Is MPZ p.Arg186Ser (c.558G>T) pathogenic?

MPZ p.Arg186Ser (c.558G>T) is classified Uncertain significance in MPZ (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: likely pathogenic (0.7985); Very rare (popmax 0.00186%, nfe); Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with MPZ p.Arg186Ser (c.558G>T)?

MPZ p.Arg186Ser (c.558G>T) is associated with Charcot-Marie-Tooth disease type 1 (ClinVar).

How common is MPZ p.Arg186Ser (c.558G>T) in the general population?

MPZ p.Arg186Ser (c.558G>T) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about MPZ p.Arg186Ser (c.558G>T)?

AlphaMissense predicts likely pathogenic (score 0.7985) — an in-silico prediction, not a clinical call.

MPZ p.Arg186Ser

c.558G>T · rs1427001812 · VCV2079767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7985 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
AlphaMissense	0.7985	likely pathogenic
REVEL	0.542	indeterminate
SaProt	LLR -9.61	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.35	GERP -0.68, phastCons 0.99
Regional constraint	o/e 1.08	unconstrained · MANE · 506 bp · p 0.45 · regional, not allelic
Overall
CADD	22.7	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 0.00186% European (non-Finnish) · 22/1,180,048 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00167% 27/1,614,114 alleles · very rare exomes 25/1,461,892 · genomes 2/152,222 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,498
European (non-Finnish)grpmax	0.00186%	53,639

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MPZ
Protein: p.Arg186Ser
Coding: c.558G>T
MANE Select: NM_000530
dbSNP: rs1427001812
Type: single nucleotide variant
Location: chr1:161306355 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB

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

Disease context

Charcot-Marie-Tooth disease type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MPZ p.Arg186= Likely benign ★ same residue
MPZ c.235-1G>T Pathogenic/Likely pathogenic ★★ same condition
MPZ c.448+1G>A Pathogenic/Likely pathogenic ★★ same condition
MPZ c.448+1G>T Likely pathogenic ★★ same condition
MPZ c.448+2T>G Likely pathogenic ★★ same condition
MPZ c.584+2T>G Pathogenic ★★ same condition
MPZ c.68-1G>A Pathogenic/Likely pathogenic ★★ same condition
MPZ c.68-1G>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/mpz-p-arg186ser (accessed [today's date]).

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