Is MPV17 p.Gln93Pro (c.278A>C) pathogenic?

MPV17 p.Gln93Pro (c.278A>C) is classified Pathogenic/Likely pathogenic in MPV17 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-07-29). AlphaMissense: likely pathogenic (0.9484); Absent from gnomAD v4.1; Associated with mitochondrial DNA depletion syndrome 6 (hepatocerebral type).

What condition is associated with MPV17 p.Gln93Pro (c.278A>C)?

MPV17 p.Gln93Pro (c.278A>C) is associated with mitochondrial DNA depletion syndrome 6 (hepatocerebral type) (ClinVar).

How common is MPV17 p.Gln93Pro (c.278A>C) in the general population?

MPV17 p.Gln93Pro (c.278A>C) 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.

What do computational predictors say about MPV17 p.Gln93Pro (c.278A>C)?

AlphaMissense predicts likely pathogenic (score 0.9484) — an in-silico prediction, not a clinical call.

MPV17 p.Gln93Pro

c.278A>C · rs200938111 · VCV694362

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9484 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

Computational evidence

Protein change
AlphaMissense	0.9484	likely pathogenic ✓ concordant with ClinVar
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -17.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 13 kb · p 0.22 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Gln93Pro
Coding: c.278A>C
MANE Select: NM_002437
dbSNP: rs200938111
Type: single nucleotide variant
Location: chr2:27312681 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.23
Residue 93: a UniProt-annotated variant site (in mtdps6); a UniProt-annotated variant site (in mtdps6; results in altered ribonucleotide incorporation in mtdna from patient fibroblasts)

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.Gln93Ter Pathogenic ★ same residue
MPV17 p.Gln93Lys 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-gln93pro (accessed [today's date]).

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