POGLUT2

Chr 13

protein O-glucosyltransferase 2

Also known as: EP58, ERp58, KDEL1, KDELC1

NCBI Gene: 79070 ENSG00000134901 UniProt: Q6UW63 OMIM: 611613

This protein is an endoplasmic reticulum glucosyltransferase that modifies extracellular EGF repeats of proteins including NOTCH1, NOTCH3, and fibrillin proteins, potentially regulating Notch signaling and protein transport to the plasma membrane. Mutations cause autosomal recessive limb-girdle muscular dystrophy type R21, which presents with progressive muscle weakness affecting the shoulder and hip girdle muscles. The gene shows no constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein product localized to the lumen of the endoplasmic reticulum. As a member of the endoplasmic reticulum protein family the encoded protein contains a Lys-Asp-Glu-Leu or KDEL motif located at the extreme C-terminus which prevents all endoplasmic reticulum resident proteins from being secreted. Proteins carrying this motif are bound by a receptor in the Golgi apparatus so that the receptor-ligand complex returns to the endoplasmic reticulum. A processed non-transcribed pseudogene located in an intron of a sodium transporter gene on chromosome 5 has been defined for this gene. This gene has multiple transcript variants which are predicted to encode distinct isoforms. [provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.99

Clinical Summary— POGLUT2

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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

74 VUS of 87 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.99LOEUF

pLI 0.000

Z-score 1.61

OE 0.66 (0.45–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.02Z-score

OE missense 1.00 (0.90–1.10)

273 obs / 273.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.66 (0.45–0.99)

0≤0.351.4

Missense OE?1.00 (0.90–1.10)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 17 / 25.8Missense obs/exp: 273 / 273.7Syn Z: 0.30

This gene — mechanism propensity

0.6647th %ile

GOF

0.6053th %ile

LOF

0.3162th %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

87 submitted variants in ClinVar

ClinVar

Classification Summary

VUS74

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	74	74
Likely Benign	2	2
Benign	0	0
Total	76	76

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

View in ClinVar →

100 pathogenic / likely-pathogenic (of 107) ClinVar copy-number / structural variants overlap POGLUT2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →