PRICKLE1

Chr 12AR

prickle planar cell polarity protein 1

Also known as: EPM1B, RILP

NCBI Gene: 144165 ENSG00000139174 UniProt: Q96MT3 OMIM: 608500

The protein functions as a nuclear receptor involved in planar cell polarity signaling that controls neural tube closure and convergent extension during development, and is necessary for nuclear localization of the transcription repressor REST. Biallelic mutations cause progressive myoclonic epilepsy 1B with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.13), indicating that heterozygous loss-of-function variants are likely benign.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a nuclear receptor that may be a negative regulator of the Wnt/beta-catenin signaling pathway. The encoded protein localizes to the nuclear membrane and has been implicated in the nuclear trafficking of the transcription repressors REST/NRSF and REST4. Mutations in this gene have been linked to progressive myoclonus epilepsy. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 3. [provided by RefSeq, Sep 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.131 OMIM phenotype

Clinical Summary— PRICKLE1

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Gene-Disease Validity (ClinGen)

epilepsy · ADDisputed

Disputed — evidence questions this relationship

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 365 VUS of 628 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PRICKLE1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 5.47

OE 0.03 (0.01–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.83Z-score

OE missense 0.76 (0.69–0.83)

348 obs / 458.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.13)

0≤0.351.4

Missense OE?0.76 (0.69–0.83)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 1 / 36.8Missense obs/exp: 348 / 458.5Syn Z: 0.90

This gene — mechanism propensity

0.4587th %ile

GOF

0.5170th %ile

LOF

0.69top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.13

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

628 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS365

Likely Benign213

Benign30

Conflicting13

Pathogenic

Likely Pathogenic

365

VUS

213

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	1	0	0	1
VUS	13	331	18	3	365
Likely Benign	0	2	55	156	213
Benign	0	3	24	3	30
Conflicting	—				13
Total	13	338	97	162	623

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

12 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap PRICKLE1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →