Is MPZ p.Ala221Val (c.662C>T) pathogenic?

MPZ p.Ala221Val (c.662C>T) is classified Uncertain significance in MPZ (ClinVar, Single submitter, 2 submitters; last evaluated 2024-12-27). AlphaMissense: likely pathogenic (0.6605); Very rare (popmax 0.00017%, nfe); Associated with Charcot-Marie-Tooth disease type 1.

What condition is associated with MPZ p.Ala221Val (c.662C>T)?

MPZ p.Ala221Val (c.662C>T) is associated with Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth disease type 1B, Charcot-Marie-Tooth disease type 2I (ClinVar).

How common is MPZ p.Ala221Val (c.662C>T) in the general population?

MPZ p.Ala221Val (c.662C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about MPZ p.Ala221Val (c.662C>T)?

AlphaMissense predicts likely pathogenic (score 0.6605) — an in-silico prediction, not a clinical call.

MPZ p.Ala221Val

c.662C>T · rs1040557288 · VCV462799

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6605 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 1

Computational evidence

Protein change
AlphaMissense	0.6605	likely pathogenic
REVEL	0.746	pathogenic-leaning
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 506 bp · p 0.45 · regional, not allelic
Overall
CADD	29.8	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 0.00017% European (non-Finnish) · 2/1,179,902 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,780 alleles · very rare exomes 1/1,461,770 · genomes 1/152,010 · 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.Ala221Val
Coding: c.662C>T
MANE Select: NM_000530
dbSNP: rs1040557288
Type: single nucleotide variant
Location: chr1:161305961 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI 0.11 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 2 PDB
Residue 221: a UniProt-annotated variant site (in dss); a UniProt-annotated variant site (in chn2)

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

Also linked: Charcot-Marie-Tooth disease type 1B Charcot-Marie-Tooth disease type 2I Charcot-Marie-Tooth disease type 2J Charcot-Marie-Tooth disease dominant intermediate D

Similar variants

MPZ p.Ala221= Likely benign ★★ same residue
MPZ p.Ala221Thr 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-ala221val (accessed [today's date]).

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