PICK1

Chr 22

protein interacting with PRKCA 1

Also known as: PICK, PRKCABP

NCBI Gene: 9463 ENSG00000100151 UniProt: Q9NRD5 OMIM: 605926

The PICK1 protein functions as an adapter that organizes subcellular localization of membrane proteins and regulates synaptic plasticity by controlling AMPA receptor trafficking and internalization. Mutations in PICK1 cause neurodevelopmental disorders with intellectual disability and seizures. The gene shows autosomal recessive inheritance and is not highly constrained to loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene contains a PDZ domain, through which it interacts with protein kinase C, alpha (PRKCA). This protein may function as an adaptor that binds to and organizes the subcellular localization of a variety of membrane proteins. It has been shown to interact with multiple glutamate receptor subtypes, monoamine plasma membrane transporters, as well as non-voltage gated sodium channels, and may target PRKCA to these membrane proteins and thus regulate their distribution and function. This protein has also been found to act as an anchoring protein that specifically targets PRKCA to mitochondria in a ligand-specific manner. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.67

Clinical Summary— PICK1

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

33 VUS of 51 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.008

Z-score 2.64

OE 0.36 (0.20–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.01Z-score

OE missense 0.65 (0.57–0.74)

172 obs / 264.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.36 (0.20–0.67)

0≤0.351.4

Missense OE?0.65 (0.57–0.74)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 7 / 19.6Missense obs/exp: 172 / 264.0Syn Z: -0.06

This gene — mechanism propensity

0.6646th %ile

GOF

0.74top 25%

LOF

0.3648th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

51 submitted variants in ClinVar

ClinVar

Classification Summary

VUS33

Likely Benign1

Benign3

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	33	0	0	33
Likely Benign	0	0	1	1
Benign	0	2	1	3
Total	33	2	2	37

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap PICK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →