ASGR1

Chr 17

asialoglycoprotein receptor 1

Also known as: ASGPR, ASGPR1, CLEC4H1, HL-1

NCBI Gene: 432 ENSG00000141505 UniProt: P07306 OMIM: 108360

The asialoglycoprotein receptor major subunit mediates hepatocyte endocytosis of circulating glycoproteins lacking terminal sialic acid residues, facilitating clearance of desialylated platelets and maintaining serum glycoprotein homeostasis. Biallelic ASGR1 mutations cause autosomal recessive thrombocytopenia with absent or reduced platelet glycoprotein clearance. This gene is not loss-of-function intolerant, consistent with the recessive inheritance pattern of associated disease.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a subunit of the asialoglycoprotein receptor. This receptor is a transmembrane protein that plays a critical role in serum glycoprotein homeostasis by mediating the endocytosis and lysosomal degradation of glycoproteins with exposed terminal galactose or N-acetylgalactosamine residues. The asialoglycoprotein receptor may facilitate hepatic infection by multiple viruses including hepatitis B, and is also a target for liver-specific drug delivery. The asialoglycoprotein receptor is a hetero-oligomeric protein composed of major and minor subunits, which are encoded by different genes. The protein encoded by this gene is the more abundant major subunit. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.74

Clinical Summary— ASGR1

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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

38 VUS of 51 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?

1.74LOEUF

pLI 0.000

Z-score -0.82

OE 1.22 (0.85–1.74)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.13Z-score

OE missense 0.97 (0.86–1.10)

175 obs / 179.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.22 (0.85–1.74)

0≤0.351.4

Missense OE?0.97 (0.86–1.10)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 20 / 16.4Missense obs/exp: 175 / 179.9Syn Z: 1.21

This gene — mechanism propensity

0.7227th %ile

GOF

0.7029th %ile

LOF

0.2872th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

51 submitted variants in ClinVar

ClinVar

Classification Summary

VUS38

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	38	38
Likely Benign	2	2
Benign	0	0
Total	40	40

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap ASGR1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →