# NM_004813.4(PEX16):c.370C>A (p.Arg124=)

https://sugi.bio/variant/pex16-p-arg124

## Summary

**PEX16 p.Arg124= (c.370C>A)** is classified **Likely benign** in PEX16 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-27). Very rare (popmax 0.000593%, nfe); Associated with peroxisome biogenesis disorder.

**At a glance:** Likely benign · review: Single submitter · rsID rs754748410 · 1 submitter · 1 linked condition · very rare (popmax 0.000593%, nfe)

## For patients & families {#patients}

This is a change in the PEX16 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to peroxisome biogenesis disorder.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0011890/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.Arg124= |
| Coding change (HGVS c.) | c.370C>A |
| MANE Select transcript | [NM_004813](https://www.ncbi.nlm.nih.gov/nuccore/NM_004813) |
| dbSNP | [rs754748410](https://www.ncbi.nlm.nih.gov/snp/rs754748410/) |
| Variant type | single nucleotide variant |
| Location | chr11:45915558-45915558 (GRCh38) |
| ClinVar | [VCV2896506](https://www.ncbi.nlm.nih.gov/clinvar/variation/2896506/) |

**All HGVS expressions:** `NC_000011.10:g.45915558G>T`, `NC_000011.9:g.45937109G>T`, `NG_008460.1:g.7566C>A`, `NG_008460.2:g.8264C>A`, `NM_004813.4:c.370C>A`, `NM_057174.3:c.370C>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 5.099, GERP 1.16, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 10.61**. 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 (G>C, Δ0.33 acceptor loss), 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.*
- Pangolin: Δ**0.25** (loss), gain 0.06 / loss 0.25. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000593%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,180,002 in the highest group · 8/1,614,118 alleles overall — very rare (popmax 0.000593%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00156% | 64,008 |
| European (non-Finnish) (grpmax) | 0.000593% | 168,572 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}


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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-27.

**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 | 2025-06-27 |

## Associated conditions {#conditions}

[peroxisome biogenesis disorder](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder/).

**Reported phenotype names (ClinVar):** Peroxisome biogenesis disorder.

## Similar variants {#similar}

Related PEX16 variant pages (same residue, condition, or type): [PEX16 p.Arg124Trp](/variant/pex16-p-arg124trp), [PEX16 p.Arg124Gln](/variant/pex16-p-arg124gln), [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 p.Arg287Cys](/variant/pex16-p-arg287cys), [PEX16 p.Arg287His](/variant/pex16-p-arg287his), [PEX16 c.225+3G>A](/variant/pex16-c-225-plus-3g-a).

### 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 2896506). 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.*