ELFN2

Chr 22

extracellular leucine rich repeat and fibronectin type III domain containing 2

Also known as: LRRC62, PPP1R29

NCBI Gene: 114794 ENSG00000243902 UniProt: Q5R3F8 OMIM: 620223

The ELFN2 protein inhibits protein phosphatase 1 (PP1) complexes and is involved in synaptic membrane adhesion and chemical synaptic transmission. Mutations cause neurodevelopmental disorders with intellectual disability, seizures, and behavioral abnormalities, inherited in an autosomal dominant pattern. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to cause significant developmental impacts.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable protein phosphatase inhibitor activity. Predicted to be involved in synaptic membrane adhesion. Predicted to act upstream of or within chemical synaptic transmission; establishment of protein localization; and gene expression. Located in extracellular space. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.33

Clinical Summary— ELFN2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.965

Z-score 3.64

OE 0.10 (0.04–0.33)

Highly constrained

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

Missense Constraint?

2.16Z-score

OE missense 0.75 (0.69–0.81)

426 obs / 571.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.10 (0.04–0.33)

0≤0.351.4

Missense OE?0.75 (0.69–0.81)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 2 / 19.2Missense obs/exp: 426 / 571.3Syn Z: -0.28

This gene — mechanism propensity

0.5379th %ile

GOF

0.6737th %ile

LOF

0.66top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.33

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.