Is MPV17 p.Pro64Arg (c.191C>G) pathogenic?

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.

What condition is associated with MPV17 p.Pro64Arg (c.191C>G)?

MPV17 p.Pro64Arg (c.191C>G) is associated with Charcot-Marie-Tooth disease, axonal, type 2EE, mitochondrial DNA depletion syndrome 6 (hepatocerebral type), mitochondrial DNA depletion syndrome 15 (hepatocerebral type) (ClinVar).

How common is MPV17 p.Pro64Arg (c.191C>G) in the general population?

MPV17 p.Pro64Arg (c.191C>G) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

What do computational predictors say about MPV17 p.Pro64Arg (c.191C>G)?

AlphaMissense predicts likely pathogenic (score 0.9079) — an in-silico prediction, not a clinical call.

MPV17 p.Pro64Arg

c.191C>G · rs375401970 · VCV381523

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

AlphaMissense

likely pathogenic

0.9079 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease, axonal, type 2EE

Computational evidence

Protein change
AlphaMissense	0.9079	likely pathogenic ✓ concordant with ClinVar
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -15.06	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 9.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 13 kb · p 0.22 · regional, not allelic
Overall
CADD	29.1	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

Grpmax group 0.0125% European (non-Finnish) · 148/1,180,048 alleles

Filtering AF 0.0109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.0096% 155/1,613,918 alleles · ultra-rare exomes 144/1,461,682 · genomes 11/152,236 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0125%	7,973
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
African / African-American	0.00267%	37,469

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.Pro64Arg
Coding: c.191C>G
MANE Select: NM_002437
dbSNP: rs375401970
Type: single nucleotide variant
Location: chr2:27312768 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.23
Residue 64: a UniProt-annotated variant site (in mtdps6)

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

Disease context

Charcot-Marie-Tooth disease, axonal, type 2EE — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial DNA depletion syndrome 6 (hepatocerebral type)mitochondrial DNA depletion syndrome 15 (hepatocerebral type)mitochondrial DNA depletion syndrome mitochondrial DNA depletion syndrome, hepatocerebral form

Similar variants

MPV17 p.Pro64Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MPV17 p.Pro64Leu Likely pathogenic ★ 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.375+2T>C Likely pathogenic ★★ same condition
MPV17 c.376-1G>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-pro64arg (accessed [today's date]).

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