rs72551348 — UGT1A1 Q331R

Rare pathogenic missense variant in the UGT1A1 gene that severely reduces bilirubin glucuronidation; homozygotes develop Crigler-Najjar syndrome type II with persistent unconjugated hyperbilirubinemia that responds to phenobarbital treatment

See your personal result for UGT1A1

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

UGT1A1 Q331R — A Rare Cause of Crigler-Najjar Syndrome Type II

Every day your liver handles a continuous stream of spent red blood cells, converting their released haemoglobin into bilirubin and then rendering that bilirubin water-soluble so it can be excreted in bile. The enzyme that carries out this final conjugation step is UGT1A111 UGT1A1
UDP-glucuronosyltransferase 1A1, a phase II detoxification enzyme that attaches glucuronic acid to unconjugated bilirubin, making it soluble and excretable, encoded by the UGT1A1 gene on chromosome 2q37. When this enzyme is severely reduced, unconjugated bilirubin — fat-soluble and capable of crossing the blood-brain barrier — accumulates in blood and tissues, causing jaundice and, at extreme levels, neurological damage.

The rs72551348 variant (c.992A>G) causes a glutamine-to-arginine substitution at position 331 of the UGT1A1 protein (p.Gln331Arg, also written Q331R). This missense change disrupts the enzyme's catalytic efficiency for bilirubin conjugation, leaving only a fraction of normal activity. ClinVar classifies it as Pathogenic22 ClinVar classifies it as Pathogenic
RCV000013058, associated with Crigler-Najjar syndrome type II, and it was first described by Moghrabi et al.33 Moghrabi et al.
Moghrabi N et al. Identification of an A-to-G missense mutation in exon 2 of the UGT1 gene complex that causes Crigler-Najjar syndrome type 2. Genomics, 1993 in a 72-year-old Irish man born of consanguineous parents, whose diagnosis was established when phenobarbital treatment significantly lowered his chronically elevated bilirubin.

The variant affects a shared exon of the UGT1A gene complex, meaning the same nucleotide change disrupts multiple UGT1A isoforms (UGT1A1, UGT1A3–A10 all read from this exon). However, UGT1A1 is the only isoform directly responsible for bilirubin glucuronidation, and Crigler-Najjar syndrome is the primary clinical consequence.

The Mechanism

Gln331 sits in the C-terminal membrane-anchoring domain of UGT1A1, a region important for proper enzyme folding and substrate binding. The arginine substitution introduced by the G allele alters local protein conformation, substantially impairing the enzyme's ability to glucuronidate bilirubin. Unlike type I Crigler-Najjar mutations, which completely abolish UGT1A1 activity, Q331R leaves residual activity — estimated at less than 10% of normal in type II patients — a threshold established by functional expression studies44 a threshold established by functional expression studies
Seppen J et al. Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. J Clin Invest, 1994. This residual activity is the mechanistic basis for the key clinical feature of type II disease: phenobarbital responsiveness. Phenobarbital is an inducer of UGT1A1 gene expression; boosting transcription from the residual functional allele can meaningfully increase the amount of conjugated bilirubin produced, lowering serum levels by 30% or more.

The Evidence

Crigler-Najjar syndrome type II is rare — fewer than 300 cases have been documented in the medical literature. The Q331R variant (rs72551348) is ultrarare even among UGT1A1 disease alleles, with a G allele frequency of approximately 3.7 × 10⁻⁵ in the gnomAD exome dataset (predominantly in individuals of European ancestry). No homozygous individuals have been observed in population databases, consistent with the rarity of type II Crigler-Najjar syndrome.

Functional characterisation established55 Functional characterisation established
Seppen et al. 1994 that the hallmark of type II mutations is partial enzyme inactivation (residual activity 4–38% across patients), versus zero activity in type I. This residual activity keeps serum bilirubin below 20 mg/dL in most type II patients — well below the levels that cause kernicterus — and explains the far better neurological prognosis compared to type I.

A comprehensive genotype-phenotype review66 A comprehensive genotype-phenotype review
Kadakol A et al. Hum Mutat, 2000 cataloguing more than 50 UGT1A1 mutations confirmed that the partial-vs-complete enzyme inactivation distinction maps reliably to type II vs type I phenotype, with the critical threshold being whether any residual bilirubin-conjugating activity remains.

Practical Actions

For homozygous carriers (GG) — clinically the relevant genotype for Crigler-Najjar type II — the management priorities are phenobarbital therapy to upregulate residual UGT1A1 expression, bilirubin monitoring, and awareness of drug interactions. Because UGT1A1 metabolises several chemotherapy agents (particularly irinotecan and belinostat), any cancer treatment plan should account for the severely reduced enzyme activity. UV-A phototherapy can be used adjunctively during bilirubin spikes. Liver transplantation is curative and is typically reserved for cases where phenobarbital cannot maintain safe bilirubin levels or when quality of life is severely impaired.

Heterozygous carriers (AG) — one G allele with one normal A allele — have approximately 50% of normal UGT1A1 activity and are clinically normal. Their primary concern is reproductive: if both partners carry a pathogenic UGT1A1 allele, there is a 25% probability of a homozygous child with Crigler-Najjar syndrome.

Interactions

rs72551348 falls on the same UGT1A1 gene that harbours several other clinically significant variants. Compound heterozygosity with the common UGT1A1*28 promoter variant (rs8175347, extra TA repeat reducing expression by ~70% when homozygous) or with *6 Gly71Arg (rs4148323, prevalent in East Asia) can produce a combined UGT1A1 impairment intermediate between Gilbert syndrome and Crigler-Najjar type II. Any individual carrying one Q331R allele should be tested for other UGT1A1 variants, particularly if bilirubin levels are higher than expected for a simple carrier.

Drug Interactions

irinotecan increased_toxicity DPWG
belinostat dose_adjustment FDA
atazanavir increased_toxicity CPIC

Genotype Interpretations

What each possible genotype means for this variant.

AA Non-Carrier Normal

Normal UGT1A1 bilirubin glucuronidation — two reference alleles

With two A alleles, your UGT1A1 enzyme at position 331 retains its native glutamine residue, preserving proper folding and bilirubin-binding capacity. Your liver can conjugate bilirubin normally, and you carry no added risk for neonatal jaundice from this specific variant. Your bilirubin metabolism may still be influenced by other UGT1A1 variants (such as the common *28 promoter variant, rs8175347) — those are assessed separately.

AG Carrier Carrier

Heterozygous carrier — one Q331R allele; personally unaffected, reproductive implications if partner also carries a UGT1A1 disease allele

Single-allele Q331R carriers produce one normal UGT1A1 enzyme and one with impaired bilirubin-conjugating capacity. The functional allele is sufficient to maintain normal or near-normal bilirubin levels under most circumstances. You may have mildly elevated serum bilirubin compared to non-carriers, particularly if you also carry the common UGT1A1*28 promoter variant (rs8175347), but clinical jaundice is not expected from carrier status alone.

The primary clinical significance of carrier status is reproductive. If your partner also carries any pathogenic UGT1A1 allele — including Q331R, another Crigler-Najjar allele, or (in combination with the common *28 promoter variant) a more complex genotype — each pregnancy has a meaningful probability of producing a child with significantly impaired bilirubin glucuronidation. Given the rarity of Q331R, the most actionable step is confirming your partner's UGT1A1 status through clinical genetic testing.

Because UGT1A1 also metabolises irinotecan (a colorectal and ovarian cancer chemotherapy agent) and belinostat (a lymphoma treatment), carrier status may modestly increase chemotherapy toxicity risk — discuss with your oncologist if these drugs are relevant to your care.

GG Crigler-Najjar Type II Homozygous

Homozygous Q331R — severely reduced UGT1A1 activity causing Crigler-Najjar syndrome type II; phenobarbital-responsive hyperbilirubinemia

Homozygous Q331R results in two copies of an enzyme with a glutamine-to-arginine substitution at position 331 — a region critical for proper UGT1A1 protein conformation and bilirubin binding. Functional expression studies have confirmed that type II Crigler-Najjar mutations, including this class of missense changes, leave residual enzyme activity of roughly 4–38% across patients (Seppen et al., 1994). The residual activity is sufficient to prevent the complete bilirubin accumulation seen in type I, keeping levels below the 20 mg/dL threshold at which kernicterus risk becomes significant under normal circumstances.

Critically, phenobarbital — a classic inducer of liver detoxification enzymes — upregulates transcription of the residual functional UGT1A1, meaningfully increasing conjugation capacity. This distinguishes type II from type I (which has zero activity to induce) and is used both therapeutically and diagnostically.

Adult type II patients generally survive without neurological impairment, though bilirubin control typically requires some combination of phenobarbital, UV-A phototherapy, and dietary management. Because UGT1A1 also metabolises multiple anticancer drugs (irinotecan, belinostat) and some antivirals (atazanavir), drug interactions are a significant clinical concern. Liver transplantation is curative and may be considered in severe or refractory cases.