Is MPV17 p.Arg125= (c.375G>A) pathogenic?

MPV17 p.Arg125= (c.375G>A) is classified Likely pathogenic in MPV17 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2018-10-31). Absent from gnomAD v4.1; Associated with mitochondrial DNA depletion syndrome 6 (hepatocerebral type).

What condition is associated with MPV17 p.Arg125= (c.375G>A)?

MPV17 p.Arg125= (c.375G>A) is associated with mitochondrial DNA depletion syndrome 6 (hepatocerebral type) (ClinVar).

How common is MPV17 p.Arg125= (c.375G>A) in the general population?

MPV17 p.Arg125= (c.375G>A) is absent from gnomAD v4.1 (gnomAD).

How is Navajo neurohepatopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MPV17 p.Arg125=

c.375G>A · rs1064793178 · VCV418309

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.60	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.58	loss · gain 0.15 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.8	GERP 2.4, phastCons 1
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MPV17
Protein: p.Arg125=
Coding: c.375G>A
MANE Select: NM_002437
dbSNP: rs1064793178
Type: single nucleotide variant
Location: chr2:27312494 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.23
Residue 125: a UniProt-annotated variant site (in mtdps6)

Full MPV17 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial DNA depletion syndrome 6 (hepatocerebral type) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Navajo neurohepatopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

MPV17 p.Arg125Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
MPV17 p.Arg125Gln Uncertain significance ★★ ⚠ same residue
MPV17 c.186+2T>C Pathogenic/Likely pathogenic ★★ same condition
MPV17 c.279+1G>T Pathogenic ★★ same condition
MPV17 c.375+1G>A Likely pathogenic ★★ same condition
MPV17 c.375+1G>T Likely pathogenic ★★ same condition
MPV17 c.376-1G>A Pathogenic/Likely pathogenic ★★ same condition
MPV17 c.376-2A>C Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mpv17-p-arg125 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown