POGLUT1

Chr 3ADAR

protein O-glucosyltransferase 1

Also known as: C3orf9, CLP46, KDELCL1, KTELC1, LGMD2Z, LGMDR21, MDS010, MDSRP

NCBI Gene: 56983 ENSG00000163389 UniProt: Q8NBL1 OMIM: 615618

The protein is a dual specificity glycosyltransferase that catalyzes the transfer of glucose and xylose to serine residues in extracellular EGF repeats of proteins including NOTCH2, acting as a positive regulator of Notch signaling during muscle development and early gastrulation. Mutations cause Dowling-Degos disease 4 (autosomal dominant) and limb-girdle muscular dystrophy type 21 (autosomal recessive), affecting skin and muscle systems respectively. The gene shows extremely high constraint against loss-of-function variants (pLI near 1.0), indicating intolerance to protein-disrupting mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein with both O-glucosyltransferase and O-xylosyltransferase activity which localizes to the lumen of the endoplasmic reticulum. This protein has a carboxy-terminal KTEL motif which is predicted to function as an endoplasmic reticulum retention signal. This gene is an essential regulator of Notch signalling and likely plays a role in cell fate and tissue formation during development. It may also play a role in the pathogenesis of leukemia. Mutations in this gene have been associated with the autosomal dominant genodermatosis Dowling-Degos disease 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismAD/ARLOEUF 0.892 OMIM phenotypes

Clinical Summary— POGLUT1

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Gene-Disease Validity (ClinGen)

autosomal recessive limb-girdle muscular dystrophy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

24 unique Pathogenic / Likely Pathogenic· 151 VUS of 339 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — POGLUT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.89LOEUF

pLI 0.000

Z-score 2.00

OE 0.60 (0.41–0.89)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.15Z-score

OE missense 0.78 (0.68–0.89)

164 obs / 211.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.41–0.89)

0≤0.351.4

Missense OE?0.78 (0.68–0.89)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 17 / 28.6Missense obs/exp: 164 / 211.0Syn Z: -0.83

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPOGLUT1-related Dowling-Degos diseaseOTHERAD

This gene — mechanism propensity

0.6840th %ile

GOF

0.5269th %ile

LOF

0.2775th %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

339 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic9

VUS151

Likely Benign109

Benign35

Conflicting8

Pathogenic

Likely Pathogenic

151

VUS

109

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	1	0	0	15
Likely Pathogenic	7	1	1	0	9
VUS	6	135	9	1	151
Likely Benign	0	4	55	50	109
Benign	0	1	29	5	35
Conflicting	—				8
Total	27	142	94	56	327

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap POGLUT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →