ALPL

protein-coding

alkaline phosphatase, biomineralization associated, the group of Alkaline phosphatases

Gene summary

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]

Previous symbols:

HOPS

MANE transcript

NM_000478.6

Inheritance

AR, AD, SD

ClinVar variants

P:652U:340B:299

Top phenotype

Hypophosphatasia, infantile; Hypophosphatasia, childhood; Hypophosphatasia, adult; Odontohypophosphatasia

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr1:21,509,397-21,578,410

External References & Databases

Ensembl (ENSG00000162551)

Transcript & Mutation Effects

hg38 • Region Span ~69.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

infantile hypophosphatasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009427

Submitter: Orphanet

childhood hypophosphatasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009428

Submitter: Orphanet

odontohypophosphatasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016607

Submitter: Orphanet

perinatal lethal hypophosphatasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016605

Submitter: Orphanet

childhood hypophosphatasiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009428

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

adult hypophosphatasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007798

Submitter: Labcorp Genetics (formerly Invitae)

hypophosphatasiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018570

Submitter: G2P

infantile hypophosphatasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009427

Submitter: Labcorp Genetics (formerly Invitae)

ALPL-related autosomal recessive hypophosphatasiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100609

Submitter: ClinGen

*ALPL* was first reported in relation to* ALPL*-related autosomal recessive hypophosphatasia in 1988 (Weiss et al., PMID: 3174660). *ALPL*-related autosomal recessive hypophosphatasia is characterized by defective mineralization of bone and/or teeth, premature loss of teeth with intact roots, and reduced serum alkaline phosphatase (ALP) activity. Individuals can present with this form of hypophosphatasia in infancy, childhood, or adulthood. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following autosomal recessive disease entities (Hypophosphatasia, adult, MIM:146300; Hypophosphatasia, childhood, MIM: 241510; Hypophosphatasia, infantile, MIM:241500; Odontohypophosphatasia, MIM:146300) have been lumped into one disease entity, *ALPL*-related autosomal recessive hypophosphatasia. The split curation for *ALPL*-related autosomal dominant hypophosphatasia has been curated separately. 14 missense, 2 splicing, and 1 nonsense variants that have been reported in 11 probands in 4 publications (PMIDs: 3174660, 1409720, 32160374, 25731960) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is reported to be loss of function. This gene-disease relationship is also supported by animal models and a rescue study (PMIDs: 30446691, 18086009, 10620060, 14982838). In summary, there is definitive evidence supporting the relationship between *ALPL* and *ALPL*-related autosomal recessive hypophosphatasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date January 19th, 2021 (SOP Version 8).

adult hypophosphatasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007798

Submitter: Orphanet

ALPL-related autosomal dominant hypophosphatasiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100608

Submitter: ClinGen

*ALPL* was reported in relation to *ALPL*-related autosomal dominant hypophosphatasia as early as 1962 (Silverman et al., PMID: 13912932). *ALPL*-related autosomal dominant hypophosphatasia is characterized by defective mineralization of bone and/or teeth, premature loss of teeth with intact roots, and reduced serum alkaline phosphatase (ALP) activity. Individuals can present with this form of hypophosphatasia in infancy, childhood, or adulthood. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following autosomal dominant disease entities (Hypophosphatasia, adult, MIM:146300; Odontohypophosphatasia, MIM:146300) have been lumped into one disease entity, *ALPL*-related autosomal dominant hypophosphatasia. The split curation for *ALPL*-related autosomal recessive hypophosphatasia has been curated separately. 20 missense, 1 frameshift, 1 nonsense, and one splicing variants that have been reported in 23 probands in 3 publications (PMIDs: 10690885, 19500388, 29236161) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is reported to be dominant negative. This gene-disease relationship is also supported by two animal models and expression studies (PMIDs: 25716980, 23715323). In summary, there is definitive evidence supporting the relationship between *ALPL* and *ALPL*-related autosomal dominant hypophosphatasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date May 19th, 2021 (SOP Version 8).

hypophosphatasiaSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0018570

Submitter: PanelApp Australia

hypophosphatasiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018570

Submitter: Myriad Women's Health

hypophosphatasiaDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0018570

Submitter: Natera

Clinical Genomic Database (CGD)

Hypophosphatasia, infantile; Hypophosphatasia, childhood; Hypophosphatasia, adult; OdontohypophosphatasiaAD/AR

Manifestation: Dental; Endocrine; Musculoskeletal; Neurologic

Intervention: Endocrine; Neurologic

Rationale: In some forms, abnormal calcium levels can be treated; Seizures can be treated with vitamin B6; Bisphosphonates and excess vitamin D should be avoided due to potential hypercalcemia leading to renal damage; Enzymatic therapy has shown benefit in individuals with severe forms of hypophosphatasia

Refs: 18110134 ; 13800162; 4288761; 4309618 ; 5013867; 7235780; 7305584; 7072744; 7182980; 3960066; 1409720; 3174660; 8406453; 10332035; 10872988; 11479741; 11999978; 12357339; 17519318; 17213282; 21488855; 20978533; 20301329; 22397652

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALPL variants in ClinVar

29 Conditions Cataloged

not providedTotal: 1114

HypophosphatasiaTotal: 745

Adult hypophosphatasiaTotal: 330

Infantile hypophosphatasiaTotal: 296

Childhood hypophosphatasiaTotal: 232

ALPL-related disorderTotal: 145

not specifiedTotal: 126

Inborn genetic diseasesTotal: 56

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000478.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	16 clinvar	288 clinvar	1 clinvar	306
missense	39 clinvar	396 clinvar	314 clinvar	10 clinvar		759
nonsense	26 clinvar	19 clinvar	2 clinvar			47
start loss	2 clinvar	3 clinvar				5
frameshift	70 clinvar	54 clinvar	2 clinvar			126
splice donor/acceptor (+/-2bp)	20 clinvar	22 clinvar	6 clinvar			48
Total	157	495	340	298	1	1291

Highest pathogenic variant AF is 0.0014131942

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000478.6	RefSeq	NP_000469.3	11	MANE Select
ENST00000374840.8	Ensembl	ENSP00000363973.3	11	MANE Select
NM_001127501.4	RefSeq	NP_001120973.2	10	Standard
NM_001177520.3	RefSeq	NP_001170991.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Folate biosynthesis - Homo sapiens (human)
Thiamine metabolism - Homo sapiens (human)
Hypophosphatasia
Vitamin B6 Metabolism
AGE-RAGE pathway

Biological Process

skeletal system development
osteoblast differentiation
endochondral ossification
developmental process involved in reproduction
dephosphorylation

Molecular Function

alkaline phosphatase activity
protein binding
pyrophosphatase activity
metal ion binding

Cellular Component

extracellular region
plasma membrane
membrane
extracellular matrix
anchored component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374840
Coding exons: 11
Length: 69048
Individuals with no LoFs: 125701
Homozygous LoFs: 0
Heterozygous LoFs: 47
Defined: 125748
p: 0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.27	266	331	0.804	0.0000210	3421
Missense (PolyPhen)		110	161.7	0.68028		1678
Synonymous	-0.717	161	150	1.07	0.0000117	1053
Loss of Function	2.71	10	24.5	0.409	0.00000133	267

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This isozyme may play a role in skeletal mineralization.;
Disease: DISEASE: Hypophosphatasia (HOPS) [MIM:146300]: A metabolic bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase. Four forms are distinguished, depending on the age of onset: perinatal, infantile, childhood and adult type. The perinatal form is the most severe and is almost always fatal. The adult form is mild and characterized by recurrent fractures, osteomalacia, rickets, and loss of teeth. Some cases are asymptomatic, while some patients manifest dental features without skeletal manifestations (odontohypophosphatasia). {ECO:0000269|PubMed:10094560, ECO:0000269|PubMed:10332035, ECO:0000269|PubMed:10679946, ECO:0000269|PubMed:10690885, ECO:0000269|PubMed:10834525, ECO:0000269|PubMed:11438998, ECO:0000269|PubMed:11479741, ECO:0000269|PubMed:11745997, ECO:0000269|PubMed:11760847, ECO:0000269|PubMed:11834095, ECO:0000269|PubMed:11855933, ECO:0000269|PubMed:11999978, ECO:0000269|PubMed:12815606, ECO:0000269|PubMed:12920074, ECO:0000269|PubMed:1409720, ECO:0000269|PubMed:15135428, ECO:0000269|PubMed:15694177, ECO:0000269|PubMed:19500388, ECO:0000269|PubMed:22266140, ECO:0000269|PubMed:23039266, ECO:0000269|PubMed:23688511, ECO:0000269|PubMed:25982064, ECO:0000269|PubMed:3174660, ECO:0000269|PubMed:7833929, ECO:0000269|PubMed:8406453, ECO:0000269|PubMed:8954059, ECO:0000269|PubMed:9452105, ECO:0000269|PubMed:9747027, ECO:0000269|PubMed:9781036}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hypophosphatasia childhood type (HOPSC) [MIM:241510]: A bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase. {ECO:0000269|PubMed:11760847}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hypophosphatasia infantile type (HOPSI) [MIM:241500]: A severe bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase. Three more or less distinct types of infantile hypophosphatasia can be identified: (1) type 1 with onset in utero or in early postnatal life, craniostenosis, severe skeletal abnormalities, hypercalcemia, and death in the first year or so of life; (2) type 2 with later, more gradual development of symptoms, moderately severe 'rachitic' skeletal changes and premature loss of teeth; (3) type 3 with no symptoms, the condition being determined on routine studies. {ECO:0000269|PubMed:10834525, ECO:0000269|PubMed:11438998, ECO:0000269|PubMed:7833929, ECO:0000269|PubMed:8954059}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.928

Intolerance Scores

LoFtool: 0.0447
RVIS EVS: 0.0000761
RVIS percentile EVS: 53.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.944

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium