PLCL1

Chr 2

phospholipase C like 1 (inactive)

Also known as: PLCE, PLCL, PLDL1, PPP1R127, PRIP

NCBI Gene: 5334 ENSG00000115896 UniProt: Q15111 OMIM: 600597

The PLCL1 protein is involved in inositol phospholipid signaling and regulates GABA-A receptor endocytosis, contributing to the maintenance of GABAergic synaptic inhibition. Mutations cause autosomal recessive intellectual disability and epilepsy, typically with infantile onset seizures. The gene is highly constrained against loss-of-function variants (LOEUF 0.476), reflecting its critical role in neurodevelopment and synaptic function.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable GABA receptor binding activity and phosphatidylinositol-4,5-bisphosphate phospholipase C activity. Predicted to be involved in several processes, including gamma-aminobutyric acid signaling pathway; negative regulation of cold-induced thermogenesis; and phosphatidylinositol-mediated signaling. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.48

Clinical Summary— PLCL1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

133 VUS of 146 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.012

Z-score 4.09

OE 0.29 (0.18–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.86Z-score

OE missense 0.78 (0.72–0.84)

437 obs / 561.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.18–0.48)

0≤0.351.4

Missense OE?0.78 (0.72–0.84)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 11 / 38.3Missense obs/exp: 437 / 561.2Syn Z: -0.70

This gene — mechanism propensity

0.6356th %ile

GOF

0.6930th %ile

LOF

0.3357th %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

146 submitted variants in ClinVar

ClinVar

Classification Summary

VUS133

Likely Benign3

Benign2

Conflicting1

133

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	132	0	1	133
Likely Benign	0	1	1	1	3
Benign	0	0	0	2	2
Conflicting	—				1
Total	0	133	1	4	139

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

View in ClinVar →

38 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap PLCL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →