Is MPZ p.Val129Ile (c.385G>A) pathogenic?

MPZ p.Val129Ile (c.385G>A) is classified Conflicting classifications of pathogenicity in MPZ (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.2459); Very rare (popmax 0.00267%, afr); Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with MPZ p.Val129Ile (c.385G>A)?

MPZ p.Val129Ile (c.385G>A) is associated with Charcot-Marie-Tooth disease type 1 (ClinVar).

How common is MPZ p.Val129Ile (c.385G>A) in the general population?

MPZ p.Val129Ile (c.385G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MPZ p.Val129Ile (c.385G>A)?

AlphaMissense predicts likely benign (score 0.2459) — an in-silico prediction, not a clinical call.

MPZ p.Val129Ile

c.385G>A · rs201156403 · VCV447729

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2459 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
AlphaMissense	0.2459	likely benign
REVEL	0.543	indeterminate
SaProt	LLR -9.21	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 3,519 bp · p 4.1e-06 · regional, not allelic
Overall
CADD	26.4	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 0.00267% African / African-American · 2/74,842 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00161% 26/1,613,864 alleles · very rare exomes 24/1,461,888 · genomes 2/151,976 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,421
European (non-Finnish)	0.00195%	51,305
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Val129Ile
Coding: c.385G>A
MANE Select: NM_000530
dbSNP: rs201156403
Type: single nucleotide variant
Location: chr1:161306771 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 129: a β-strand; the ig-like v-type domain

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.Val129Gly Uncertain significance ★ ⚠ same residue
MPZ p.Val129Phe 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

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-val129ile (accessed [today's date]).

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