ALPL

Chr 1ADAR

alkaline phosphatase, biomineralization associated

Also known as: AP-TNAP, APTNAP, HOPS, HPPA, HPPC, HPPI, HPPO, TNALP

NCBI Gene: 249 ENSG00000162551 UniProt: P05186 OMIM: 171760

This gene encodes tissue-nonspecific alkaline phosphatase, a membrane-bound enzyme that hydrolyzes inorganic pyrophosphate and other phosphate compounds to promote bone and tooth mineralization, and also dephosphorylates pyridoxal 5'-phosphate for vitamin B6 metabolism in the brain. Mutations cause hypophosphatasia, which presents across a spectrum from severe infantile forms with life-threatening skeletal defects to milder childhood, adult, and dental-only variants. Inheritance can be either autosomal recessive (typically for severe early-onset forms) or autosomal dominant (often for milder presentations).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the alkaline phosphatase family of proteins. There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue non-specific). The first three are located together on chromosome 2, while the tissue non-specific form is located on chromosome 1. The product of this gene is a membrane bound glycosylated enzyme that is not expressed in any particular tissue and is, therefore, referred to as the tissue-nonspecific form of the enzyme. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature enzyme. This enzyme may play a role in bone mineralization. Mutations in this gene have been linked to hypophosphatasia, a disorder that is characterized by hypercalcemia and skeletal defects. [provided by RefSeq, Oct 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hypophosphatasia, adultMIM #146300

ADAR

Hypophosphatasia, childhoodMIM #241510

Hypophosphatasia, infantileMIM #241500

OdontohypophosphatasiaMIM #146300

ADAR

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

267

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.69

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — ALPL

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.000

Z-score 2.71

OE 0.41 (0.25–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.27Z-score

OE missense 0.80 (0.73–0.89)

266 obs / 330.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.41 (0.25–0.69)

0≤0.351.4

Missense OE?0.80 (0.73–0.89)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 10 / 24.5Missense obs/exp: 266 / 330.9Syn Z: -0.72

Background carrier burden — how many people carry a rare variant somewhere in ALPL?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 74

621 rare PASS variants

Rare truncating (LoF)

1 in 570

113 rare PASS variants

Rare synonymous (reference)

1 in 110

298 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ALPL. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 84	1 in 530
South Asian	~43k	1 in 130	1 in 3,100
Remaining (unassigned)	~30k	1 in 110	1 in 570
European (Finnish)	~27k	1 in 320	≈ 1 in 11,000
Admixed American	~22k	1 in 170	1 in 680
African / African American	~21k	1 in 130	1 in 1,100
East Asian	~20k	1 in 73	1 in 330
Ashkenazi Jewish	~13k	1 in 520	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 160	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

ALPL · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — ALPL

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Hypophosphatasia

Characteristics of Hypophosphatasia in Adult Patients in Rheumatology and Their Value in Developing an Algorithm to HPP-diagnosis - the COHIR Multi-center Study

RECRUITING

NCT06574282University of BonnStarted 2024-08-25

Second alkaline phosphatase measurement

Hypophosphatasia

Natural History Study of Patients With Hypophosphatasia (HPP)

RECRUITING

NCT02237625Duke UniversityStarted 2014-09

Hypophosphatasia

The Effect of Monoallelic Variants in the ALPL Gene on the Natural Course of Hypophosphatasia in Russia

RECRUITING

NCT07390240AstraZenecaStarted 2025-12-29

Clinical Literature