# NM_001127649.3(PEX26):c.336C>T (p.Val112=)

https://sugi.bio/variant/pex26-p-val112

## Summary

**PEX26 p.Val112= (c.336C>T)** is classified **Likely benign** in PEX26 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-22). Ultra-rare (popmax 0.0143%, sas); Associated with peroxisome biogenesis disorder 7A (Zellweger).

**At a glance:** Likely benign · review: Single submitter · rsID rs753324008 · 1 submitter · 2 linked conditions · ultra-rare (popmax 0.0143%, sas)

## For patients & families {#patients}

This is a change in the PEX26 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to peroxisome biogenesis disorder 7A (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/0015866/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PEX26](https://sugi.bio/atlas/gene/PEX26/) |
| Protein change (HGVS p.) | p.Val112= |
| Coding change (HGVS c.) | c.336C>T |
| MANE Select transcript | [NM_001127649](https://www.ncbi.nlm.nih.gov/nuccore/NM_001127649) |
| dbSNP | [rs753324008](https://www.ncbi.nlm.nih.gov/snp/rs753324008/) |
| Variant type | single nucleotide variant |
| Location | chr22:18079979-18079979 (GRCh38) |
| ClinVar | [VCV2086782](https://www.ncbi.nlm.nih.gov/clinvar/variation/2086782/) |

**All HGVS expressions:** `NC_000022.10:g.18562745C>T`, `NC_000022.11:g.18079979C>T`, `NG_008339.2:g.6991C>T`, `NM_001127649.3:c.336C>T`, `NM_001199319.2:c.336C>T`, `NM_017929.6:c.336C>T`

## 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 -0.004, GERP 1.1, phastCons 0.005 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.984**. 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 (C>A, Δ0.59 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 **0.0143%** (sas) · FAF95 0.00844% · FAF99 0.00661% · 13/91,076 in the highest group · 14/1,614,114 alleles overall — ultra-rare (popmax 0.0143%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0143% | 7,006 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,508 |

*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}

**PEX26** population constraint: LOEUF 0.893, pLI 0.00037786, missense-Z -0.068794. *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 79.87, 48% of residues very-high.

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

*Describes the biological roles of PEX26 (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:** PEX26's established molecular role includes protein-membrane adaptor activity.


### Pathways affected {#pathways}

PEX26 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Class I peroxisomal membrane protein import](https://reactome.org/content/detail/R-HSA-9603798) | curated |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |

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

**Molecular function:** protein-membrane adaptor activity, protein-containing complex binding, ATPase binding.

**Biological process:** protein import into peroxisome matrix, protein to membrane docking.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-22.

**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 | 2023-10-22 |

## Associated conditions {#conditions}

[peroxisome biogenesis disorder 7A (Zellweger)](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-7a-zellweger/), [peroxisome biogenesis disorder 7B](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-7b/).

**Reported phenotype names (ClinVar):** Peroxisome biogenesis disorder 7A (Zellweger), Peroxisome biogenesis disorder 7B, Peroxisome biogenesis disorder 7A.

## Similar variants {#similar}

Related PEX26 variant pages (same residue, condition, or type): [PEX26 p.Val112Leu](/variant/pex26-p-val112leu), [PEX26 c.230+1G>T](/variant/pex26-c-230-plus-1g-t), [PEX26 c.667+2T>C](/variant/pex26-c-667-plus-2t-c), [PEX26 p.Arg192Ter](/variant/pex26-p-arg192ter), [PEX26 p.Arg98Trp](/variant/pex26-p-arg98trp), [PEX26 p.Gln146Ter](/variant/pex26-p-gln146ter), [PEX26 p.Gly89Arg](/variant/pex26-p-gly89arg), [PEX26 p.Trp62Ter](/variant/pex26-p-trp62ter).

### 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 2086782). 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.*