# NM_000530.8(MPZ):c.384C>T (p.Asp128=)

https://sugi.bio/variant/mpz-p-asp128

## Summary

**MPZ p.Asp128= (c.384C>T)** is classified **Likely benign** in MPZ (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-11). Very rare (popmax 0.00891%, eas); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs772611598 · 3 submitters · 2 linked conditions · very rare (popmax 0.00891%, eas)

## For patients & families {#patients}

This is a change in the MPZ gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to Inborn genetic diseases.

*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.Asp128= |
| Coding change (HGVS c.) | c.384C>T |
| MANE Select transcript | [NM_000530](https://www.ncbi.nlm.nih.gov/nuccore/NM_000530) |
| dbSNP | [rs772611598](https://www.ncbi.nlm.nih.gov/snp/rs772611598/) |
| Variant type | single nucleotide variant |
| Location | chr1:161306772-161306772 (GRCh38) |
| ClinVar | [VCV531702](https://www.ncbi.nlm.nih.gov/clinvar/variation/531702/) |

**All HGVS expressions:** `LRG_256:g.8201C>T`, `LRG_256t1:c.384C>T`, `NC_000001.10:g.161276562G>A`, `NC_000001.11:g.161306772G>A`, `NG_008055.1:g.8201C>T`, `NM_000530.8:c.384C>T`, `NM_001315491.2:c.384C>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 -0.035, GERP -3.67, phastCons 0.076 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 12.89**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.24 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00891%** (eas) · FAF95 0.00298% · FAF99 0.00195% · 4/44,880 in the highest group · 53/1,613,888 alleles overall — very rare (popmax 0.00891%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0437% | 2,286 |
| East Asian (grpmax) | 0.00891% | 11,220 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,495 |
| African / African-American | 0.00668% | 14,965 |
| South Asian | 0.00659% | 15,181 |
| European (non-Finnish) | 0.000424% | 236,005 |

Finnish 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}

**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 **128** lies in a β-strand; the ig-like v-type domain; a UniProt-annotated variant site (in cmt1b); a UniProt-annotated variant site (in dss; associated in cis with thr-114 and his-116 in one patient).

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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-11.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-07-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-11 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-15 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Charcot-Marie-Tooth disease, type I, not specified, Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth, Type 1, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **128** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [MPZ p.Asp128Asn](/variant/mpz-p-asp128asn), [MPZ p.Asp128delinsGluTer](/variant/mpz-p-asp128delinsgluter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MPZ variant pages (same residue, condition, or type): [MPZ p.Asp128Asn](/variant/mpz-p-asp128asn), [MPZ p.Asp128His](/variant/mpz-p-asp128his), [MPZ p.Asp128Tyr](/variant/mpz-p-asp128tyr), [MPZ p.Asp128delinsGluTer](/variant/mpz-p-asp128delinsgluter), [MPZ p.Asp128Glu](/variant/mpz-p-asp128glu), [MPZ p.Asp128Gly](/variant/mpz-p-asp128gly), [MPZ c.235-1G>T](/variant/mpz-c-235-minus-1g-t), [MPZ c.448+1G>A](/variant/mpz-c-448-plus-1g-a).

### 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 531702). 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.*