Is PLP2 p.Pro138Arg (c.413C>G) pathogenic?

PLP2 p.Pro138Arg (c.413C>G) is classified Uncertain significance in PLP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-03). AlphaMissense: likely benign (0.0708); Ultra-rare (popmax 0.0232%, mid).

How common is PLP2 p.Pro138Arg (c.413C>G) in the general population?

PLP2 p.Pro138Arg (c.413C>G) is ultra-rare (popmax 0.0232%, mid) (gnomAD).

What do computational predictors say about PLP2 p.Pro138Arg (c.413C>G)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

PLP2 p.Pro138Arg

c.413C>G · rs1557099566 · VCV2315176

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0232%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -6.31	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 5.6	GERP 0.67, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 2,690 bp · p 0.75 · regional, not allelic
Overall
CADD	12.99	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 0.0232% Middle Eastern · 1/4,319 alleles

Filtering AF 0.000722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00057%

Overall 0.00109% 13/1,190,210 alleles · ultra-rare exomes 13/1,094,973 · genomes 0/95,237 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0232%	4,319
European (non-Finnish)	0.00135%	73,866

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.Pro138Arg
Coding: c.413C>G
MANE Select: NM_002668
dbSNP: rs1557099566
Type: single nucleotide variant
Location: chrX:49174402 (GRCh38)
Structure: AlphaFold pLDDT 78.76

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-pro138arg (accessed [today's date]).

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