Is PLP1 p.Pro173Arg (c.518C>G) pathogenic?

PLP1 p.Pro173Arg (c.518C>G) is classified Uncertain significance in PLP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-11). AlphaMissense: likely pathogenic (0.9991); Absent from gnomAD v4.1; Associated with Pelizaeus-Merzbacher spectrum disorder.

What condition is associated with PLP1 p.Pro173Arg (c.518C>G)?

PLP1 p.Pro173Arg (c.518C>G) is associated with Pelizaeus-Merzbacher spectrum disorder (ClinVar).

How common is PLP1 p.Pro173Arg (c.518C>G) in the general population?

PLP1 p.Pro173Arg (c.518C>G) is absent from gnomAD v4.1 (gnomAD).

How is Pelizaeus-Merzbacher disease inherited?

Typically X-linked dominant, X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PLP1 p.Pro173Arg (c.518C>G)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

PLP1 p.Pro173Arg

c.518C>G · rs1556269029 · VCV547754

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Pelizaeus-Merzbacher spectrum disorder

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic
REVEL	0.974	strongly pathogenic-leaning
SaProt	LLR -18.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 14 kb · p 1.2e-12 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: PLP1
Protein: p.Pro173Arg
Coding: c.518C>G
MANE Select: NM_000533
dbSNP: rs1556269029
Type: single nucleotide variant
Location: chrX:103787862 (GRCh38)

Full PLP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Pelizaeus-Merzbacher spectrum disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pelizaeus-Merzbacher disease (Orphanet):

Inheritance: X-linked dominant, X-linked recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

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/plp1-p-pro173arg (accessed [today's date]).

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