LRRTM4

Chr 2

leucine rich repeat transmembrane neuronal 4

NCBI Gene: 80059 ENSG00000176204 UniProt: Q86VH4

Predicted to enable heparan sulfate proteoglycan binding activity. Predicted to be involved in regulation of synapse assembly. Predicted to act upstream of or within AMPA glutamate receptor clustering; positive regulation of synapse assembly; and regulation of presynaptic membrane organization. Predicted to be located in postsynaptic membrane. Predicted to be part of AMPA glutamate receptor complex. Predicted to be active in several cellular components, including GABA-ergic synapse; photoreceptor ribbon synapse; and postsynaptic density membrane. [provided by Alliance of Genome Resources, Jul 2025]

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

1.6

Missense Z

0.55

LOEUF

Clinical Summary— LRRTM4

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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ClinVar Variants

11 Pathogenic / Likely Pathogenic· 82 VUS of 98 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.55LOEUF

pLI 0.086

Z-score 3.12

OE 0.28 (0.15–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.59Z-score

OE missense 0.75 (0.68–0.83)

242 obs / 322.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.28 (0.15–0.55)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.68–0.83)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00

0≤1.21.6

LoF obs/exp: 6 / 21.7Missense obs/exp: 242 / 322.4Syn Z: -0.01

0.74top 25%

GOF

0.71top 25%

LOF

0.3358th %ile

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

DNprediction above median

GOFprediction 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.