KDELR3

Chr 22

KDEL endoplasmic reticulum protein retention receptor 3

Also known as: ERD23, ERD2L3

NCBI Gene: 11015 ENSG00000100196 UniProt: O43731 OMIM: 619900

The protein functions as a receptor that recognizes the KDEL sequence motif on endoplasmic reticulum resident proteins and mediates their retrieval from the Golgi apparatus back to the endoplasmic reticulum. Mutations in KDELR3 cause neurodevelopmental disorders with intellectual disability, seizures, and distinctive facial features, following an autosomal recessive inheritance pattern. The gene shows extremely low constraint against loss-of-function variants, suggesting tolerance to protein disruption in the general population.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the KDEL endoplasmic reticulum protein retention receptor family. Retention of resident soluble proteins in the lumen of the endoplasmic reticulum (ER) is achieved in both yeast and animal cells by their continual retrieval from the cis-Golgi, or a pre-Golgi compartment. Sorting of these proteins is dependent on a C-terminal tetrapeptide signal, usually lys-asp-glu-leu (KDEL) in animal cells, and his-asp-glu-leu (HDEL) in S. cerevisiae. This process is mediated by a receptor that recognizes, and binds the tetrapeptide-containing protein, and returns it to the ER. In yeast, the sorting receptor encoded by a single gene, ERD2, is a seven-transmembrane protein. Unlike yeast, several human homologs of the ERD2 gene, constituting the KDEL receptor gene family, have been described. KDELR3 was the third member of the family to be identified. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.94

Clinical Summary— KDELR3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

30 VUS of 42 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.94LOEUF

pLI 0.000

Z-score -1.51

OE 1.56 (0.98–1.94)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.22Z-score

OE missense 1.06 (0.91–1.23)

123 obs / 116.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.56 (0.98–1.94)

0≤0.351.4

Missense OE?1.06 (0.91–1.23)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 13 / 8.3Missense obs/exp: 123 / 116.3Syn Z: -0.74

This gene — mechanism propensity

0.75top 25%

GOF

0.6346th %ile

LOF

0.3455th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

42 submitted variants in ClinVar

ClinVar

Classification Summary

VUS30

Likely Benign1

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	0	30	30
Likely Benign	0	1	1
Benign	1	0	1
Total	1	31	32

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap KDELR3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →