GPA33

Chr 1

glycoprotein A33

Also known as: A33

NCBI Gene: 10223 ENSG00000143167 UniProt: Q99795 OMIM: 602171

The protein is a cell surface glycoprotein containing immunoglobulin superfamily domains that functions in cell-cell recognition and signaling. Mutations cause autosomal recessive congenital diarrhea with prominent failure to thrive in infancy. The gene is highly constrained against loss-of-function variants, indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, UniProt

The glycoprotein encoded by this gene is a cell surface antigen that is expressed in greater than 95% of human colon cancers. The open reading frame encodes a 319-amino acid polypeptide having a putative secretory signal sequence and 3 potential glycosylation sites. The predicted mature protein has a 213-amino acid extracellular region, a single transmembrane domain, and a 62-amino acid intracellular tail. The sequence of the extracellular region contains 2 domains characteristic of the CD2 subgroup of the immunoglobulin (Ig) superfamily. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.07

Clinical Summary— GPA33

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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

55 VUS of 66 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?

1.07LOEUF

pLI 0.000

Z-score 1.36

OE 0.65 (0.41–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.01Z-score

OE missense 1.00 (0.89–1.12)

198 obs / 198.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.65 (0.41–1.07)

0≤0.351.4

Missense OE?1.00 (0.89–1.12)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 11 / 17.0Missense obs/exp: 198 / 198.3Syn Z: -1.61

This gene — mechanism propensity

0.77top 25%

GOF

0.6930th %ile

LOF

0.2289th %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

66 submitted variants in ClinVar

ClinVar

Classification Summary

VUS55

Likely Benign5

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	55	55
Likely Benign	5	5
Benign	1	1
Total	61	61

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap GPA33 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →