Alpha-1 antitrypsin deficiency (SERPINA1): what Pi*Z and Pi*S carriers should know

Genetics explainer · Updated June 2026

What alpha-1 antitrypsin does

Alpha-1 antitrypsin (AAT) is a protein your liver makes and releases into the bloodstream. Its main job is to protect tissues — especially the delicate tissue of the lungs — from enzymes that the body releases during inflammation. Think of it as a shield: it keeps those enzymes from breaking down healthy tissue once they've done their job.

The specific enzyme AAT is best known for restraining is neutrophil elastase. Neutrophils are white blood cells that rush to sites of infection or irritation and release elastase to break down debris and invaders. Elastase is powerful and indiscriminate — left unchecked, it will digest healthy lung tissue along with everything else. AAT circulates through the lungs and neutralises elastase once it has done its job, keeping the cleanup from turning into collateral damage.

This sets up what clinicians call the protease–antiprotease balance. Elastase (a protease) breaks tissue down; AAT (the antiprotease) holds it in check. In healthy lungs the two are balanced, and the elastic, spongy tissue that lets you breathe stays intact. When AAT is low, the balance tips toward the protease side, and over years unopposed elastase can erode the walls of the tiny air sacs (alveoli) that do the work of gas exchange. That slow erosion is the biological root of the emphysema seen in alpha-1 antitrypsin deficiency.

The protein is produced from instructions in the SERPINA1 gene. Certain variants in this gene change the protein so that less of it reaches the bloodstream, or so the version that's made works less effectively. The result is alpha-1 antitrypsin deficiency — less of the protective shield in circulation, and a protease–antiprotease balance that sits closer to the tipping point.

The SERPINA1 variants: PiZ and PiS

Most people inherit two normal copies of SERPINA1, written as the M type. The two variant alleles people typically check are:

• Pi*Z (rs28929474) — the more significant of the two, and the single most clinically important deficiency allele. The Z change alters the protein so that much of it misfolds inside the liver cells that make it, meaning far less working AAT is exported into the bloodstream. Two copies are linked to the lowest protein levels.
• Pi*S (rs17580) — generally milder than Z on its own. The S protein is made and secreted but at reduced levels, and it is most relevant when it appears together with a Z allele.

These are the two variants that consumer raw DNA files typically report; rs28929474 (Z) and rs17580 (S) are the entries you'd actually see if you searched your own file.

You inherit one allele from each parent, so the combination matters. Broadly:

• MM — two normal copies; the common variants are not present.
• MZ or MS — a single variant copy. You're a carrier. Carriers usually have only a mild reduction in protein and most never develop problems.
• SZ — one S and one Z; an intermediate picture.
• ZZ — two Z copies, linked to the lowest levels and the genotype most associated with clinical deficiency. This is the combination most worth discussing with a clinician.

The reason ZZ sits at the severe end is straightforward once you know the mechanism. With one Z copy, you still have one normal M gene producing working protein, so levels are reduced but not collapsed. With two Z copies, both genes are producing the misfolding version, very little functional AAT reaches the lungs, and — as the liver section below explains — the misfolded protein has nowhere to go but the liver cells that made it. SZ falls between: one S and one Z each contribute a reduced amount, so the total lands in an intermediate range that's usually milder than ZZ but lower than a single-carrier state.

Why most carriers are mild

This is the part that matters most for a single-copy result. Carrying one PiZ or PiS allele — being MZ or MS — usually means a mild reduction in protein, and most carriers never develop symptoms. The genetics describe a predisposition, not a diagnosis.

Even among people with two variant copies, the picture varies a great deal from person to person. Age, smoking, other exposures, and individual differences all influence whether low protein levels ever translate into actual lung or liver problems. So a carrier result on a raw-data file is a reason to ask a question, not an answer in itself.

Why smoking matters enormously

If there's one thing to take away, it's this: with low alpha-1 antitrypsin, not smoking is the single most important protective step.

Here's the logic. Alpha-1 antitrypsin shields lung tissue from enzymes released during inflammation. Tobacco smoke does two unhelpful things at once — it ramps up the enzyme load in the lungs, and it reduces how well alpha-1 antitrypsin works. In someone with normal protein levels, the shield can keep up. In someone with low levels, the balance tips toward tissue damage, and over years that can accelerate the kind of lung damage seen in emphysema and COPD.

That's why the same genetics can play out so differently: a person with low protein levels who never smokes may stay well for life, while smoking can substantially raise the risk and bring lung problems on earlier in life. When emphysema does develop in alpha-1 antitrypsin deficiency, it tends to appear at a younger age than typical smoking-related COPD, and smoking is the factor that most reliably shifts the timeline earlier. Avoiding tobacco smoke — and secondhand smoke — is the clearest, most actionable step within your control. Occupational dusts, fumes, and heavy air pollution add to the elastase load in a similar way, so they're worth minimising too. It's worth raising any of these exposures with your doctor.

The liver side

SERPINA1 variants can also affect the liver, and the mechanism is a mirror image of the lung problem rather than the same thing. The lung issue is about too little AAT arriving where it's needed; the liver issue is about the misfolded protein getting stuck where it's made.

Here's why. The liver is where AAT is manufactured. The Z protein doesn't fold into its proper shape, and instead of being packaged up and secreted into the blood, a portion of it clumps together and accumulates inside the liver cells. So the Z variant creates two problems from one cause: not enough AAT downstream in the lungs, and a build-up of sticky, misfolded protein upstream in the liver. In a minority of people that accumulation can stress liver cells and contribute to liver disease over time — sometimes noticed in infancy, sometimes only in adulthood. This is largely a Z-allele phenomenon, because the S protein doesn't misfold and accumulate in the same way; it's simply made at a lower level.

As with the lungs, most carriers are unaffected, and whether anything develops varies widely between individuals. This is simply the reason that a proper evaluation looks at both lung and liver health — for example checking liver enzymes alongside a lung assessment — and why a doctor, not a raw-data file, is the right place to sort it out.

How a deficiency is actually confirmed

Alpha-1 antitrypsin deficiency is confirmed in the clinic, not by reading DNA letters. A doctor can order a blood test that measures your actual alpha-1 antitrypsin level and, if needed, identifies the specific protein type. Those results — together with your symptoms, history, and any lung or liver findings — are what establish whether a real deficiency is present and what, if anything, to do about it.

Genetic results can support the picture and prompt the right conversation, but the blood tests are what matter. If your raw data shows a PiZ or PiS allele, the sensible next move is to mention it to your doctor and let proper testing fill in the rest.

Why early awareness can help

None of this is meant to alarm — the point of clinical confirmation is that it opens the door to sensible, undramatic steps. For people who do turn out to have a significant deficiency, doctors have real options: monitoring lung function over time, staying current with vaccinations that protect the lungs, addressing exposures, and — in selected cases — treatments that a specialist can discuss. The specifics belong entirely with a clinician, and not everyone with an at-risk genotype needs anything beyond reassurance and the advice not to smoke.

What early awareness buys you is time to make the one change that matters most before any damage accumulates. Knowing you carry a Z or S allele long before any symptoms is exactly when the decision never to smoke, or to quit, has the most protective value. That's the constructive way to read a raw-data result: not as a verdict, but as an early, private nudge to have a conversation and to protect your lungs.

Why raw DNA data isn't diagnostic

Consumer raw data from 23andMe or AncestryDNA can flag the common S and Z alleles, and that's genuinely useful as a prompt. But it is not clinical-grade, and there are real limits to what it can tell you:

• It only covers the common variants. Alpha-1 antitrypsin deficiency can also involve rarer or so-called null alleles that consumer chips don't test for. A "normal" raw-data result doesn't fully rule deficiency out, and a flagged allele doesn't establish severity.
• Raw data can contain errors. Consumer genotyping is optimised for breadth, not diagnostic accuracy, and individual calls can be wrong. A single surprising marker is a reason to test, not to conclude.
• Genotype isn't the same as protein level. What actually matters clinically is how much working AAT is in your blood, and that's measured directly — it can't be read off the DNA letters alone.

That's why the whole point of a raw-data flag is to route you toward a proper AAT blood level and genotyping or phenotyping, ordered and interpreted by a doctor. It should never be used to self-diagnose or to change anything about your care on your own.

Looking it up safely

Your genome is the one piece of data you can never change, so the safest way to read any health marker is on your own device rather than uploading your file to a server. For the full genotype-by-genotype breakdown, see SERPINA1 / alpha-1 antitrypsin in our gene library. To search your own file for these markers right in your browser with nothing uploaded, try our DNA explorer. And for more plain-language explainers like this one, browse the Quanome blog.

Frequently asked questions

What is alpha-1 antitrypsin deficiency?

It is an inherited condition in which the body makes too little working alpha-1 antitrypsin, a protein that protects the lungs. It is linked to the SERPINA1 gene, and the two variants people most often check are Pi*Z and Pi*S.

I'm a Pi*Z or Pi*S carrier. Should I be worried?

A single copy makes you a carrier, and most carriers have normal or near-normal protein levels and never develop symptoms. A carrier result is a reason to ask your doctor a question, not a diagnosis. The biggest single thing within your control is not smoking.

Why does smoking matter so much with SERPINA1 variants?

Alpha-1 antitrypsin shields lung tissue from enzymes released during inflammation. Smoking both increases that enzyme load and lowers the protein's effectiveness, so it accelerates lung damage far more in people with low levels than in others. Avoiding smoke is the most important protective step.

How is alpha-1 antitrypsin deficiency actually confirmed?

It is confirmed by a doctor with blood tests that measure your alpha-1 antitrypsin level and identify the protein type (genotyping or phenotyping), not by reading raw DNA alone. Genetic results can support the picture, but the blood tests determine whether a real deficiency is present.

What's the difference between the Pi*Z and Pi*S alleles?

The Z allele (rs28929474) is the more clinically important one: the Z protein misfolds inside the liver, so much less working protein reaches the blood, and two Z copies (ZZ) are linked to the lowest levels. The S allele (rs17580) is generally milder — the protein is made but at reduced levels — and it matters most when it appears alongside a Z allele, as in the SZ combination.

Why does the Z variant affect the liver as well as the lungs?

The liver is where the protein is made. The Z version misfolds, and instead of being secreted into the blood, some of it accumulates inside liver cells. That's a different problem from the lungs: the lungs suffer from too little protein arriving, while the liver can be affected by the misfolded protein building up. In a minority of people this contributes to liver issues, which is why an evaluation looks at both organs.

Can 23andMe or AncestryDNA raw data diagnose this condition?

No. Raw data can flag the common S and Z alleles, which is a useful prompt, but it is not clinical-grade. It doesn't capture rarer variants, individual calls can be wrong, and genotype isn't the same as your actual protein level. A flagged or concerning result should always be confirmed with a doctor through a blood test.

Does an at-risk genotype mean I'll definitely get sick?

No. Expression varies enormously from person to person. Many people with an at-risk genotype never develop lung or liver disease, especially if they don't smoke. Smoking and other exposures matter far more than the genotype alone in determining whether problems ever appear.