Is MPZ p.Pro26Leu (c.77C>T) pathogenic?

MPZ p.Pro26Leu (c.77C>T) is classified Conflicting classifications of pathogenicity in MPZ (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-15). AlphaMissense: likely benign (0.222); Ultra-rare (popmax 0.0379%, eas); Associated with Charcot-Marie-Tooth disease.

What condition is associated with MPZ p.Pro26Leu (c.77C>T)?

MPZ p.Pro26Leu (c.77C>T) is associated with Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 1B, Roussy-Levy syndrome (ClinVar).

How common is MPZ p.Pro26Leu (c.77C>T) in the general population?

MPZ p.Pro26Leu (c.77C>T) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

What do computational predictors say about MPZ p.Pro26Leu (c.77C>T)?

AlphaMissense predicts likely benign (score 0.222) — an in-silico prediction, not a clinical call.

MPZ p.Pro26Leu

c.77C>T · rs530923760 · VCV293314

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.222 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.222	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -6.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -0.38, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 3,519 bp · p 4.1e-06 · regional, not allelic
Overall
CADD	23.6	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 0.0379% East Asian · 17/44,892 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00297% 48/1,614,136 alleles · ultra-rare exomes 42/1,461,768 · genomes 6/152,368 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,641
Remaining individualsnot grpmax-eligible	0.0208%	4,808
South Asian	0.00329%	30,361
Admixed American	0.00167%	60,022
Finnishnot grpmax-eligible	0.00156%	64,040
European (non-Finnish)	0.0011%	90,772

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.Pro26Leu
Coding: c.77C>T
MANE Select: NM_000530
dbSNP: rs530923760
Type: single nucleotide variant
Location: chr1:161307415 (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 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.Pro26= Likely benign ★ same residue
MPZ p.Pro26fs 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

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-pro26leu (accessed [today's date]).

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