Is MPZ p.Thr65Ser (c.194C>G) pathogenic?

MPZ p.Thr65Ser (c.194C>G) is classified Uncertain significance in MPZ (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-21). AlphaMissense: ambiguous (0.3928); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with MPZ p.Thr65Ser (c.194C>G)?

MPZ p.Thr65Ser (c.194C>G) is associated with Charcot-Marie-Tooth disease type 1 (ClinVar).

How common is MPZ p.Thr65Ser (c.194C>G) in the general population?

MPZ p.Thr65Ser (c.194C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MPZ p.Thr65Ser (c.194C>G)?

AlphaMissense predicts ambiguous (score 0.3928) — an in-silico prediction, not a clinical call.

MPZ p.Thr65Ser

c.194C>G · VCV3694459

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3928 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
AlphaMissense	0.3928	ambiguous
REVEL	0.213	benign-leaning
SaProt	LLR -6.21	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 12	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	23.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MPZ
Protein: p.Thr65Ser
Coding: c.194C>G
MANE Select: NM_000530
Type: single nucleotide variant
Location: chr1:161307298 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 65: a β-strand; a UniProt-annotated variant site (in cmt1b); 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.Thr65Ala Likely pathogenic ★★ ⚠ same residue
MPZ p.Thr65Asn Pathogenic/Likely pathogenic ★★ ⚠ same residue
MPZ p.Thr65Ile Pathogenic ★ ⚠ same residue
MPZ p.Thr65= Likely benign ★ 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-thr65ser (accessed [today's date]).

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