# NM_002437.5(MPV17):c.191C>G (p.Pro64Arg)

https://sugi.bio/variant/mpv17-p-pro64arg

## Summary

**MPV17 p.Pro64Arg (c.191C>G)** is classified **Pathogenic/Likely pathogenic** in MPV17 (ClinVar, Multiple submitters, 16 submitters; last evaluated 2025-10-30). AlphaMissense: likely pathogenic (0.9079); Ultra-rare (popmax 0.0125%, nfe); Associated with Charcot-Marie-Tooth disease, axonal, type 2EE.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs375401970 · 16 submitters · 5 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0125%, nfe)

## For patients & families {#patients}

This is a change in the MPV17 gene that is considered likely disease-causing, submitted by 16 submitters, and is linked to Charcot-Marie-Tooth disease, axonal, type 2EE.

*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/0025730/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MPV17](https://sugi.bio/atlas/gene/MPV17/) |
| Protein change (HGVS p.) | p.Pro64Arg |
| Coding change (HGVS c.) | c.191C>G |
| MANE Select transcript | [NM_002437](https://www.ncbi.nlm.nih.gov/nuccore/NM_002437) |
| dbSNP | [rs375401970](https://www.ncbi.nlm.nih.gov/snp/rs375401970/) |
| Variant type | single nucleotide variant |
| Location | chr2:27312768-27312768 (GRCh38) |
| ClinVar | [VCV381523](https://www.ncbi.nlm.nih.gov/clinvar/variation/381523/) |

**All HGVS expressions:** `NC_000002.11:g.27535635G>C`, `NC_000002.12:g.27312768G>C`, `NG_008075.1:g.14797C>G`, `NG_033055.1:g.496C>G`, `NM_002437.5:c.191C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9079) — concordant with the pathogenic call
- REVEL 0.948 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.06 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.842, GERP 1.49, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.1**. 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 0.92** across the covering region of the MANE Select transcript (27,309,915–27,322,517), spanning 12,602 bp. Chi-square p 0.22. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0125%** (nfe) · FAF95 0.0109% · FAF99 0.0102% · 148/1,180,048 in the highest group · 155/1,613,918 alleles overall — ultra-rare (popmax 0.0125%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0125% | 7,973 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,621 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |
| African / African-American | 0.00267% | 37,469 |

*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}

**MPV17** population constraint: LOEUF 1.368, pLI 1.4056e-10, missense-Z 0.72753. *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):

- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}

Residue **64** lies in a UniProt-annotated variant site (in mtdps6).

AlphaFold model confidence (whole protein): pLDDT 90.23, 64% of residues very-high.

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

*Describes the biological roles of MPV17 (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.*

**How this variant is thought to act:** MPV17's established molecular role includes channel activity.


### Pathways affected {#pathways}

MPV17 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |

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

**Molecular function:** channel activity.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-30.

**Submitter consensus:** conflicting (9 Pathogenic, 5 Likely pathogenic, 1 not provided, 1 Likely Pathogenic).

**Submission history:** 16 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| SIB Swiss Institute of Bioinformatics | Likely pathogenic | criteria provided, single submitter | curation | 2019-08-13 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-10 |
| Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-01 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-26 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2016-12-22 |
| GenomeConnect, ClinGen | not provided | no classification provided | phenotyping only |  |
| MGZ Medical Genetics Center | Pathogenic | criteria provided, single submitter | clinical testing | 2022-04-22 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-11-07 |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-07-13 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-09 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-04-01 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-10-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-07 |
| Variantyx, Inc. | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-09 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-01 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2020-01-30 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease, axonal, type 2EE](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-axonal-type-2ee/), [mitochondrial DNA depletion syndrome 6 (hepatocerebral type)](https://sugi.bio/atlas/disease/mitochondrial-dna-depletion-syndrome-6-hepatocerebral-type/), [mitochondrial DNA depletion syndrome 15 (hepatocerebral type)](https://sugi.bio/atlas/disease/mitochondrial-dna-depletion-syndrome-15-hepatocerebral-type/), [mitochondrial DNA depletion syndrome](https://sugi.bio/atlas/disease/mitochondrial-dna-depletion-syndrome/), [mitochondrial DNA depletion syndrome, hepatocerebral form](https://sugi.bio/atlas/disease/mitochondrial-dna-depletion-syndrome-hepatocerebral-form/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease, axonal, type 2EE, not provided, Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), Mitochondrial DNA depletion syndrome, Mitochondrial DNA depletion syndrome, hepatocerebral form, Autosomal recessive MPV17-related disorders, MPV17-related disorder, CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2EE, NAVAJO NEUROPATHY.

## Same-residue context {#hotspot}

Residue **64** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MPV17 p.Pro64Leu](/variant/mpv17-p-pro64leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MPV17 variant pages (same residue, condition, or type): [MPV17 p.Pro64Ser](/variant/mpv17-p-pro64ser), [MPV17 p.Pro64Leu](/variant/mpv17-p-pro64leu), [MPV17 c.186+2T>C](/variant/mpv17-c-186-plus-2t-c), [MPV17 c.279+1G>T](/variant/mpv17-c-279-plus-1g-t), [MPV17 c.375+1G>A](/variant/mpv17-c-375-plus-1g-a), [MPV17 c.375+1G>T](/variant/mpv17-c-375-plus-1g-t), [MPV17 c.375+2T>C](/variant/mpv17-c-375-plus-2t-c), [MPV17 c.376-1G>A](/variant/mpv17-c-376-minus-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 381523). 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.*