# NM_000530.8(MPZ):c.424G>T (p.Val142Phe)

https://sugi.bio/variant/mpz-p-val142phe

## Summary

**MPZ p.Val142Phe (c.424G>T)** is classified **Conflicting classifications of pathogenicity** in MPZ (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-09-20). AlphaMissense: likely pathogenic (0.9796); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs876661257 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MPZ gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Charcot-Marie-Tooth disease type 1.

*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/0012433/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.Val142Phe |
| Coding change (HGVS c.) | c.424G>T |
| MANE Select transcript | [NM_000530](https://www.ncbi.nlm.nih.gov/nuccore/NM_000530) |
| dbSNP | [rs876661257](https://www.ncbi.nlm.nih.gov/snp/rs876661257/) |
| Variant type | single nucleotide variant |
| Location | chr1:161306732-161306732 (GRCh38) |
| ClinVar | [VCV234852](https://www.ncbi.nlm.nih.gov/clinvar/variation/234852/) |

**All HGVS expressions:** `LRG_256:g.8241G>T`, `LRG_256t1:c.424G>T`, `NC_000001.10:g.161276522C>A`, `NC_000001.11:g.161306732C>A`, `NG_008055.1:g.8241G>T`, `NM_000530.8:c.424G>T`, `NM_001315491.2:c.424G>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9796)
- REVEL 0.757 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.411 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor loss** (Δ 0.45) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 5.966, GERP -0.158, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.69** across the covering region of the MANE Select transcript (161,306,386–161,309,905), spanning 3,519 bp. Chi-square p 4.1e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.45**, acceptor gain **0.00**, donor gain **0.20**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.20**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **142** lies in a β-strand; 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-09-20.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2021–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-09-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-10-22 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease type 1](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-1/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease, type I, not provided, Charcot-Marie-Tooth, Type 1, Charcot-Marie-Tooth disease type 1, none provided.

## Same-residue context {#hotspot}

Residue **142** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MPZ p.Val142fs](/variant/mpz-p-val142fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MPZ variant pages (same residue, condition, or type): [MPZ p.Val142Ile](/variant/mpz-p-val142ile), [MPZ p.Val142=](/variant/mpz-p-val142), [MPZ p.Val142fs](/variant/mpz-p-val142fs), [MPZ c.235-1G>T](/variant/mpz-c-235-minus-1g-t), [MPZ c.448+1G>A](/variant/mpz-c-448-plus-1g-a), [MPZ c.448+1G>T](/variant/mpz-c-448-plus-1g-t), [MPZ c.448+2T>G](/variant/mpz-c-448-plus-2t-g), [MPZ c.584+2T>G](/variant/mpz-c-584-plus-2t-g).

### 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 234852). 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.*