Is MPZ p.Ser228= (c.684C>T) pathogenic?

MPZ p.Ser228= (c.684C>T) is classified Benign/Likely benign in MPZ (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-03). Low-frequency (popmax 2.95%, nfe); Associated with Charcot-Marie-Tooth disease.

What condition is associated with MPZ p.Ser228= (c.684C>T)?

MPZ p.Ser228= (c.684C>T) is associated with Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 1B, Roussy-Levy syndrome (ClinVar).

How common is MPZ p.Ser228= (c.684C>T) in the general population?

MPZ p.Ser228= (c.684C>T) is low-frequency (popmax 2.95%, nfe) (gnomAD).

MPZ p.Ser228=

c.684C>T · rs34307129 · VCV129619

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.95%, nfe)

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.336	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.7, phastCons 1
Overall
CADD	12.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.95% European (non-Finnish) · 34,776/1,179,812 alleles

Filtering AF 2.92% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.91%

Overall 2.44% 39,428/1,613,780 alleles · low-frequency exomes 36,542/1,461,688 · genomes 2,886/152,092 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	2.95%	34
Finnishnot grpmax-eligible	2.57%	39
Remaining individualsnot grpmax-eligible	2.04%	49
Admixed American	1.66%	60
Middle Eastern	0.858%	117
Ashkenazi Jewishnot grpmax-eligible	0.443%	226
Amishnot grpmax-eligible	0.439%	228
African / African-American	0.422%	237
South Asian	0.256%	391
East Asian	0.00223%	44,854

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.Ser228=
Coding: c.684C>T
MANE Select: NM_000530
dbSNP: rs34307129
Type: single nucleotide variant
Location: chr1:161305939 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 228: the 'disordered' region; a modified residue (phosphoserine); a UniProt-annotated variant site (in chn2)

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 1B Roussy-Levy syndrome Charcot-Marie-Tooth disease dominant intermediate D Charcot-Marie-Tooth disease type 1 neuropathy, congenital hypomyelinating, 2

Similar variants

MPZ p.Ser228Asn 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
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-ser228 (accessed [today's date]).

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