Is PLPBP p.Ser253Pro (c.757T>C) pathogenic?

PLPBP p.Ser253Pro (c.757T>C) is classified Uncertain significance in PLPBP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1517); Very rare (popmax 0.000806%); Associated with Inborn genetic diseases.

What condition is associated with PLPBP p.Ser253Pro (c.757T>C)?

PLPBP p.Ser253Pro (c.757T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PLPBP p.Ser253Pro (c.757T>C) in the general population?

PLPBP p.Ser253Pro (c.757T>C) is very rare (popmax 0.000806%) (gnomAD).

What do computational predictors say about PLPBP p.Ser253Pro (c.757T>C)?

AlphaMissense predicts likely benign (score 0.1517) — an in-silico prediction, not a clinical call.

PLPBP p.Ser253Pro

c.757T>C · VCV4139883

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1517 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000806%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1517	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.71	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 2.3	GERP 0.55, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 12 kb · p 9.5e-06 · regional, not allelic
Overall
CADD	19.57	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 0.000806%

Overall 0.000806% 13/1,613,742 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.Ser253Pro
Coding: c.757T>C
MANE Select: NM_007198
Type: single nucleotide variant
Location: chr8:37778033 (GRCh38)
Gene constraint: LOEUF 1.049 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49
Residue 253: the 'disordered' region; 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

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-ser253pro (accessed [today's date]).

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