Is MPZ p.Val146Phe (c.436G>T) pathogenic?

MPZ p.Val146Phe (c.436G>T) is classified Uncertain significance in MPZ (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9916); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease.

What condition is associated with MPZ p.Val146Phe (c.436G>T)?

MPZ p.Val146Phe (c.436G>T) is associated with Charcot-Marie-Tooth disease (ClinVar).

How common is MPZ p.Val146Phe (c.436G>T) in the general population?

MPZ p.Val146Phe (c.436G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MPZ p.Val146Phe (c.436G>T)?

AlphaMissense predicts likely pathogenic (score 0.9916) — an in-silico prediction, not a clinical call.

MPZ p.Val146Phe

c.436G>T · rs1571818627 · VCV637789

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9916 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.9916	likely pathogenic · top 9% in MPZ
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -17.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.62	donor loss · deltas
Constraint at this position
Conservation	phyloP 7.7	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	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: MPZ
Protein: p.Val146Phe
Coding: c.436G>T
MANE Select: NM_000530
dbSNP: rs1571818627
Type: single nucleotide variant
Location: chr1:161306720 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 146: a β-strand; a UniProt-annotated variant site (in cmt1b)

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

Disease context

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

Similar variants

MPZ p.Val146Gly Uncertain significance ⚠ same residue
MPZ p.Val146Ala Pathogenic ★ same residue
MPZ c.448+2T>G Likely pathogenic ★★ same condition
MPZ c.584+2T>G Pathogenic ★★ same condition
MPZ p.Arg227Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
MPZ p.Arg98His Pathogenic/Likely pathogenic ★★ same condition
MPZ p.Arg98Pro Pathogenic/Likely pathogenic ★★ same condition
MPZ p.Asp224Tyr 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-val146phe (accessed [today's date]).

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