rs4841132 — PPP1R3B

Near-gene PPP1R3B variant used as primary tagging SNP in the Stender 2018 study; minor A allele promotes hepatic glycogen accumulation, elevating liver enzymes and raising the risk of hepatic glycogenosis, non-alcoholic fatty liver disease, and gallstones

See your personal result for PPP1R3B

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.

PPP1R3B rs4841132 — The Hepatic Glycogen Switch

Most people associate liver disease with fat. Yet for carriers of the minor A allele at rs4841132, the primary problem begins one step earlier in liver metabolism: the regulation of glycogen11 glycogen
The body's main short-term glucose storage molecule. The liver stores glycogen and releases glucose into the blood between meals to maintain stable blood sugar levels synthesis and breakdown. This variant is in complete linkage disequilibrium22 linkage disequilibrium
LD: the tendency of nearby genetic variants to be inherited together. Two SNPs in complete LD are interchangeable genetic markers for the same underlying biological signal with rs4240624, and the two positions tag the same PPP1R3B signal. The landmark Stender 2018 study (n=112,428) used rs4841132 as the primary tagging SNP, making it the most directly-cited variant for this locus in the literature.

PPP1R3B encodes a regulatory subunit of protein phosphatase 1 (PP1), a master switch that governs glycogen synthesis and breakdown in the liver. The A allele at rs4841132 — carried by roughly 9% of Europeans and up to 20% of people of Latino ancestry — influences how much glycogen the liver stores, pushing the balance toward accumulation. The downstream effects extend beyond glycogen: elevated liver enzymes, increased hepatic glycogenosis susceptibility, and a meaningful increase in gallstone risk have all been documented across large population studies.

The Mechanism

Protein phosphatase 133 Protein phosphatase 1
PP1: one of the most abundant phosphatases in the body, involved in glycogen metabolism, muscle contraction, protein synthesis, and many other processes. Its activity is tightly regulated by dozens of binding proteins (PP1) is a central regulator of glycogen metabolism. PPP1R3B acts as a glycogen-targeting subunit that directs PP1 to two key enzymes: glycogen synthase (which builds glycogen) and glycogen phosphorylase (which breaks it down). By activating glycogen synthase and inhibiting glycogen phosphorylase, PPP1R3B tips the liver toward glycogen storage.

The rs4841132 A allele is a near-gene regulatory variant — annotated as a non-coding transcript variant affecting the LOC157273 lncRNA locus adjacent to PPP1R3B — that increases PPP1R3B activity or expression. Mouse studies confirm the mechanism directly: overexpression of PPP1R3B causes hepatic glycogen accumulation and elevated plasma ALT, while knockouts produce glycogen-deficient livers. In humans, the minor A allele is associated with increased hepatic X-ray attenuation — a hallmark of glycogen loading — and elevated liver enzymes across the large Stender 2018 cohort.

Importantly, the excess glycogen from this variant does not appear to directly increase hepatic triglyceride content. This distinguishes the PPP1R3B signal from the well-known PNPLA3 rs738409 variant, which directly promotes liver fat accumulation. Instead, the effect reflects hepatic glycogenosis44 hepatic glycogenosis
Abnormal glycogen accumulation in the liver. Can cause hepatomegaly and elevated liver enzymes, and is associated with metabolic syndrome even in the absence of excess fat, a condition independently harmful even without steatosis.

Because rs4841132 and rs4240624 are in complete LD, they measure the same biological effect. Individuals genotyped at either position carry the same functional risk information. rs4841132 is included in the GeneOps database because it is the primary rsid analyzed in the Stender 2018 landmark study and is present on chip platforms where rs4240624 may not be represented.

The Evidence

The foundational work comes from Stender et al. 201855 Stender et al. 2018
Stender S, Smagris E, et al. "Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride." Hepatology, 2018, which analyzed 112,428 participants across three large cohorts. The minor A allele at rs4841132 showed consistent ALT elevation (P = 3×10⁻⁴ in the Copenhagen cohort; P = 0.004 in the Dallas Heart Study), and liver disease odds ratios of 1.13–1.23. Crucially, no association was found with hepatic triglyceride content, pointing specifically at glycogen as the culprit. This study explicitly identifies rs4841132 as being in complete LD with rs4240624 and uses both rsids to describe the same locus.

Hernaez et al. 201366 Hernaez et al. 2013
Hernaez R, McLean J, et al. "Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis." Clin Gastroenterol Hepatol, 2013 used NHANES III data (n=4,804) and found an OR of 1.28 (P=.03) for ultrasound-defined hepatic steatosis in non-Hispanic white adults — suggesting that glycogen accumulation in the liver may mimic the appearance of steatosis on standard ultrasound, even when triglycerides are not elevated.

The 2021 Männistö study (n=242 bariatric surgery patients) found that risk-allele carriers produced dramatically different bile acid profiles and that 13 of 17 bile lipid classes were elevated in carriers — a pattern that mirrors bile composition in gallstone patients.

Practical Actions

The primary lever for managing hepatic glycogen burden is dietary carbohydrate quality and quantity. The liver processes dietary carbohydrates — and especially fructose — almost exclusively, making this the highest-impact dietary modification for A-allele carriers. Prioritize low-glycemic carbohydrate sources (vegetables, legumes, lentils, barley) over refined carbohydrates and added sugars. Minimize fructose from sugary beverages, fruit juice, and high-fructose sweeteners.

Annual liver enzyme monitoring (ALT/AST) is warranted for heterozygous carriers; homozygous AA carriers should pursue a more thorough evaluation including discussion of hepatic imaging. Mildly elevated ALT in the absence of alcohol use or obesity should be flagged as potentially related to hepatic glycogen accumulation.

Gallstone risk is elevated for A-allele carriers, particularly in the context of obesity or planned rapid weight loss, which can mobilize bile cholesterol and precipitate stone formation.

Interactions

rs4841132 and rs4240624 are in complete LD and represent the same functional signal at the PPP1R3B locus. Carrying risk alleles at this locus is expected to have additive effects with PNPLA3 rs738409 (hepatic fat accumulation via a distinct lipid pathway) and GCKR rs780094 (impaired hepatic glucose sensing and elevated triglycerides). Individuals with risk alleles across these three genes face compounding liver stress through glycogen overload (PPP1R3B), lipid dysregulation (PNPLA3), and altered glucose metabolism (GCKR).

Nutrient Interactions

carbohydrates altered_metabolism
fructose increased_need

Genotype Interpretations

What each possible genotype means for this variant.

GG Standard Glycogen Regulation Normal

Your liver glycogen metabolism follows the common pattern

You carry two copies of the common G allele at rs4841132. Your hepatic glycogen regulation is not influenced by this variant, and you do not have the elevated liver enzyme or glycogen accumulation risk associated with the minor A allele. This genotype is found in approximately 82% of people globally and over 83% of people of European descent.

AG One Copy — Moderate Risk Intermediate

One A allele — modestly elevated risk of hepatic glycogen accumulation

The A allele increases the activity or expression of PPP1R3B, a key regulatory subunit that targets protein phosphatase 1 (PP1) to promote hepatic glycogen synthesis. With one A copy, this effect is intermediate: the liver stores somewhat more glycogen than typical, which can manifest as mildly elevated ALT/AST on blood tests even without significant hepatic fat on imaging.

Because rs4841132 is in complete LD with rs4240624, the biological effect is identical to that of the rs4240624 G allele described in the companion entry. The two variants are interchangeable markers for the same functional locus.

Gallstone risk is also modestly elevated for heterozygous carriers, mediated by alterations in bile lipid composition documented in the Männistö 2021 study.

AA Two Copies — Higher Risk High Risk

Two A alleles — elevated hepatic glycogen accumulation risk and gallstone susceptibility

Homozygous A carriers have two copies of the variant that increases PPP1R3B expression and activity. This means hepatic PP1 is more strongly directed toward glycogen synthesis on both alleles simultaneously, leading to the greatest degree of glycogen accumulation in the liver. Mouse models of PPP1R3B overexpression directly replicate this phenotype, showing hepatic glycogen accumulation along with elevated plasma ALT — mirroring the human genetic findings from Stender 2018.

Because rs4841132 and rs4240624 are in complete LD, a person who is AA at rs4841132 is also GG at rs4240624 (both risk-homozygous). The biological consequence is identical.

The Männistö 2021 and 2024 studies found dramatic alterations in bile lipid composition in risk-allele carriers (13 of 17 bile lipid classes elevated), consistent with substantially increased gallstone risk, especially in individuals with obesity or planned rapid weight loss.