Alpha-1-antitrypsin deficiency: genes and variants
Alpha-1-antitrypsin deficiency is linked to 1 analyzed protein (SERPINA1). 30 DNA variants are known to cause it; 42 more are uncertain, and 1 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: alpha 1-antitrypsin deficiency
Genes linked to Alpha-1-antitrypsin deficiency
SERPINA1: Alpha-1-antitrypsin
Its circulating alpha-1-antitrypsin activity protects lung tissue by neutralizing neutrophil elastase and related proteases. Severe deficiency predisposes to early emphysema, while accumulation of misfolded protein in hepatocytes can cause chronic liver disease.
30 disease-causing and 42 uncertain variants in SERPINA1 are linked to Alpha-1-antitrypsin deficiency.
Known disease-causing variants in Alpha-1-antitrypsin deficiency
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| SERPINA1 P393L | 393 | Disease-causing (★★) | |
| SERPINA1 P393R | 393 | Disease-causing (★★) | |
| SERPINA1 P393S | 393 | Disease-causing (★★) | |
| SERPINA1 R63C | 63 | Disease-causing (★★) | |
| SERPINA1 L65P | 65 | Disease-causing (★★) | |
| SERPINA1 M409T | 409 | Disease-causing (★★) | |
| SERPINA1 D280V | 280 | Disease-causing (★★) | |
| SERPINA1 E366G | 366 | Disease-causing (★) | |
| SERPINA1 E366Q | 366 | Disease-causing (★) | |
| SERPINA1 E366K | 366 | Disease-causing (★) | |
| SERPINA1 L12P | 12 | Disease-causing (★) | |
| SERPINA1 Q64K | 64 | Disease-causing (★) | |
| SERPINA1 G249R | 249 | Disease-causing (★) | |
| SERPINA1 E288V | 288 | Disease-causing (★) | |
| SERPINA1 P52L | 52 | Disease-causing (★) | |
| SERPINA1 A82P | 82 | Disease-causing (★) | |
| SERPINA1 D201G | 201 | Disease-causing (★) | |
| SERPINA1 R247C | 247 | Disease-causing (★) | |
| SERPINA1 H39N | 39 | Disease-causing (★) | |
| SERPINA1 S77F | 77 | Disease-causing | |
| SERPINA1 F76S | 76 | Disease-causing | |
| SERPINA1 G91E | 91 | Disease-causing | |
| SERPINA1 I116N | 116 | Disease-causing | |
| SERPINA1 G216C | 216 | Disease-causing | |
| SERPINA1 H358R | 358 | Disease-causing | |
| SERPINA1 M1V | 1 | Disease-causing | |
| SERPINA1 F57L | 57 | Disease-causing | |
| SERPINA1 G139S | 139 | Disease-causing | |
| SERPINA1 T320P | 320 | Disease-causing | |
| SERPINA1 M382R | 382 | RCL | Disease-causing |
Uncertain variants in Alpha-1-antitrypsin deficiency that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| SERPINA1 P393T | 393 | Conflicting reports (★) | +7: 3 other pathogenic changes within 3 positions; P393L at the same position is pathogenic; seen in 6.8e-07 of gnomAD DNA copies; REVEL 0.853 |
Which prediction tools work for Alpha-1-antitrypsin deficiency
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- EVE: 88 out of 100
- REVEL: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MutPred2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 80 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MetaLR: 79 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 77 out of 100
- SIFT: 76 out of 100
- AlphaMissense: 74 out of 100
- phyloP: 74 out of 100
Diseases related to Alpha-1-antitrypsin deficiency
- Carpal tunnel syndrome, also linked to SERPINA1
Frequently asked questions
Which genes are linked to Alpha-1-antitrypsin deficiency?
In CATVariant, Alpha-1-antitrypsin deficiency is linked to 1 analyzed protein: SERPINA1 (Alpha-1-antitrypsin).
How many genetic variants are linked to Alpha-1-antitrypsin deficiency?
129 variants: 30 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 42 are of uncertain significance or have conflicting reports.
Which uncertain variants in Alpha-1-antitrypsin deficiency look disease-causing?
1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SERPINA1 P393T. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for Alpha-1-antitrypsin deficiency?
Among tools not trained on clinical labels, EVE separates this disease's known disease-causing variants from harmless ones best (AUROC 0.88, based on 8 disease-causing and 9 harmless variants).
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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