# NM_000530.8(MPZ):c.396_397del (p.Pro133fs)

https://sugi.bio/variant/mpz-p-pro133fs

## Summary

**MPZ p.Pro133fs (c.396_397del)** is classified **Uncertain significance** in MPZ (ClinVar, No assertion criteria, 1 submitter). No gnomAD frequency available for this variant; Associated with Charcot-Marie-Tooth disease.

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs1571818797 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the MPZ gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease.

*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 | 59 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006034/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MPZ](https://sugi.bio/atlas/gene/MPZ/) |
| Protein change (HGVS p.) | p.Pro133fs |
| Coding change (HGVS c.) | c.396_397del |
| MANE Select transcript | [NM_000530](https://www.ncbi.nlm.nih.gov/nuccore/NM_000530) |
| dbSNP | [rs1571818797](https://www.ncbi.nlm.nih.gov/snp/rs1571818797/) |
| Variant type | Deletion |
| Location | chr1:161306759-161306760 (GRCh38) |
| ClinVar | [VCV637795](https://www.ncbi.nlm.nih.gov/clinvar/variation/637795/) |

**All HGVS expressions:** `LRG_256:g.8213_8214del`, `LRG_256t1:c.396_397del`, `NC_000001.10:g.161276550_161276551del`, `NC_000001.11:g.161306760_161306761del`, `NG_008055.1:g.8213_8214del`, `NM_000530.6:c.396_397delTC`, `NM_000530.8:c.396_397del`, `NM_001315491.2:c.396_397del`

## 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 9.926, GERP 1.84, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.708, pLI 0.11226. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 6**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**MPZ** population constraint: LOEUF 0.708, pLI 0.11226, missense-Z 1.4841; ClinGen dosage — haploinsufficiency 2/3, triplosensitivity 1/3. *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):

- **Charcot-Marie-Tooth disease** — Definitive (AD)

## Protein context {#protein}

Residue **133** lies in the ig-like v-type domain.

AlphaFold model confidence (whole protein): pLDDT 82.38, 57% of residues very-high.

**2 experimental structure(s)** (PDB): [3OAI](https://www.rcsb.org/structure/3OAI), [8IIA](https://www.rcsb.org/structure/8IIA).

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

*Describes the biological roles of MPZ (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}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [EGR2 and SOX10-mediated initiation of Schwann cell myelination](https://reactome.org/content/detail/R-HSA-9619665) | curated |

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

**Biological process:** myelination, cell-cell adhesion, cell aggregation.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Inherited Neuropathy Consortium | Uncertain significance | no assertion criteria provided | literature only |  |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease, Charcot-Marie-Tooth Hereditary Neuropathy, Charcot-Marie-Tooth Neuropathy.

## Same-residue context {#hotspot}

Residue **133** carries **5 other pathogenic ClinVar variants** — a recurrently-mutated position: [MPZ p.Pro133Thr](/variant/mpz-p-pro133thr), [MPZ p.Pro133Arg](/variant/mpz-p-pro133arg), [MPZ p.Pro133Ala](/variant/mpz-p-pro133ala), [MPZ p.Pro133Leu](/variant/mpz-p-pro133leu), [MPZ p.Pro133Ser](/variant/mpz-p-pro133ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MPZ variant pages (same residue, condition, or type): [MPZ p.Pro133Ser](/variant/mpz-p-pro133ser), [MPZ p.Asp104fs](/variant/mpz-p-asp104fs), [MPZ p.Ile162fs](/variant/mpz-p-ile162fs), [MPZ p.Leu144fs](/variant/mpz-p-leu144fs), [MPZ p.Pro133Ala](/variant/mpz-p-pro133ala), [MPZ p.Pro133Arg](/variant/mpz-p-pro133arg), [MPZ p.Pro133Thr](/variant/mpz-p-pro133thr), [MPZ p.Ser44fs](/variant/mpz-p-ser44fs).

### 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 637795). 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.*