PLPBP

protein-coding

pyridoxal phosphate binding protein

Gene summary

This gene encodes a pyridoxal 5'-phosphate binding protein involved in the homeostatic regulation of intracellular pyridoxal 5'-phosphate. This gene has a tumor suppressive effect on hepatocellular carcinoma and other solid tumors of epithelial origin. Naturally occurring mutations in this gene are associated with a pyridoxine-dependent epilepsy. [provided by RefSeq, Mar 2017]

Previous symbols:

PROSC

MANE transcript

NM_007198.4

Inheritance

ClinVar variants

P:29U:118B:75

Top phenotype

Epilepsy, early-onset 1, vitamin B6-dependent

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr8:37,762,595-37,779,768

External References & Databases

Ensembl (ENSG00000147471)

Transcript & Mutation Effects

hg38 • Region Span ~17.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pyridoxine-dependent epilepsySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009945

Submitter: Orphanet

epilepsy, early-onset, vitamin B6-dependentSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015005

Submitter: PanelApp Australia

epilepsy, early-onset, vitamin B6-dependentSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015005

Submitter: G2P

pyridoxine-dependent epilepsyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009945

Submitter: ClinGen

*PLPBP* (note, previous gene symbol *PROSC*) was described in relation to autosomal recessive pyridoxine dependent epilepsy in 2016 by Darin *et al.* by studying a large consanguineous Syrian family in whom *PNPO* and *ALDH7A1* deficiency were excluded (PMID: 27912044). Homozygosity mapping demonstrated a loss of heterozygosity region at 8p11.23-p21.2 and exome sequencing of the region detected homozygous *PLPBP* p.Ser78* in the affected family members. An additional 29 affected individuals were evaluated by *PLPBP* sequencing, and four additional affected individuals were found to have biallelic *PLPBP* variants. Over 50 affected individuals with *PLPBP* deficiency have since been reported in the literature and the mutation spectrum includes nonsense, missense, frameshift, and splice site variants (PMID: 28391250; PMID 30525118; PMID: 30668673). The condition is typically associated with neonatal onset of seizures (epileptic spasms without hypsarrhythmia, tonic, clonic, generalized tonic-clonic, myoclonic), although a rare late onset form has also been reported (PMID:30525118). Additional findings include developmental delay/intellectual disability (>50% of affected individuals), acquired microcephaly, movement disorder, and MRI abnormalities (white matter abnormalities, cortical atrophy, simplified cortical gyral pattern, periventricular cysts, thinning of the corpus callosum). Several of the reported pathogenic variants have supporting functional evidence, including complementation studies in a pyridoxine sensitive E.coli mutant lacking the *PLPBP* homolog (ΔYggS)(PMID: 27912044; PMID: 29689137). Experimental evidence includes a zebrafish knock out model which demonstrates spontaneous seizure-like behavior and increased survival with pyridoxine treatment with reemergence of seizures and death after treatment cessation (PMID: 30668673). In summary, there is definitive evidence to support the relationship between *PLPBP* and autosomal recessive pyridoxine dependent epilepsy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date February 17, 2026 (SOP Version 12).

epilepsy, early-onset, vitamin B6-dependentSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015005

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Epilepsy, early-onset 1, vitamin B6-dependentAR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: The condition involves neonatal or early-onset seizures, and medical treatment (with activated vitamin B6 and/or pyridoxine) has been reported as beneficial related to seizure control

Refs: 27912044

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLPBP variants in ClinVar

6 Conditions Cataloged

not providedTotal: 256

Epilepsy, early-onset, vitamin B6-dependentTotal: 39

Inborn genetic diseasesTotal: 36

not specifiedTotal: 21

PLPBP-related disorderTotal: 8

PLPBP & PROSC-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007198.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	67 clinvar		71
missense	1 clinvar	8 clinvar	104 clinvar	8 clinvar		121
nonsense	5 clinvar	2 clinvar	1 clinvar			8
start loss			1 clinvar			1
frameshift	7 clinvar	1 clinvar	2 clinvar			10
splice donor/acceptor (+/-2bp)	3 clinvar	2 clinvar	6 clinvar			11
Total	16	13	118	75	0	222

Highest pathogenic variant AF is 0.00027195172

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007198.4	RefSeq	NP_009129.1	8	MANE Select
ENST00000328195.8	Ensembl	ENSP00000333551.3	8	MANE Select
NM_001349346.2	RefSeq	NP_001336275.1	8	Standard
NM_001349347.2	RefSeq	NP_001336276.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

biological_process

Molecular Function

pyridoxal phosphate binding

Cellular Component

cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000328195
Coding exons: 8
Length: 17173
Individuals with no LoFs: 125693
Homozygous LoFs: 0
Heterozygous LoFs: 55
Defined: 125748
p: 0.000219

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.981	125	160	0.782	0.00000886	1784
Missense (PolyPhen)		36	49.077	0.73354		536
Synonymous	-0.381	68	64.1	1.06	0.00000388	528
Loss of Function	2.41	5	15.1	0.331	8.26e-7	163

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00058	0.00058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00021	0.00021	rare
South Asian	0.00023	0.00023	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Pyridoxal 5'-phosphate (PLP)-binding protein, which may be involved in intracellular homeostatic regulation of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6. {ECO:0000255|HAMAP-Rule:MF_03225, ECO:0000269|PubMed:27912044}.;
Disease: DISEASE: Epilepsy, early-onset, vitamin B6-dependent (EPVB6D) [MIM:617290]: An autosomal recessive neurologic disorder characterized by seizures responsive to treatment with activated vitamin B6 and/or pyridoxine. Most patients show delayed psychomotor development, mental retardation and learning disability. Seizures onset is in the first days or months of life. {ECO:0000269|PubMed:27912044}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.192

Intolerance Scores

RVIS EVS: -0.16
RVIS percentile EVS: 41.91

Essentials

Essential (gene trap): N