# NM_000288.4(PEX7):c.615C>T (p.Asp205=)

https://sugi.bio/variant/pex7-p-asp205

## Summary

**PEX7 p.Asp205= (c.615C>T)** is classified **Conflicting classifications of pathogenicity** in PEX7 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-02-01). Rare (popmax 0.148%, mid); Associated with peroxisome biogenesis disorder 9B.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs147298444 · 13 submitters · 2 linked conditions · rare (popmax 0.148%, mid)

## For patients & families {#patients}

This is a change in the PEX7 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 13 submitters, and is linked to peroxisome biogenesis disorder 9B.

*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/0015871/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PEX7](https://sugi.bio/atlas/gene/PEX7/) |
| Protein change (HGVS p.) | p.Asp205= |
| Coding change (HGVS c.) | c.615C>T |
| MANE Select transcript | [NM_000288](https://www.ncbi.nlm.nih.gov/nuccore/NM_000288) |
| dbSNP | [rs147298444](https://www.ncbi.nlm.nih.gov/snp/rs147298444/) |
| Variant type | single nucleotide variant |
| Location | chr6:136866715-136866715 (GRCh38) |
| ClinVar | [VCV355532](https://www.ncbi.nlm.nih.gov/clinvar/variation/355532/) |

**All HGVS expressions:** `NC_000006.11:g.137187853C>T`, `NC_000006.12:g.136866715C>T`, `NG_008462.1:g.49136C>T`, `NM_000288.4:c.615C>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 1.069, GERP 0.011, phastCons 1 — weakly conserved position
- CADD: **PHRED 7.922**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, C>G, IS in the release and scores Δ0.52 donor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.148%** (mid) · FAF95 0.0774% · FAF99 0.0578% · 9/6,062 in the highest group · 1,032/1,613,710 alleles overall — rare (popmax 0.148%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 2.06% | 49 |
| Remaining individuals (not grpmax-eligible) | 0.158% | 631 |
| Middle Eastern (grpmax) | 0.148% | 674 |
| European (non-Finnish) | 0.0253% | 3,946 |
| Admixed American | 0.0167% | 6,002 |
| African / African-American | 0.008% | 12,502 |

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}

**PEX7** population constraint: LOEUF 0.941, pLI 0.0018388, missense-Z -0.56812. *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 95.54, 93% of residues very-high.

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

*Describes the biological roles of PEX7 (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:** PEX7's established molecular role includes obsolete peroxisome matrix targeting signal-2 binding.


### Pathways affected {#pathways}

PEX7 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** obsolete peroxisome matrix targeting signal-2 binding, enzyme binding, protein homodimerization activity.

**Biological process:** peroxisome organization, ether lipid biosynthetic process, protein import into peroxisome matrix.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (6 Benign, 5 Likely benign, 3 Uncertain significance).

**Submission history:** 14 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2017-12-22 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2018-12-10 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-14 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-06-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-18 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-01-17 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2016-12-05 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-22 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-06-01 |

## Associated conditions {#conditions}

[peroxisome biogenesis disorder 9B](https://sugi.bio/atlas/disease/peroxisome-biogenesis-disorder-9b/), [rhizomelic chondrodysplasia punctata type 1](https://sugi.bio/atlas/disease/rhizomelic-chondrodysplasia-punctata-type-1/).

**Reported phenotype names (ClinVar):** Peroxisome biogenesis disorder 9B, Rhizomelic chondrodysplasia punctata type 1, not specified, not provided, Inborn genetic diseases, PEX7-related disorder, AllHighlyPenetrant, Refsum disease, adult, 2, PEX7-Related Refsum Disease, PEROXISOME BIOGENESIS DISORDER, PEX7-RELATED, ATYPICAL.

## Similar variants {#similar}

Related PEX7 variant pages (same residue, condition, or type): [PEX7 c.130+1G>A](/variant/pex7-c-130-plus-1g-a), [PEX7 c.131-1G>A](/variant/pex7-c-131-minus-1g-a), [PEX7 c.188+1G>A](/variant/pex7-c-188-plus-1g-a), [PEX7 c.188+1G>C](/variant/pex7-c-188-plus-1g-c), [PEX7 c.340-1G>T](/variant/pex7-c-340-minus-1g-t), [PEX7 c.634-2A>G](/variant/pex7-c-634-minus-2a-g), [PEX7 c.748-2A>G](/variant/pex7-c-748-minus-2a-g), [PEX7 c.803+1G>A](/variant/pex7-c-803-plus-1g-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 355532). 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.*