Is MPZ p.Val142Phe (c.424G>T) pathogenic?

MPZ p.Val142Phe (c.424G>T) is classified Conflicting classifications of pathogenicity in MPZ (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-09-20). AlphaMissense: likely pathogenic (0.9796); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with MPZ p.Val142Phe (c.424G>T)?

MPZ p.Val142Phe (c.424G>T) is associated with Charcot-Marie-Tooth disease type 1 (ClinVar).

How common is MPZ p.Val142Phe (c.424G>T) in the general population?

MPZ p.Val142Phe (c.424G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MPZ p.Val142Phe (c.424G>T)?

AlphaMissense predicts likely pathogenic (score 0.9796) — an in-silico prediction, not a clinical call.

MPZ p.Val142Phe

c.424G>T · rs876661257 · VCV234852

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9796 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
AlphaMissense	0.9796	likely pathogenic
REVEL	0.757	pathogenic-leaning
SaProt	LLR -12.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.45	donor loss · deltas
Constraint at this position
Conservation	phyloP 6	GERP -0.16, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 3,519 bp · p 4.1e-06 · regional, not allelic
Overall
CADD	33.0	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

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.Val142Phe
Coding: c.424G>T
MANE Select: NM_000530
dbSNP: rs876661257
Type: single nucleotide variant
Location: chr1:161306732 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 142: a β-strand; 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 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MPZ p.Val142Ile Uncertain significance ★ ⚠ same residue
MPZ p.Val142= Likely benign ★ same residue
MPZ p.Val142fs Pathogenic ★ 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

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-val142phe (accessed [today's date]).

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