Is PLPBP p.Ala57Ser (c.169G>T) pathogenic?

PLPBP p.Ala57Ser (c.169G>T) is classified Uncertain significance in PLPBP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: ambiguous (0.4002); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PLPBP p.Ala57Ser (c.169G>T)?

PLPBP p.Ala57Ser (c.169G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PLPBP p.Ala57Ser (c.169G>T) in the general population?

PLPBP p.Ala57Ser (c.169G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about PLPBP p.Ala57Ser (c.169G>T)?

AlphaMissense predicts ambiguous (score 0.4002) — an in-silico prediction, not a clinical call.

PLPBP p.Ala57Ser

c.169G>T · VCV4628006

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4002 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4002	ambiguous
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -11.68	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.26	unconstrained · MANE · 2,963 bp · p 0.011 · regional, not allelic
Overall
CADD	26.7	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

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,002 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,842 alleles · very rare

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.Ala57Ser
Coding: c.169G>T
MANE Select: NM_007198
Type: single nucleotide variant
Location: chr8:37765595 (GRCh38)
Gene constraint: LOEUF 1.049 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLPBP p.Arg250Gln Uncertain significance ★★ ⚠ same condition
PLPBP p.Arg63Cys Uncertain significance ★★ ⚠ same condition
PLPBP p.Asn110Ser Uncertain significance ★★ ⚠ same condition
PLPBP p.Asp189His Uncertain significance ★★ same condition
PLPBP p.Cys209Gly Uncertain significance ★★ ⚠ same condition
PLPBP p.Glu56Lys Uncertain significance ★★ ⚠ same condition
PLPBP p.His275Leu Uncertain significance ★★ ⚠ same condition
PLPBP p.Ile162Thr Uncertain significance ★★ ⚠ 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/plpbp-p-ala57ser (accessed [today's date]).

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