Is MPZ p.Asp60His (c.178G>C) pathogenic?

MPZ p.Asp60His (c.178G>C) is classified Conflicting classifications of pathogenicity in MPZ (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-14). AlphaMissense: ambiguous (0.4584); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with MPZ p.Asp60His (c.178G>C)?

MPZ p.Asp60His (c.178G>C) is associated with Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth disease type 1B, Charcot-Marie-Tooth disease type 2I (ClinVar).

How common is MPZ p.Asp60His (c.178G>C) in the general population?

MPZ p.Asp60His (c.178G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MPZ p.Asp60His (c.178G>C)?

AlphaMissense predicts ambiguous (score 0.4584) — an in-silico prediction, not a clinical call.

MPZ p.Asp60His

c.178G>C · rs121913604 · VCV14193

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4584 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
AlphaMissense	0.4584	ambiguous
REVEL	0.286	benign-leaning
SaProt	LLR -9.93	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.88, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 3,519 bp · p 4.1e-06 · regional, not allelic
Overall
CADD	31.0	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.Asp60His
Coding: c.178G>C
MANE Select: NM_000530
dbSNP: rs121913604
Type: single nucleotide variant
Location: chr1:161307314 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 60: a UniProt-annotated variant site (in cmt2i); 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 type 1B Charcot-Marie-Tooth disease type 2I

Similar variants

MPZ p.Asp60Asn Uncertain significance ★★ ⚠ same residue
MPZ p.Asp60Val 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-asp60his (accessed [today's date]).

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