Is PLPBP p.Ser226Pro (c.676T>C) pathogenic?

PLPBP p.Ser226Pro (c.676T>C) is classified Conflicting classifications of pathogenicity in PLPBP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-05-29). AlphaMissense: likely pathogenic (0.9876); Very rare (popmax 0.0022%, sas); Associated with epilepsy, early-onset, vitamin B6-dependent.

What condition is associated with PLPBP p.Ser226Pro (c.676T>C)?

PLPBP p.Ser226Pro (c.676T>C) is associated with epilepsy, early-onset, vitamin B6-dependent (ClinVar).

How common is PLPBP p.Ser226Pro (c.676T>C) in the general population?

PLPBP p.Ser226Pro (c.676T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about PLPBP p.Ser226Pro (c.676T>C)?

AlphaMissense predicts likely pathogenic (score 0.9876) — an in-silico prediction, not a clinical call.

PLPBP p.Ser226Pro

Q: How is Pyridoxine-dependent-developmental and epileptic encephalopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.676T>C · rs201046156 · VCV1965429

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epilepsy, early-onset, vitamin B6-dependent

Computational evidence

Protein change
AlphaMissense	0.9876	likely pathogenic · top 3% in PLPBP
REVEL	0.899	moderately pathogenic-leaning
SaProt	LLR -13.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 12 kb · p 9.5e-06 · regional, not allelic
Overall
CADD	29.4	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 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00167% 27/1,613,782 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,543
European (non-Finnish)	0.00203%	49,163
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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.Ser226Pro
Coding: c.676T>C
MANE Select: NM_007198
dbSNP: rs201046156
Type: single nucleotide variant
Location: chr8:37775996 (GRCh38)
Gene constraint: LOEUF 1.049 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49
Residue 226: 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); a modified residue (phosphoserine)

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

Disease context

epilepsy, early-onset, vitamin B6-dependent — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pyridoxine-dependent-developmental and epileptic encephalopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

PLPBP p.Ser226= Likely benign ★ same residue
PLPBP c.207+1G>T Pathogenic/Likely pathogenic ★★ same condition
PLPBP c.320-2A>G Pathogenic ★★ same condition
PLPBP p.Arg241Gln Pathogenic/Likely pathogenic ★★ same condition
PLPBP p.Pro87Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
PLPBP p.Arg205Trp Uncertain significance ★★ ⚠ same condition
PLPBP c.244-18T>C Likely benign ★★ same condition
PLPBP c.455-16G>C Likely benign ★★ 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-ser226pro (accessed [today's date]).

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