# NM_000530.8(MPZ):c.276G>A (p.Val92=)

https://sugi.bio/variant/mpz-p-val92

## Summary

**MPZ p.Val92= (c.276G>A)** is classified **Pathogenic** in MPZ (ClinVar, Single submitter, 3 submitters; last evaluated 2025-05-05). Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1558154193 · 3 submitters · 3 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MPZ gene that is reported as disease-causing, but on limited review, submitted by 3 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.Val92= |
| Coding change (HGVS c.) | c.276G>A |
| MANE Select transcript | [NM_000530](https://www.ncbi.nlm.nih.gov/nuccore/NM_000530) |
| dbSNP | [rs1558154193](https://www.ncbi.nlm.nih.gov/snp/rs1558154193/) |
| Variant type | single nucleotide variant |
| Location | chr1:161306880-161306880 (GRCh38) |
| ClinVar | [VCV14200](https://www.ncbi.nlm.nih.gov/clinvar/variation/14200/) |

**All HGVS expressions:** `LRG_256:g.8093G>A`, `LRG_256t1:c.276G>A`, `NC_000001.10:g.161276670C>T`, `NC_000001.11:g.161306880C>T`, `NG_008055.1:g.8093G>A`, `NM_000530.8:c.276G>A`, `NM_001315491.2:c.276G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.40) — consistent with the pathogenic call
- Conservation: phyloP 1.786, GERP 0.667, phastCons 1 — weakly conserved position
- CADD: **PHRED 18.51**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.40**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.40**.
- 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 **92** lies in a β-strand; a UniProt-annotated variant site (in cmt2i; patient carrying also asn-89 and met-162); 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** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-05.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Uncertain significance).

**Submission history:** 3 submissions (2010–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2010-02-01 |
| Inherited Neuropathy Consortium | Uncertain significance | no assertion criteria provided | literature only |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-05 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease, type I, Charcot-Marie-Tooth disease type 1B, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth Hereditary Neuropathy, Charcot-Marie-Tooth Neuropathy, Charcot-Marie-Tooth, Type 1, Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth disease, type IB, Charcot-Marie-Tooth disease, demyelinating, type 1b, Hereditary motor and sensory neuropathy 1B.

## Similar variants {#similar}

Related MPZ variant pages (same residue, condition, or type): [MPZ p.Val92Glu](/variant/mpz-p-val92glu), [MPZ p.Val92Met](/variant/mpz-p-val92met), [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), [MPZ c.68-1G>A](/variant/mpz-c-68-minus-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 14200). 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.*