Is PLP1 p.Ser253Phe (c.758C>T) pathogenic?

PLP1 p.Ser253Phe (c.758C>T) is classified Likely pathogenic in PLP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely pathogenic (0.9534); Absent from gnomAD v4.1; Associated with Pelizaeus-Merzbacher spectrum disorder.

What condition is associated with PLP1 p.Ser253Phe (c.758C>T)?

PLP1 p.Ser253Phe (c.758C>T) is associated with Pelizaeus-Merzbacher spectrum disorder (ClinVar).

How common is PLP1 p.Ser253Phe (c.758C>T) in the general population?

PLP1 p.Ser253Phe (c.758C>T) 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.Ser253Phe (c.758C>T)?

AlphaMissense predicts likely pathogenic (score 0.9534) — an in-silico prediction, not a clinical call.

PLP1 p.Ser253Phe

c.758C>T · rs2522323235 · VCV3255456

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9534 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Pelizaeus-Merzbacher spectrum disorder

Computational evidence

Protein change
AlphaMissense	0.9534	likely pathogenic ✓ concordant with ClinVar
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -9.90	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 14 kb · p 1.2e-12 · regional, not allelic
Overall
CADD	27.6	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: PLP1
Protein: p.Ser253Phe
Coding: c.758C>T
MANE Select: NM_000533
dbSNP: rs2522323235
Type: single nucleotide variant
Location: chrX:103789394 (GRCh38)
Structure: AlphaFold pLDDT 77.81 · 1 PDB
Residue 253: a UniProt-annotated variant site (in hld1)

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)

Similar variants

PLP1 p.Ser253Cys Likely pathogenic ★ ⚠ same residue
PLP1 c.453+2T>C Pathogenic/Likely pathogenic ★★ same condition
PLP1 c.454-1G>A Pathogenic ★★ same condition
PLP1 c.696+1G>A Pathogenic/Likely pathogenic ★★ same condition
PLP1 p.Asp203Asn Pathogenic ★★ same condition
PLP1 p.Cys220Gly Likely pathogenic ★★ same condition
PLP1 p.Gln69Leu Likely pathogenic ★★ same condition
PLP1 p.Gly246Ala 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/plp1-p-ser253phe (accessed [today's date]).

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