rs201038679 — ATP7B P992L

Pathogenic missense variant in the copper transporter ATP7B; heterozygous carriers are asymptomatic but can pass Wilson disease to children if their partner also carries an ATP7B pathogenic variant

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ATP7B P992L — Carrying One Dose of the Wilson Disease Gene

Every cell that makes proteins must also manage copper — an essential mineral that acts as a cofactor for dozens of enzymes yet becomes toxic when it accumulates. The ATP7B protein is the liver's primary copper disposal system: it pumps excess copper into bile for excretion and loads copper onto ceruloplasmin11 ceruloplasmin
The major copper-carrying protein in blood, made in the liver; synthesised as apoprotein and activated when copper is loaded onto it by ATP7B. Low ceruloplasmin is one of the diagnostic markers of Wilson disease.. When both copies of ATP7B are damaged, copper builds up in the liver, then spills into the brain, cornea, and kidneys — this is Wilson disease.

The P992L variant (rs201038679) replaces proline with leucine at position 992 of the ATP7B protein. It is one of the best-characterised pathogenic ATP7B variants: classified as Pathogenic/Likely pathogenic by 16 independent clinical laboratories22 classified as Pathogenic/Likely pathogenic by 16 independent clinical laboratories
ClinVar VCV000188831, review status 2 stars: criteria provided, multiple submitters, no conflicts. In East Asian populations — particularly Chinese — it is the second most common Wilson disease allele, found in 13-16% of Wilson disease chromosomes33 found in 13-16% of Wilson disease chromosomes
Yang et al. Genes, 2021; Li et al. BMC Gastroenterology, 2021.

The Mechanism

Position 992 sits in transmembrane domain 6 (TM6) of ATP7B — one of the eight membrane-spanning helices that form the copper-conducting channel. The proline at this position creates a structural kink in the helix that is conserved across P-type ATPase copper transporters in multiple species. Replacing proline with the bulkier, more flexible leucine disrupts this geometry, destabilising the channel.

Functional studies in Menkes fibroblast cell lines find that P992L retains approximately 17% of wild-type copper transport activity44 approximately 17% of wild-type copper transport activity
Członkowska et al. 2018 and subsequent functional screens; PMC12259332 — substantially reduced but not zero. Notably, the variant retains near-normal phosphorylation activity (~129% of wild-type), meaning the ATP-binding machinery is intact; the defect is in copper translocation across the membrane rather than in the catalytic cycle itself. This partial activity is consistent with the clinical observation that P992L homozygotes tend to present at a younger average age (mean 9.7 ± 4.2 years) than patients with milder variants55 younger average age (mean 9.7 ± 4.2 years) than patients with milder variants
Li et al. BMC Gastroenterol, 2021, while still occasionally showing incomplete penetrance.

The Evidence

Wilson disease is rare in the general population — estimated prevalence of 1:30,000, with a carrier frequency of approximately 1:9066 1:30,000, with a carrier frequency of approximately 1:90
Ferenci P. Wilson Disease. GeneReviews, 2010. Newer population genomic studies suggest the true prevalence may be closer to 1:7,000, because many carriers are compound heterozygotes with mild or asymptomatic presentations. P992L is globally rare (allele frequency ~0.00006 in TOPMED, ~0.00018 in Japanese/ToMMo data) but enriched in East Asian populations, particularly mainland Chinese, where it has a founder effect centred on Jiangxi province.

Among 715 unrelated Chinese Wilson disease patients77 715 unrelated Chinese Wilson disease patients
Yang et al. Genes, 2021, PMID 33668890, P992L accounted for 15.7% of all disease alleles, with regional allele frequencies ranging from 9.8% in Zhejiang to 22.1% in Jiangxi. Haplotype analysis identified six distinct P992L haplogroups, with haplogroup E dominating at 72.4% of affected chromosomes (vs. 3.4% in controls), consistent with a founder mutation.

A cohort of 196 Chinese patients88 cohort of 196 Chinese patients
Li et al. BMC Gastroenterol, 2021, PMID 34470610 found that P992L homozygotes presented at a mean age of 9.7 ± 4.2 years, compound heterozygotes at 15.7 ± 11.6 years, and non-P992L patients at 20.5 ± 12.2 years (P = 0.01 and P = 0.017 respectively). Clinical presentation was predominantly hepatic (50.5%) or asymptomatic (16.8%).

Most Wilson disease patients are compound heterozygotes99 compound heterozygotes
A person who carries two different pathogenic variants in the same gene — one on each chromosome. For Wilson disease, both variants together prevent adequate copper transport., carrying one P992L allele paired with a different ATP7B variant. Disease only manifests when both copies are non-functional.

Practical Implications

For heterozygous carriers (GA): you have one functioning and one P992L copy of ATP7B. One functioning copy is sufficient to maintain copper homeostasis; clinical disease is not expected in carriers. The primary significance is reproductive: if your partner also carries any pathogenic ATP7B variant, there is a 25% chance with each pregnancy that the child will inherit Wilson disease. First-degree relatives of known Wilson disease patients should be offered molecular genetic testing to determine their carrier status.

Treatment of Wilson disease (for homozygous or compound heterozygous individuals) relies on copper chelation with D-penicillamine (750–1,500 mg/day in divided doses) or trientine (1,200–2,000 mg/day)1010 D-penicillamine (750–1,500 mg/day in divided doses) or trientine (1,200–2,000 mg/day)
AASLD practice guidance; Roberts EA et al. Hepatology, 2008, or zinc salts (150 mg/day in three doses) for maintenance or asymptomatic patients. Neurological and hepatic manifestations respond well to early chelation — outcomes are excellent when diagnosis precedes organ damage.

Interactions

Wilson disease requires two damaged ATP7B copies. The most clinically relevant interaction is therefore between rs201038679 (P992L) and any other pathogenic ATP7B variant in trans (on the opposite chromosome). Common co-occurring variants in East Asian patients include R778L (rs755523048), A874V, and p.Ile1102Thr. The combination of P992L with a second severe loss-of-function allele (e.g. R778L) typically produces earlier onset and more severe hepatic disease than P992L compound-heterozygous with milder alleles.

There is no established interaction between heterozygous P992L carrier status and other copper-regulating genes (e.g. ATOX1, CCS) that would produce clinical effects in a single-carrier context.

Drug Interactions

D-penicillamine dose_adjustment literature
trientine dose_adjustment literature

Nutrient Interactions

copper altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-Carrier Normal

No ATP7B P992L variant detected — standard copper metabolism

The GG genotype means neither copy of your ATP7B gene carries the Pro992Leu substitution. Copper transport from hepatocytes into bile and onto ceruloplasmin is not impaired by this variant. This does not exclude other rare ATP7B variants — comprehensive Wilson disease testing requires full-gene sequencing — but rs201038679 specifically is not contributing any disease risk.

AG Carrier Carrier

One copy of ATP7B P992L — carrier status for Wilson disease

Heterozygous P992L carriers have one normally functioning ATP7B protein and one with the Pro992Leu substitution. Single-copy ATP7B function is sufficient for copper homeostasis — biochemical markers (ceruloplasmin, urinary copper) are typically normal or only borderline in carriers, making standard biochemical tests unreliable for distinguishing carriers from non-carriers.

The clinical importance of carrier status lies in reproductive risk. Wilson disease is autosomal recessive: disease requires both copies to be non-functional. If both parents carry a pathogenic ATP7B variant, each child has a 25% chance of inheriting Wilson disease, 50% chance of being a carrier, and 25% chance of being unaffected. Genetic counselling before family planning is strongly recommended.

Functional studies classify P992L as a partial loss-of-function allele: it retains approximately 17% of wild-type copper transport activity with intact ATP hydrolysis, indicating the defect is in copper translocation rather than ATP binding. The single carrier copy (GA) is unaffected and compensates fully.

AA Homozygous Homozygous

Two copies of ATP7B P992L — consistent with Wilson disease; specialist assessment required

With both copies of ATP7B carrying the Pro992Leu substitution, copper transport from hepatocytes into bile is severely impaired. P992L retains approximately 17% of wild-type copper transport activity, placing it in the partial loss-of-function category. Clinically, P992L homozygotes in Chinese cohorts presented at a mean age of 9.7 ± 4.2 years, most commonly with hepatic manifestations (jaundice, elevated transaminases, hepatomegaly) or asymptomatically on screening.

Diagnosis is confirmed biochemically by low serum ceruloplasmin (<20 mg/dL), elevated 24-hour urine copper (>100 μg/day in symptomatic patients), and slit-lamp examination for Kayser-Fleischer rings (corneal copper deposits). Liver biopsy copper content >250 μg/g dry weight strongly supports the diagnosis. Molecular confirmation via ATP7B sequencing is definitive.

Treatment is lifelong and highly effective: D-penicillamine or trientine for initial copper chelation, with zinc salts for maintenance. Patients who begin treatment before neurological symptoms develop typically achieve normal life expectancy.