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

Proteins that are unfolded or misfolded in the endoplasmic reticulum (ER) must be refolded or degraded to maintain the homeostasis of the ER. DERL2 is involved in the degradation of misfolded glycoproteins in the ER (Oda et al., 2006 [PubMed 16449189]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

15 VUS of 21 total submissions

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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 OE?0.07 (0.02–0.33)

0≤0.351.4

Missense OE?0.60 (0.50–0.73)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

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

This gene — mechanism propensity

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.

ClinVar Variant Classifications

21 submitted variants in ClinVar

ClinVar

Classification Summary

VUS15

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	15	0	15
Likely Benign	0	1	1
Benign	0	0	0
Total	15	1	16

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap DERL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →