Is MPZ p.His39Pro (c.116A>C) pathogenic?

MPZ p.His39Pro (c.116A>C) is classified Pathogenic/Likely pathogenic in MPZ (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.6392); Very rare (popmax 8.47e-05%, nfe); Associated with MPZ-related disorder.

What condition is associated with MPZ p.His39Pro (c.116A>C)?

MPZ p.His39Pro (c.116A>C) is associated with MPZ-related disorder, Charcot-Marie-Tooth disease type 1B, Charcot-Marie-Tooth disease type 1 (ClinVar).

How common is MPZ p.His39Pro (c.116A>C) in the general population?

MPZ p.His39Pro (c.116A>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MPZ p.His39Pro (c.116A>C)?

AlphaMissense predicts likely pathogenic (score 0.6392) — an in-silico prediction, not a clinical call.

MPZ p.His39Pro

c.116A>C · rs371856018 · VCV217232

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.6392 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MPZ-related disorder

Computational evidence

Protein change
AlphaMissense	0.6392	likely pathogenic ✓ concordant with ClinVar
REVEL	0.266	benign-leaning
SaProt	LLR -10.47	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 0.68, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 3,519 bp · p 4.1e-06 · regional, not allelic
Overall
CADD	24.8	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 8.47e-05% European (non-Finnish) · 1/1,180,054 alleles

Overall 6.2e-05% 1/1,614,138 alleles · very rare exomes 0/1,461,886 · genomes 1/152,252 · 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.His39Pro
Coding: c.116A>C
MANE Select: NM_000530
dbSNP: rs371856018
Type: single nucleotide variant
Location: chr1:161307376 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 39: a β-strand; a UniProt-annotated variant site (in cmt1b; slightly reduces intercellular adhesion; does not affect targeting to the cell membrane); the ig-like v-type domain

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

Disease context

MPZ-related disorder

Also linked: Charcot-Marie-Tooth disease type 1B Charcot-Marie-Tooth disease type 1

Similar variants

MPZ p.His39Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
MPZ p.His39Gln Uncertain significance ★ ⚠ 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

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-his39pro (accessed [today's date]).

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