Is MPZ p.Pro133Ser (c.397C>T) pathogenic?

MPZ p.Pro133Ser (c.397C>T) is classified Likely pathogenic in MPZ (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-02-01). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with MPZ p.Pro133Ser (c.397C>T)?

MPZ p.Pro133Ser (c.397C>T) is associated with Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth disease (ClinVar).

How common is MPZ p.Pro133Ser (c.397C>T) in the general population?

MPZ p.Pro133Ser (c.397C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MPZ p.Pro133Ser (c.397C>T)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

MPZ p.Pro133Ser

c.397C>T · rs1553259648 · VCV637337

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9975 · 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	0.9975	likely pathogenic ✓ concordant with ClinVar · top 4% in MPZ
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -13.65	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 9.9	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	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.Pro133Ser
Coding: c.397C>T
MANE Select: NM_000530
dbSNP: rs1553259648
Type: single nucleotide variant
Location: chr1:161306759 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 133: 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

Also linked: Charcot-Marie-Tooth disease

Similar variants

MPZ p.Pro133Ala Likely pathogenic ★★ same residue
MPZ p.Pro133Arg Likely pathogenic ★★ same residue
MPZ p.Pro133Thr Pathogenic/Likely pathogenic ★★ same residue
MPZ p.Pro133fs Uncertain significance same residue
MPZ p.Pro133Leu Likely 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

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-pro133ser (accessed [today's date]).

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