Is MPZ p.Trp183Arg (c.547T>C) pathogenic?

MPZ p.Trp183Arg (c.547T>C) is classified Uncertain significance in MPZ (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-22). AlphaMissense: ambiguous (0.4594); Very rare (popmax 0.00347%, nfe); Associated with Charcot-Marie-Tooth disease.

What condition is associated with MPZ p.Trp183Arg (c.547T>C)?

MPZ p.Trp183Arg (c.547T>C) is associated with Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 1 (ClinVar).

How common is MPZ p.Trp183Arg (c.547T>C) in the general population?

MPZ p.Trp183Arg (c.547T>C) is very rare (popmax 0.00347%, nfe) (gnomAD).

What do computational predictors say about MPZ p.Trp183Arg (c.547T>C)?

AlphaMissense predicts ambiguous (score 0.4594) — an in-silico prediction, not a clinical call.

MPZ p.Trp183Arg

c.547T>C · rs753107323 · VCV581905

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.4594	ambiguous
REVEL	0.413	indeterminate
SaProt	LLR -4.56	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 506 bp · p 0.45 · regional, not allelic
Overall
CADD	28.0	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 0.00347% European (non-Finnish) · 41/1,180,042 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00266% 43/1,614,074 alleles · very rare exomes 41/1,461,894 · genomes 2/152,180 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00347%	28,782
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Trp183Arg
Coding: c.547T>C
MANE Select: NM_000530
dbSNP: rs753107323
Type: single nucleotide variant
Location: chr1:161306366 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 1

Similar variants

MPZ p.Trp183Ter Likely pathogenic ★ 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
MPZ c.68-1G>C 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-trp183arg (accessed [today's date]).

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