Is MPZ p.Ile62Val (c.184A>G) pathogenic?

MPZ p.Ile62Val (c.184A>G) is classified Uncertain significance in MPZ (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.1288); Very rare (popmax 8.47e-05%, nfe); Associated with Charcot-Marie-Tooth disease type 1B.

What condition is associated with MPZ p.Ile62Val (c.184A>G)?

MPZ p.Ile62Val (c.184A>G) is associated with Charcot-Marie-Tooth disease type 1B, Roussy-Levy syndrome, Charcot-Marie-Tooth disease dominant intermediate D (ClinVar).

How common is MPZ p.Ile62Val (c.184A>G) in the general population?

MPZ p.Ile62Val (c.184A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Charcot-Marie-Tooth disease type 1B inherited?

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

What do computational predictors say about MPZ p.Ile62Val (c.184A>G)?

AlphaMissense predicts likely benign (score 0.1288) — an in-silico prediction, not a clinical call.

MPZ p.Ile62Val

c.184A>G · rs121913602 · VCV875495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1288 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 1B

Computational evidence

Protein change
AlphaMissense	0.1288	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -3.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 3,519 bp · p 4.1e-06 · regional, not allelic
Overall
CADD	15.86	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,038 alleles

Overall 6.19e-05% 1/1,614,234 alleles · very rare exomes 1/1,461,882 · genomes 0/152,352 · joint denominator

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.Ile62Val
Coding: c.184A>G
MANE Select: NM_000530
dbSNP: rs121913602
Type: single nucleotide variant
Location: chr1:161307308 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 62: a UniProt-annotated variant site (in cmt1b); a UniProt-annotated variant site (in cmt2i); the ig-like v-type domain

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

Disease context

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

Also linked: Roussy-Levy syndrome Charcot-Marie-Tooth disease dominant intermediate D neuropathy, congenital hypomyelinating, 2

For Charcot-Marie-Tooth disease type 1B (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

MPZ p.Ile62Met Conflicting classifications of pathogenicity ★ ⚠ same residue
MPZ p.Ile62Phe Pathogenic ★ ⚠ same residue
MPZ c.448+1G>A Pathogenic/Likely pathogenic ★★ same condition
MPZ c.584+2T>G Pathogenic ★★ same condition
MPZ p.Arg227Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
MPZ p.Arg98Cys Pathogenic ★★ same condition
MPZ p.Arg98His Pathogenic/Likely pathogenic ★★ same condition
MPZ p.Arg98Pro 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-ile62val (accessed [today's date]).

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