Is PLPBP p.Ser84fs (c.249_252del) pathogenic?

PLPBP p.Ser84fs (c.249252del) is classified Pathogenic in PLPBP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-29). Very rare (popmax 0.00225%, eas).

How common is PLPBP p.Ser84fs (c.249_252del) in the general population?

PLPBP p.Ser84fs (c.249_252del) is very rare (popmax 0.00225%, eas) (gnomAD).

PLPBP p.Ser84fs

c.249_252del · rs1323938116 · VCV2136656

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00225% East Asian · 1/44,508 alleles

Filtering AF 0.00036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000685% 11/1,606,586 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00225%	44,508
South Asian	0.00111%	89,698
European (non-Finnish)	0.000765%	130,778

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: PLPBP
Protein: p.Ser84fs
Coding: c.249_252del
MANE Select: NM_007198
dbSNP: rs1323938116
Type: Deletion
Location: chr8:37766282 (GRCh38)
Gene constraint: LOEUF 1.049 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49
Residue 84: a UniProt-annotated variant site (in epeo1); a UniProt-annotated variant site (in epeo1; decreased expression at the mrna level; undetectable at the protein level in patient's fibroblasts)

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

Similar variants

PLPBP p.Ser84Pro Uncertain significance ★ ⚠ same residue
PLPBP p.Asp124fs Pathogenic ★★ same type
PLPBP p.Pro258fs Uncertain significance ★★ same type
PLPBP c.243+17_243+18del Benign/Likely benign ★★ same type
PLPBP p.Met106fs Pathogenic ★ same type
PLPBP p.Pro215fs Likely pathogenic ★ same type
PLPBP p.Trp130fs Pathogenic ★ same type
PLPBP p.Pro136del 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/plpbp-p-ser84fs (accessed [today's date]).

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