# NM_000530.8(MPZ):c.129_136del (p.Ser44fs)

https://sugi.bio/variant/mpz-p-ser44fs

## Summary

**MPZ p.Ser44fs (c.129_136del)** is classified **Pathogenic/Likely pathogenic** in MPZ (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-29). Very rare (popmax 0.000424%, nfe); Associated with MPZ-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs760730366 · 7 submitters · 5 linked conditions · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the MPZ gene that is considered likely disease-causing, submitted by 7 submitters, and is linked to MPZ-related 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.*

**Support & next steps:** [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.Ser44fs |
| Coding change (HGVS c.) | c.129_136del |
| MANE Select transcript | [NM_000530](https://www.ncbi.nlm.nih.gov/nuccore/NM_000530) |
| dbSNP | [rs760730366](https://www.ncbi.nlm.nih.gov/snp/rs760730366/) |
| Variant type | Deletion |
| Location | chr1:161307356-161307363 (GRCh38) |
| ClinVar | [VCV246122](https://www.ncbi.nlm.nih.gov/clinvar/variation/246122/) |

**All HGVS expressions:** `LRG_256:g.7610_7617del`, `LRG_256t1:c.129_136del`, `NC_000001.10:g.161277149_161277156del`, `NC_000001.11:g.161307359_161307366del`, `NG_008055.1:g.7610_7617del`, `NM_000530.8:c.129_136del`, `NM_000530.8:c.129_136delCTCCCGGG`, `NM_001315491.2:c.129_136del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.175, GERP 0.692, 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 2 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 (gnomAD v4.1): grpmax **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,180,042 in the highest group · 5/1,614,268 alleles overall — very rare (popmax 0.000424%, nfe).

*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 **44** lies in a UniProt-annotated variant site (in cmt2i and cmt1b); 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-29.

**Submitter consensus:** conflicting (6 Pathogenic, 1 Likely pathogenic).

**Submission history:** 7 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-09 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-01 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2017-01-09 |
| Inherited Neuropathy Consortium | Pathogenic | no assertion criteria provided | literature only |  |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-29 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-07-09 |

## Associated conditions {#conditions}

[MPZ-related disorder](https://sugi.bio/atlas/disease/mpz-related-disorder/), [Charcot-Marie-Tooth disease type 1B](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-1b/), [Charcot-Marie-Tooth disease type 3](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-3/), [Charcot-Marie-Tooth disease](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease/), [Charcot-Marie-Tooth disease type 1](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-1/).

**Reported phenotype names (ClinVar):** MPZ-related disorder, not provided, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease, type I, Charcot-Marie-Tooth disease type 1B, Dejerine-Sottas disease, MPZ-related condition, MPZ-related disorders, Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth, Type 1.

## Same-residue context {#hotspot}

Residue **44** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [MPZ p.Ser44Pro](/variant/mpz-p-ser44pro), [MPZ p.Ser44Phe](/variant/mpz-p-ser44phe), [MPZ p.Ser44_Thr47del](/variant/mpz-p-ser44-thr47del). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MPZ variant pages (same residue, condition, or type): [MPZ p.Ser44_Thr47del](/variant/mpz-p-ser44-thr47del), [MPZ p.Ser44Phe](/variant/mpz-p-ser44phe), [MPZ p.Ser44Cys](/variant/mpz-p-ser44cys), [MPZ p.Arg186fs](/variant/mpz-p-arg186fs), [MPZ p.Asp104fs](/variant/mpz-p-asp104fs), [MPZ p.Ile162fs](/variant/mpz-p-ile162fs), [MPZ p.Leu144fs](/variant/mpz-p-leu144fs), [MPZ p.Pro26fs](/variant/mpz-p-pro26fs).

### 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 246122). 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.*