Hypophosphatasia: genes and variants
Hypophosphatasia is linked to 1 analyzed protein (ALPL). 172 DNA variants are known to cause it; 88 more are uncertain, and 7 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Hypophosphatasia
ALPL: Alkaline phosphatase, tissue-nonspecific isozyme
It hydrolyzes extracellular pyrophosphate and other phosphate-containing substrates, enabling normal mineralization of bone and teeth. Loss-of-function variants cause hypophosphatasia, with severity ranging from lethal perinatal skeletal hypomineralization to adult fractures and dental disease.
172 disease-causing and 88 uncertain variants in ALPL are linked to Hypophosphatasia.
Known disease-causing variants in Hypophosphatasia
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| ALPL A443V | 443 | Disease-causing (★★★★) | |
| ALPL A443S | 443 | Disease-causing (★★★★) | |
| ALPL G63V | 63 | Disease-causing (★★) | |
| ALPL R71C | 71 | Disease-causing (★★) | |
| ALPL R71H | 71 | Disease-causing (★★) | |
| ALPL R71G | 71 | Disease-causing (★★) | |
| ALPL R71S | 71 | Disease-causing (★★) | |
| ALPL Q106H | 106 | Disease-causing (★★) | |
| ALPL A111T | 111 | Disease-causing (★★) | |
| ALPL A116S | 116 | Disease-causing (★★) | |
| ALPL R136C | 136 | Disease-causing (★★) | |
| ALPL T141N | 141 | Disease-causing (★★) | |
| ALPL G162V | 162 | Disease-causing (★★) | |
| ALPL H171Y | 171 | Disease-causing (★★) | |
| ALPL H171R | 171 | Disease-causing (★★) | |
| ALPL R184Q | 184 | Disease-causing (★★) | |
| ALPL R184W | 184 | Disease-causing (★★) | |
| ALPL G220R | 220 | Disease-causing (★★) | |
| ALPL G220V | 220 | Disease-causing (★★) | |
| ALPL G221C | 221 | Disease-causing (★★) | |
| ALPL G221R | 221 | Disease-causing (★★) | |
| ALPL G221V | 221 | Disease-causing (★★) | |
| ALPL E291K | 291 | Disease-causing (★★) | |
| ALPL P292L | 292 | Disease-causing (★★) | |
| ALPL F327C | 327 | Disease-causing (★★) | |
| ALPL G334S | 334 | Disease-causing (★★) | |
| ALPL G339R | 339 | Disease-causing (★★) | |
| ALPL D378H | 378 | Disease-causing (★★) | |
| ALPL T389N | 389 | Disease-causing (★★) | |
| ALPL A399V | 399 | Disease-causing (★★) | |
| ALPL G420D | 420 | Disease-causing (★★) | |
| ALPL G426D | 426 | Disease-causing (★★) | |
| ALPL R428Q | 428 | Disease-causing (★★) | |
| ALPL G456R | 456 | Disease-causing (★★) | |
| ALPL V459M | 459 | Disease-causing (★★) | |
| ALPL E476A | 476 | Disease-causing (★★) | |
| ALPL R71P | 71 | Disease-causing (★★) | |
| ALPL G112S | 112 | Disease-causing (★★) | |
| ALPL A116T | 116 | Disease-causing (★★) | |
| ALPL T141I | 141 | Disease-causing (★★) | |
| ALPL G162S | 162 | Disease-causing (★★) | |
| ALPL R223Q | 223 | Disease-causing (★★) | |
| ALPL R223W | 223 | Disease-causing (★★) | |
| ALPL E291Q | 291 | Disease-causing (★★) | |
| ALPL P292T | 292 | Disease-causing (★★) | |
| ALPL P292S | 292 | Disease-causing (★★) | |
| ALPL Y297N | 297 | Disease-causing (★★) | |
| ALPL F327L | 327 | Disease-causing (★★) | |
| ALPL D378Y | 378 | Disease-causing (★★) | |
| ALPL R428P | 428 | Disease-causing (★★) | |
| ALPL A443G | 443 | Disease-causing (★★) | |
| ALPL V459L | 459 | Disease-causing (★★) | |
| ALPL E476G | 476 | Disease-causing (★★) | |
| ALPL L37P | 37 | Disease-causing (★★) | |
| ALPL T68M | 68 | Disease-causing (★★) | |
| ALPL G75S | 75 | Disease-causing (★★) | |
| ALPL Y101C | 101 | Disease-causing (★★) | |
| ALPL A111V | 111 | Disease-causing (★★) | |
| ALPL A114T | 114 | Disease-causing (★★) | |
| ALPL T115I | 115 | Disease-causing (★★) |
Showing 60 of 172.
Uncertain variants in Hypophosphatasia that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| ALPL G397D | 397 | Conflicting reports (★) | +7: 4 other pathogenic changes within 3 positions; G397V at the same position is pathogenic; seen in 6.6e-06 of gnomAD DNA copies; REVEL 0.963 | |
| ALPL P307L | 307 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; P307S at the same position is pathogenic; REVEL 0.960 | |
| ALPL M62L | 62 | Conflicting reports (★) | +6: 5 other pathogenic changes within 3 positions; M62I at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.76 | |
| ALPL G416D | 416 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; G416V at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.99 | |
| ALPL M226T | 226 | Conflicting reports (★) | +6: 4 other pathogenic changes within 3 positions; M226I at the same position is pathogenic; REVEL 0.978 | |
| ALPL A114V | 114 | Conflicting reports (★) | +6: 8 other pathogenic changes within 3 positions; A114T at the same position is pathogenic; REVEL 0.946 | |
| ALPL S445T | 445 | Uncertain (★) | +6: 7 other pathogenic changes within 3 positions; S445C at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.98 |
Same protein, different disease
- Adult hypophosphatasia is also caused by ALPL variants; they fall in the same places as the Hypophosphatasia variants (113 disease-causing).
- Childhood hypophosphatasia is also caused by ALPL variants; they fall in the same places as the Hypophosphatasia variants (60 disease-causing).
- Infantile hypophosphatasia is also caused by ALPL variants; they fall in the same places as the Hypophosphatasia variants (40 disease-causing).
- Hypophosphataemia or rickets is also caused by ALPL variants; they fall in the same places as the Hypophosphatasia variants (8 disease-causing).
- Semidominant ALPL-related disorders is also caused by ALPL variants; they fall in the same places as the Hypophosphatasia variants (6 disease-causing).
Diseases related to Hypophosphatasia
- Osteogenesis imperfecta, also linked to ALPL
- Adult hypophosphatasia, also linked to ALPL
- Childhood hypophosphatasia, also linked to ALPL
- Infantile hypophosphatasia, also linked to ALPL
- Hypophosphataemia or rickets, also linked to ALPL
- Paediatric disorders, also linked to ALPL
- Semidominant ALPL-related disorders, also linked to ALPL
Frequently asked questions
Which genes are linked to Hypophosphatasia?
In CATVariant, Hypophosphatasia is linked to 1 analyzed protein: ALPL (Alkaline phosphatase, tissue-nonspecific isozyme).
How many genetic variants are linked to Hypophosphatasia?
314 variants: 172 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 88 are of uncertain significance or have conflicting reports.
Which uncertain variants in Hypophosphatasia look disease-causing?
7 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example ALPL G397D, ALPL P307L, ALPL M62L, ALPL G416D and ALPL M226T. These are leads for expert review, not diagnoses.
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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