Is MPZ p.Met1Val (c.1A>G) pathogenic?

MPZ p.Met1Val (c.1A>G) is classified Pathogenic in MPZ (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-07). Very rare (popmax 0.00134%, afr); Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with MPZ p.Met1Val (c.1A>G)?

MPZ p.Met1Val (c.1A>G) is associated with Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth disease (ClinVar).

How common is MPZ p.Met1Val (c.1A>G) in the general population?

MPZ p.Met1Val (c.1A>G) is very rare (popmax 0.00134%, afr) (gnomAD).

MPZ p.Met1Val

c.1A>G · rs1427063795 · VCV637506

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.605	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.4, phastCons 1
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,608 alleles

Overall 0.000126% 2/1,586,182 alleles · very rare exomes 1/1,434,452 · genomes 1/151,730 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,608
European (non-Finnish)	8.57e-05%	1,167,010

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.Met1Val
Coding: c.1A>G
MANE Select: NM_000530
dbSNP: rs1427063795
Type: single nucleotide variant
Location: chr1:161309905 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB

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 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
MPZ c.68-1G>C Pathogenic/Likely pathogenic ★★ same condition
MPZ c.68-2A>C 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-met1val (accessed [today's date]).

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