LRRC38

Chr 1

leucine rich repeat containing 38

NCBI Gene: 126755 ENSG00000162494 UniProt: Q5VT99 OMIM: 615212

The LRRC38 protein is an auxiliary subunit that modulates large-conductance calcium and voltage-activated potassium (BK) channels by shifting their voltage dependence of activation in the hyperpolarizing direction. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities, typically presenting in infancy with seizures and developmental delays. The gene shows moderate tolerance to loss-of-function variants (pLI 0.14, LOEUF 1.08), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Enables potassium channel activator activity and transmembrane transporter binding activity. Involved in positive regulation of voltage-gated potassium channel activity and potassium ion transmembrane transport. Part of voltage-gated potassium channel complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.08

Clinical Summary— LRRC38

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

36 VUS of 41 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?

1.08LOEUF

pLI 0.144

Z-score 1.47

OE 0.34 (0.14–1.08)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.23Z-score

OE missense 0.72 (0.62–0.84)

112 obs / 155.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.14–1.08)

0≤0.351.4

Missense OE?0.72 (0.62–0.84)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 2 / 5.8Missense obs/exp: 112 / 155.1Syn Z: 0.88

This gene — mechanism propensity

0.6936th %ile

GOF

0.74top 25%

LOF

0.2969th %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

41 submitted variants in ClinVar

ClinVar

Classification Summary

VUS36

Likely Benign5

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	36	36
Likely Benign	5	5
Benign	0	0
Total	41	41

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap LRRC38 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →