Is MPZ p.Arg98His (c.293G>A) pathogenic?

MPZ p.Arg98His (c.293G>A) is classified Pathogenic/Likely pathogenic in MPZ (ClinVar, Multiple submitters, 13 submitters; last evaluated 2025-10-14). AlphaMissense: likely pathogenic (0.871); Very rare (popmax 8.47e-05%, nfe); Associated with MPZ-related disorder.

What condition is associated with MPZ p.Arg98His (c.293G>A)?

MPZ p.Arg98His (c.293G>A) is associated with MPZ-related disorder, sensory peripheral neuropathy, Charcot-Marie-Tooth disease type 1B (ClinVar).

How common is MPZ p.Arg98His (c.293G>A) in the general population?

MPZ p.Arg98His (c.293G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MPZ p.Arg98His (c.293G>A)?

AlphaMissense predicts likely pathogenic (score 0.871) — an in-silico prediction, not a clinical call.

MPZ p.Arg98His

c.293G>A · rs121913589 · VCV14176

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.871 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MPZ-related disorder

Computational evidence

Protein change
AlphaMissense	0.871	likely pathogenic ✓ concordant with ClinVar
REVEL	0.677	pathogenic-leaning
SaProt	LLR -11.23	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 7.6	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,984 alleles

Overall 6.2e-05% 1/1,613,790 alleles · very rare exomes 0/1,461,828 · genomes 1/151,962 · 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.Arg98His
Coding: c.293G>A
MANE Select: NM_000530
dbSNP: rs121913589
Type: single nucleotide variant
Location: chr1:161306863 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 98: the ig-like v-type domain; a UniProt-annotated variant site (in cmt1b and dss; severe); a UniProt-annotated variant site (in cmt1b)

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

Disease context

MPZ-related disorder

Also linked: sensory peripheral neuropathy Charcot-Marie-Tooth disease type 1B Charcot-Marie-Tooth disease Charcot-Marie-Tooth disease type 1

Similar variants

MPZ p.Arg98Cys Pathogenic ★★ same residue
MPZ p.Arg98Pro Pathogenic/Likely pathogenic ★★ same residue
MPZ p.Arg98Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MPZ p.Arg98Ser 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

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-arg98his (accessed [today's date]).

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