Is PLP2 p.Pro81Ala (c.241C>G) pathogenic?

PLP2 p.Pro81Ala (c.241C>G) is classified Uncertain significance in PLP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-18). AlphaMissense: likely benign (0.1682); Very rare (popmax 8.26e-05%).

How common is PLP2 p.Pro81Ala (c.241C>G) in the general population?

PLP2 p.Pro81Ala (c.241C>G) is very rare (popmax 8.26e-05%) (gnomAD).

What do computational predictors say about PLP2 p.Pro81Ala (c.241C>G)?

AlphaMissense predicts likely benign (score 0.1682) — an in-silico prediction, not a clinical call.

PLP2 p.Pro81Ala

c.241C>G · rs992112475 · VCV2255782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.26e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1682	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -6.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.58, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 2,690 bp · p 0.75 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 8.26e-05%

Overall 8.26e-05% 1/1,210,837 alleles · very rare exomes 1/1,097,385 · genomes 0/113,452 · 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: PLP2
Protein: p.Pro81Ala
Coding: c.241C>G
MANE Select: NM_002668
dbSNP: rs992112475
Type: single nucleotide variant
Location: chrX:49173273 (GRCh38)
Structure: AlphaFold pLDDT 78.76
Residue 81: the marvel domain

Full PLP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLP2 p.Arg6Cys Benign ★★ same type
PLP2 p.Ala121Pro Uncertain significance ★ ⚠ same type
PLP2 p.Ala2Val Uncertain significance ★ ⚠ same type
PLP2 p.Arg136Trp Uncertain significance ★ ⚠ same type
PLP2 p.Arg21His Uncertain significance ★ ⚠ same type
PLP2 p.Arg87Gln Uncertain significance ★ ⚠ same type
PLP2 p.Gly118Ser Uncertain significance ★ ⚠ same type
PLP2 p.Ile33Val Uncertain significance ★ ⚠ same type

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/plp2-p-pro81ala (accessed [today's date]).

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