DERL2

Chr 17

derlin 2

Also known as: CGI-101, DERtrin-2, F-LAN-1, F-LANa, FLANa, derlin-2

NCBI Gene: 51009 ENSG00000072849 UniProt: Q9GZP9 OMIM: 610304

The DERL2 protein forms a channel that enables retrotranslocation of misfolded glycoproteins from the endoplasmic reticulum to the cytosol for degradation, serving as a functional component of ER-associated degradation (ERAD). Mutations cause autosomal recessive neurodevelopmental disorder with seizures and brain atrophy, typically presenting in infancy with developmental delays and seizures. This gene is highly constrained against loss-of-function variation (pLI 0.96, LOEUF 0.33), indicating that complete loss of protein function is likely pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

MultiplemechanismLOEUF 0.33

Clinical Summary— DERL2

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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 0.957

Z-score 3.26

OE 0.07 (0.02–0.33)

Highly constrained

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

Missense Constraint

1.62Z-score

OE missense 0.60 (0.50–0.73)

79 obs / 131.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.07 (0.02–0.33)

0≤0.351.4

Missense OE0.60 (0.50–0.73)

0≤0.61.4

Synonymous OE1.19

0≤1.21.6

LoF obs/exp: 1 / 14.3Missense obs/exp: 79 / 131.1Syn Z: -1.05

0.7033th %ile

GOF

0.74top 25%

LOF

0.3745th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). 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

LOFLOEUF 0.33

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.