rs370793608 — ALDOB ALDOB Y204X

ALDOB Y204X — A Pathogenic Stop-Codon Variant Causing Hereditary Fructose Intolerance

Most people process dietary fructose without a second thought — the sugar passes through the intestinal wall, enters the liver, and is phosphorylated by fructokinase into fructose-1-phosphate (Fru1P). One enzyme then stands between Fru1P and the rest of metabolism: aldolase B¹¹ aldolase B
encoded by the ALDOB gene on chromosome 9q22.3; the liver-specific isoform that cleaves fructose-1-phosphate into glyceraldehyde and dihydroxyacetone phosphate for entry into glycolysis and gluconeogenesis. When aldolase B fails, Fru1P cannot be cleared. It accumulates rapidly in liver and kidney cells every time fructose is consumed, setting off a cascade of metabolic disruption. The condition that results is hereditary fructose intolerance²² hereditary fructose intolerance
an autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in ALDOB; distinct from benign fructosuria and dietary fructose sensitivity.

The Y204X variant (rs370793608) introduces a premature stop codon at tyrosine 204 of the aldolase B protein, producing a severely truncated, non-functional enzyme. It is listed as Pathogenic in ClinVar³³ Pathogenic in ClinVar
VCV000632627, 2-star classification from multiple independent laboratory submitters including LabCorp Genetics and Baylor Genetics. This variant is extremely rare globally (alternate allele frequency ~1 in 100,000 alleles in population databases), consistent with a severe disease-causing allele subject to strong purifying selection.

The Mechanism

Fru1P accumulation is the central pathological event in HFI. Cellular Fru1P acts as a competitive inhibitor of the remaining glycolytic aldolase isoforms (aldolase A and C), amplifying its own toxic effect. Two parallel consequences follow: first, intracellular phosphate is sequestered in Fru1P, depleting free phosphate and ATP, which impairs glycogenolysis, gluconeogenesis, and energy production — causing the characteristic post-fructose hypoglycemia⁴⁴ first, intracellular phosphate is sequestered in Fru1P, depleting free phosphate and ATP, which impairs glycogenolysis, gluconeogenesis, and energy production — causing the characteristic post-fructose hypoglycemia
Buziau AM et al. Recent advances in the pathogenesis of HFI. Cell Mol Life Sci, 2020. Second, elevated Fru1P disrupts N-linked glycosylation pathways in the hepatocyte, contributing to chronic liver injury and fat accumulation.

The premature stop at position 204 (of 364 amino acids) results in either a severely truncated protein or, more likely, nonsense-mediated mRNA decay — meaning no functional enzyme is produced from this allele at all. The Y204X truncation removes the entire C-terminal catalytic domain of aldolase B, making this a complete loss-of-function allele. A single pathogenic allele (carrier state) is sufficient to flag reproductive risk, but clinical HFI requires biallelic disruption — either homozygous Y204X or compound heterozygosity with a second pathogenic ALDOB allele.

The Evidence

HFI is rare — the largest population prevalence study in Central Europe estimated 1:26,100⁵⁵ estimated 1:26,100, though the true prevalence may be higher due to under-diagnosis in individuals who learn to avoid sweet foods by experience. Three mutations dominate the ALDOB allele spectrum in European patients: p.A150P (64%), p.A175D (16%), and p.N335K (8%)⁶⁶ p.A150P (64%), p.A175D (16%), and p.N335K (8%)
Davit-Spraul A et al. Mol Genet Metab, 2008. Y204X is a rare variant accounting for a small fraction of pathogenic alleles, identified in Central European and likely other European family cohorts.

The clinical picture of untreated HFI in an affected individual (two non-functional ALDOB copies) is well documented: fructose ingestion triggers nausea, vomiting, abdominal pain, and sweating within 20–30 minutes. Recurrent exposure causes progressive liver and kidney damage — progressing to hepatomegaly, renal tubular acidosis, growth retardation, and in severe cases liver failure. Affected individuals characteristically develop an aversion to sweet foods and fruit, often unknowingly self-protecting before diagnosis.

Even among adherent patients, a study of 48 HFI patients over 10 years found that mean daily fructose intake of 169 mg (unavoidable trace amounts) correlated with abnormal carbohydrate-deficient transferrin glycosylation markers, indicating that even minimal ongoing exposure has measurable biochemical consequences⁷⁷ mean daily fructose intake of 169 mg (unavoidable trace amounts) correlated with abnormal carbohydrate-deficient transferrin glycosylation markers, indicating that even minimal ongoing exposure has measurable biochemical consequences
Di Dato F et al. Nutrients, 2019.

Dietary restriction of all fructose, sucrose, and sorbitol — the three molecules that yield fructose-1-phosphate — completely prevents symptoms and allows normal organ function. Long-term adherent patients have normal life expectancy and quality of life⁸⁸ normal life expectancy and quality of life
Singh SK, Sarma MS. World J Clin Pediatr, 2022.

Practical Actions

For biallelic carriers (affected individuals), the foundation of management is strict, lifelong avoidance of fructose, sucrose, sorbitol, and their derivatives. This requires label-reading expertise: sucrose (table sugar) hydrolyzes to glucose + fructose; sorbitol is oxidized to fructose intracellularly; high-fructose corn syrup, honey, agave, fruit juices, and many medications use these sugars. Vitamin C supplementation is specifically needed because the restriction removes most fruit sources — studies show that 30% of non-supplemented HFI patients develop vitamin C deficiency⁹⁹ 30% of non-supplemented HFI patients develop vitamin C deficiency
Cano A et al. Eur J Clin Nutr, 2022.

For heterozygous carriers (one Y204X allele), full enzyme function is maintained with a single functional ALDOB copy. The primary concern is reproductive: a carrier who reproduces with another ALDOB carrier (of any pathogenic allele) faces a 25% probability per pregnancy of an affected child. The three most common European ALDOB alleles (A150P, A175D, N335K) account for ~84% of pathogenic alleles and can be tested for on a targeted panel.

Interactions

The most important interaction for this variant is compound heterozygosity with other pathogenic ALDOB alleles. Because Y204X is a complete loss-of-function allele, any second pathogenic ALDOB allele in trans will result in clinical HFI. The three common European alleles (p.A150P rs45436095, p.A175D rs78654866, p.N335K rs28936415) are the most likely compound heterozygous partners for Y204X in European-ancestry individuals. Carrier partners of Y204X carriers should be offered targeted ALDOB panel testing that includes these three common alleles plus sequencing of the entire coding region.