PRIMA1

protein-coding

proline rich membrane anchor 1

Gene summary

The product of this gene functions to organize acetylcholinesterase (AChE) into tetramers, and to anchor AChE at neural cell membranes. [provided by RefSeq, Nov 2008]

MANE transcript

NM_178013.4

Inheritance

ClinVar variants

P:2U:78B:48

Top phenotype

Familial sleep-related hypermotor epilepsy

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr14:93,718,298-93,788,485

External References & Databases

Ensembl (ENSG00000175785)

Transcript & Mutation Effects

hg38 • Region Span ~70.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

frontal lobe epilepsyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0002612

Submitter: PanelApp Australia

epilepsyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005027

Submitter: ClinGen

*PRIMA1* was first reported in relation to autosomal recessive epilepsy in 2015 (Hildebrand et al., PMID: 26339676). The publication includes two affected adult siblings from a single family with sleep-related hypermotor epilepsy, intellectual disability, ataxia, and cerebellar hypoplasia. A single splice site variant has been reported in both siblings and was noted to result in skipping of exon 2 (the first coding exon), leading to reduced AChE (acetylcholinesterase) at the synapse causing acetylcholine accumulation and an enhanced cholinergic response (PMID: 26339676). There is currently no additional clinical or functional evidence available for *PRIMA1* in association with epilepsy. In summary, there is limited evidence to support the relationship of *PRIMA1* to autosomal recessive epilepsy. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Epilepsy GCEP on January 7, 2025 (SOP Version 11).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRIMA1 variants in ClinVar

4 Conditions Cataloged

Familial sleep-related hypermotor epilepsyTotal: 145

not specifiedTotal: 27

not providedTotal: 8

PRIMA1-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_178013.4. 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			1 clinvar	46 clinvar	1 clinvar	48
missense			75 clinvar	1 clinvar		76
nonsense	2 clinvar					2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	0	78	47	1	128

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_178013.4	RefSeq	NP_821092.1	4	MANE Select
ENST00000393140.6	Ensembl	ENSP00000376848.1	4	MANE Select
ENST00000316227.3	Ensembl	ENSP00000320948.3	4	Standard
ENST00000393143.5	Ensembl	ENSP00000376851.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

neurotransmitter catabolic process

Molecular Function

protein membrane anchor

Cellular Component

plasma membrane
integral component of membrane
cell junction
synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000393140
Coding exons: 4
Length: 70184
Individuals with no LoFs: 125245
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125247
p: 0.00000798

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.976	63	88.9	0.709	0.00000515	960
Missense (PolyPhen)		21	33.313	0.63039		346
Synonymous	0.754	31	36.8	0.842	0.00000249	313
Loss of Function	2.18	1	7.42	0.135	3.94e-7	76

Population LoF Frequency

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

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required to anchor acetylcholinesterase (ACHE) to the basal lamina of the neuromuscular junction and to the membrane of neuronal synapses in brain. Also able to organize ACHE into tetramers (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.159

Intolerance Scores

LoFtool: 0.129
RVIS EVS: -0.16
RVIS percentile EVS: 41.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.198

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium