Is MPZ p.Asp75Val (c.224A>T) pathogenic?

MPZ p.Asp75Val (c.224A>T) is classified Pathogenic in MPZ (ClinVar, Single submitter, 3 submitters; last evaluated 2025-09-08). AlphaMissense: likely pathogenic (0.7561); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with MPZ p.Asp75Val (c.224A>T)?

MPZ p.Asp75Val (c.224A>T) is associated with Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth disease type 1B, Charcot-Marie-Tooth disease type 2J (ClinVar).

How common is MPZ p.Asp75Val (c.224A>T) in the general population?

MPZ p.Asp75Val (c.224A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MPZ p.Asp75Val (c.224A>T)?

AlphaMissense predicts likely pathogenic (score 0.7561) — an in-silico prediction, not a clinical call.

MPZ p.Asp75Val

c.224A>T · rs121913597 · VCV14184

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7561 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
AlphaMissense	0.7561	likely pathogenic ✓ concordant with ClinVar
REVEL	0.482	indeterminate
SaProt	LLR -8.83	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
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	29.9	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.Asp75Val
Coding: c.224A>T
MANE Select: NM_000530
dbSNP: rs121913597
Type: single nucleotide variant
Location: chr1:161307268 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 75: a UniProt-annotated variant site (in cmt2j and 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 2J

Similar variants

MPZ p.Asp75Tyr Uncertain significance ★★ ⚠ same residue
MPZ p.Asp75His 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-asp75val (accessed [today's date]).

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