Is MPV17 p.Ala130= (c.390C>G) pathogenic?

MPV17 p.Ala130= (c.390C>G) is classified Conflicting classifications of pathogenicity in MPV17 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-04-24). Ultra-rare (popmax 0.0329%, mid); Associated with mitochondrial DNA depletion syndrome 6 (hepatocerebral type).

What condition is associated with MPV17 p.Ala130= (c.390C>G)?

MPV17 p.Ala130= (c.390C>G) is associated with mitochondrial DNA depletion syndrome 6 (hepatocerebral type), mitochondrial DNA depletion syndrome 15 (hepatocerebral type) (ClinVar).

How common is MPV17 p.Ala130= (c.390C>G) in the general population?

MPV17 p.Ala130= (c.390C>G) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is Navajo neurohepatopathy inherited?

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

MPV17 p.Ala130=

c.390C>G · rs760281019 · VCV706697

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.073	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 1.1, phastCons 1
Overall
CADD	9.633	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00149% 24/1,613,922 alleles · ultra-rare exomes 23/1,461,800 · genomes 1/152,122 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,922
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.00136%	73,746

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MPV17
Protein: p.Ala130=
Coding: c.390C>G
MANE Select: NM_002437
dbSNP: rs760281019
Type: single nucleotide variant
Location: chr2:27312232 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.23
Residue 130: 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

Also linked: mitochondrial DNA depletion syndrome 15 (hepatocerebral type)

For Navajo neurohepatopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

MPV17 p.Ala130Pro Conflicting classifications of pathogenicity ★ ⚠ 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
MPV17 c.408+1G>A 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-ala130 (accessed [today's date]).

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