# NM_004813.4(PEX16):c.1002T>C (p.Ser334=)

https://sugi.bio/variant/pex16-p-ser334

## Summary

**PEX16 p.Ser334= (c.1002T>C)** is classified **Conflicting classifications of pathogenicity** in PEX16 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0166%, mid); Associated with peroxisome biogenesis disorder 8A (Zellweger).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs144897515 · 5 submitters · 2 linked conditions · ultra-rare (popmax 0.0166%, mid)

## For patients & families {#patients}

This is a change in the PEX16 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 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.Ser334= |
| Coding change (HGVS c.) | c.1002T>C |
| MANE Select transcript | [NM_004813](https://www.ncbi.nlm.nih.gov/nuccore/NM_004813) |
| dbSNP | [rs144897515](https://www.ncbi.nlm.nih.gov/snp/rs144897515/) |
| Variant type | single nucleotide variant |
| Location | chr11:45910263-45910263 (GRCh38) |
| ClinVar | [VCV286888](https://www.ncbi.nlm.nih.gov/clinvar/variation/286888/) |

**All HGVS expressions:** `NC_000011.10:g.45910263A>G`, `NC_000011.9:g.45931814A>G`, `NG_008460.1:g.12861T>C`, `NM_004813.4:c.1002T>C`, `NM_057174.3:c.953-86T>C`

## 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 0.322, GERP -1.35 — weakly conserved position
- CADD: **PHRED 5.773**. 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 (A>C, Δ0.93 donor 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 **0.0166%** (mid) · FAF95 0.00543% · FAF99 0.0038% · 1/6,018 in the highest group · 328/1,613,804 alleles overall — ultra-rare (popmax 0.0166%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.787% | 127 |
| Remaining individuals (not grpmax-eligible) | 0.08% | 1,250 |
| Middle Eastern (grpmax) | 0.0166% | 6,018 |
| Admixed American | 0.0117% | 8,574 |
| European (non-Finnish) | 0.00305% | 32,775 |
| East Asian | 0.00223% | 44,864 |

Ashkenazi Jewish 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}

Residue **334** 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}

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

**Submitter consensus:** conflicting (3 Likely benign, 2 Uncertain significance).

**Submission history:** 5 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 | 2024-11-27 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-03-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-01 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related PEX16 variant pages (same residue, condition, or type): [PEX16 p.Ser334Asn](/variant/pex16-p-ser334asn), [PEX16 p.Ser334Thr](/variant/pex16-p-ser334thr), [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 2026-10-14); 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 286888). 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.*