PRICKLE2

Chr 3

prickle planar cell polarity protein 2

Also known as: EPM5

NCBI Gene: 166336 ENSG00000163637 UniProt: Q7Z3G6 OMIM: 608501

The protein regulates axon initial segment architecture by controlling ANK3/ANKG localization and microtubule bundling, which is crucial for establishing neuronal polarity. Mutations cause progressive myoclonic epilepsy type 5 with autosomal recessive inheritance. This gene is highly constrained against loss-of-function variants, indicating that complete protein loss is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a homolog of Drosophila prickle. The exact function of this gene is not known, however, studies in mice suggest that it may be involved in seizure prevention. Mutations in this gene are associated with progressive myoclonic epilepsy type 5. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.28

Clinical Summary— PRICKLE2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADLimited

Limited evidence — not for standalone diagnostic reporting

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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

5 unique Pathogenic / Likely Pathogenic· 430 VUS of 683 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.28LOEUF

pLI 0.995

Z-score 4.96

OE 0.13 (0.07–0.28)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.72Z-score

OE missense 0.78 (0.72–0.85)

396 obs / 504.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.28)

0≤0.351.4

Missense OE?0.78 (0.72–0.85)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 5 / 38.0Missense obs/exp: 396 / 504.9Syn Z: -0.38

This gene — mechanism propensity

0.5081th %ile

GOF

0.4875th %ile

LOF

0.69top 10%

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

LOFprediction above median · 60% of P/LP variants are LoF · LOEUF 0.28

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

683 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic3

VUS430

Likely Benign179

Benign32

Conflicting19

Pathogenic

Likely Pathogenic

430

VUS

179

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	0	2
Likely Pathogenic	1	2	0	0	3
VUS	5	330	90	5	430
Likely Benign	0	2	36	141	179
Benign	0	0	24	8	32
Conflicting	—				19
Total	8	334	150	154	665

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap PRICKLE2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →