Is MPZ p.Thr124= (c.372G>A) pathogenic?

MPZ p.Thr124= (c.372G>A) is classified Likely benign in MPZ (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-16). Very rare (popmax 0.00891%, eas); Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with MPZ p.Thr124= (c.372G>A)?

MPZ p.Thr124= (c.372G>A) is associated with Charcot-Marie-Tooth disease type 1 (ClinVar).

How common is MPZ p.Thr124= (c.372G>A) in the general population?

MPZ p.Thr124= (c.372G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

MPZ p.Thr124=

c.372G>A · rs536830537 · VCV696997

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -3.7
Overall
CADD	9.395	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,870 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00105% 17/1,614,044 alleles · very rare exomes 14/1,461,874 · genomes 3/152,170 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,218
African / African-American	0.004%	24,998
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,504
South Asian	0.0011%	91,084
European (non-Finnish)	0.000593%	168,573

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.Thr124=
Coding: c.372G>A
MANE Select: NM_000530
dbSNP: rs536830537
Type: single nucleotide variant
Location: chr1:161306784 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 124: a β-strand; the ig-like v-type domain; a UniProt-annotated variant site (in dss); a UniProt-annotated variant site (in chn2); a UniProt-annotated variant site (in cmt1b, cmt2i and cmt2j; cmtj2 patients present adie pupil; slightly reduces intercellular adhesion; does not affect targeting to the cell membrane; affects glycosylation)

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

Similar variants

MPZ p.Thr124Met Pathogenic ★★ same residue
MPZ p.Thr124Ser Uncertain significance ★ same residue
MPZ p.Thr124Ala Uncertain significance ★ ⚠ same residue
MPZ p.Thr124Lys 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

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-thr124 (accessed [today's date]).

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