# NM_002437.5(MPV17):c.75C>T (p.Ser25=)

https://sugi.bio/variant/mpv17-p-ser25

## Summary

**MPV17 p.Ser25= (c.75C>T)** is classified **Likely benign** in MPV17 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-31). Very rare (popmax 0.000169%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs779646719 · 1 submitter · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the MPV17 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [MPV17](https://sugi.bio/atlas/gene/MPV17/) |
| Protein change (HGVS p.) | p.Ser25= |
| Coding change (HGVS c.) | c.75C>T |
| MANE Select transcript | [NM_002437](https://www.ncbi.nlm.nih.gov/nuccore/NM_002437) |
| dbSNP | [rs779646719](https://www.ncbi.nlm.nih.gov/snp/rs779646719/) |
| Variant type | single nucleotide variant |
| Location | chr2:27313105-27313105 (GRCh38) |
| ClinVar | [VCV2748655](https://www.ncbi.nlm.nih.gov/clinvar/variation/2748655/) |

**All HGVS expressions:** `NC_000002.11:g.27535972G>A`, `NC_000002.12:g.27313105G>A`, `NG_008075.1:g.14460C>T`, `NG_008075.2:g.14992C>T`, `NG_033055.1:g.159C>T`, `NG_033055.2:g.340C>T`, `NM_002437.5:c.75C>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 1.611, GERP -2.44, phastCons 1 — weakly conserved position
- CADD: **PHRED 11.68**. 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>T, Δ0.32 acceptor gain), 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 **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,032 in the highest group · 2/1,614,180 alleles overall — very rare (popmax 0.000169%, 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}

**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}


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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-31.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-31 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related MPV17 variant pages (same residue, condition, or type): [MPV17 p.Ser25Tyr](/variant/mpv17-p-ser25tyr), [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), [MPV17 c.376-2A>C](/variant/mpv17-c-376-minus-2a-c).

### 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 2748655). 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.*