | c.859C>T |
| MANE Select transcript | [NM_004813](https://www.ncbi.nlm.nih.gov/nuccore/NM_004813) |
| dbSNP | [rs769772100](https://www.ncbi.nlm.nih.gov/snp/rs769772100/) |
| Variant type | single nucleotide variant |
| Location | chr11:45913847-45913847 (GRCh38) |
| ClinVar | [VCV561075](https://www.ncbi.nlm.nih.gov/clinvar/variation/561075/) |

**All HGVS expressions:** `NC_000011.10:g.45913847G>A`, `NC_000011.9:g.45935398G>A`, `NG_008460.1:g.9277C>T`, `NM_004813.3:c.859C>T`, `NM_004813.4:c.859C>T`, `NM_057174.3:c.859C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.7464) — concordant with the pathogenic call
- REVEL 0.686 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.073 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.76, GERP 2.2, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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 0.91** across the covering region of the MANE Select transcript (45,910,257–45,917,811), spanning 7,554 bp. Chi-square p 0.075. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.0022%** (sas) · FAF95 0.000365% · FAF99 0.00026% · 2/91,094 in the highest group · 11/1,613,640 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0022% | 45,547 |
| European (non-Finnish) | 0.000763% | 131,103 |

*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}

**PEX16** population constraint: LOEUF 0.957, pLI 9.9638e-10, missense-Z 0.5051; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 **287** lies in the 'interaction with pex19' region.

AlphaFold model confidence (whole protein): pLDDT 83.07, 36% of residues very-high.

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

*Describes the biological roles of PEX16 (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.*


### Pathways affected {#pathways}

PEX16 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Class I peroxisomal membrane protein import](https://reactome.org/content/detail/R-HSA-9603798) | electronic |

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

**Biological process:** protein targeting to peroxisome, peroxisome organization, peroxisome membrane biogenesis, protein import into peroxisome matrix, protein to membrane docking, ER-dependent peroxisome organization.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-26.

**Submitter consensus:** conflicting (4 Likely pathogenic, 2 Pathogenic, 1 Uncertain significance).

**Submission history:** 7 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | flagged submission | clinical testing | 2017-09-01 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-12-16 |
| Dubai Health Genomic Medicine Center, Dubai Health | Likely pathogenic | criteria provided, single submitter | research | 2024-10-04 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-17 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-12-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-26 |

## Associated conditions {#conditions}

[peroxisome biogenesis disorder 8A (Zellweger)](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-8a-zellweger/), [peroxisome biogenesis disorder 8B](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-8b/), [peroxisome biogenesis disorder](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder/).

**Reported phenotype names (ClinVar):** Peroxisome biogenesis disorder 8A (Zellweger), Peroxisome biogenesis disorder 8B, Peroxisome biogenesis disorder, not provided, none provided, Peroxisome biogenesis disorder 8A.

## Same-residue context {#hotspot}

Residue **287** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PEX16 p.Arg287His](/variant/pex16-p-arg287his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PEX16 variant pages (same residue, condition, or type): [PEX16 p.Arg287His](/variant/pex16-p-arg287his), [PEX16 p.Arg287=](/variant/pex16-p-arg287), [PEX16 c.888-1G>C](/variant/pex16-c-888-minus-1g-c), [PEX16 p.Arg176Ter](/variant/pex16-p-arg176ter), [PEX16 p.Arg227Trp](/variant/pex16-p-arg227trp), [PEX16 c.225+3G>A](/variant/pex16-c-225-plus-3g-a), [PEX16 p.Ala114Thr](/variant/pex16-p-ala114thr), [PEX16 p.Arg124Trp](/variant/pex16-p-arg124trp).

### 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 561075). 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.*