Is MPZ p.Arg36Ser (c.108G>C) pathogenic?

MPZ p.Arg36Ser (c.108G>C) is classified Uncertain significance in MPZ (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-30). AlphaMissense: ambiguous (0.4191); Very rare (popmax 0.000424%, nfe); Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with MPZ p.Arg36Ser (c.108G>C)?

MPZ p.Arg36Ser (c.108G>C) is associated with Charcot-Marie-Tooth disease type 1 (ClinVar).

How common is MPZ p.Arg36Ser (c.108G>C) in the general population?

MPZ p.Arg36Ser (c.108G>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about MPZ p.Arg36Ser (c.108G>C)?

AlphaMissense predicts ambiguous (score 0.4191) — an in-silico prediction, not a clinical call.

MPZ p.Arg36Ser

c.108G>C · rs1670288915 · VCV1011796

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4191 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
AlphaMissense	0.4191	ambiguous
REVEL	0.225	benign-leaning
SaProt	LLR -7.61	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.88, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 3,519 bp · p 4.1e-06 · regional, not allelic
Overall
CADD	21.1	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 0.000424% European (non-Finnish) · 5/1,180,054 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,270 alleles · very rare exomes 5/1,461,888 · genomes 0/152,382 · joint denominator

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.Arg36Ser
Coding: c.108G>C
MANE Select: NM_000530
dbSNP: rs1670288915
Type: single nucleotide variant
Location: chr1:161307384 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 36: 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.Arg36Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
MPZ p.Arg36Lys Uncertain significance ★ ⚠ same residue
MPZ p.Arg36Trp Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg36ser (accessed [today's date]).

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