Amelogenesis imperfecta

Gene: ALPL

Green List (high evidence)

Comment on list classification: There are numerous individuals reported in literature with both mono- and bi- allelic ALPL variants, diagnosed with hypophosphatasia. Tooth loss and other dental signs are very common symptoms, particularly in paediatric-onset cases. Odontohypophosphatasia cases present with an isolated dental phenotype. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next update.

Created: 27 Feb 2026, 11:45 a.m. | Last Modified: 27 Feb 2026, 11:46 a.m.

Panel Version: 4.30

PMID: 39983296 Rush et al. 2025
Cohort of US individuals with suspected HPP. 470 patients had a heterozygous ALPL mutation, and 31 had biallelic ALPL variants (mostly missense). In children, tooth loss and other dental signs/ symptoms were the most common symptom (31%), followed by pain and short stature. In the adult cohort, the most common HPP symptoms were: fractures (27 %), tooth loss and other dental problems (25 %), pain (24 %), and low bone mineral density/osteopenia/osteoporosis (19%).

PMID: 36101824 Sinha et al., 2022
27 adults with HPP and heterozygous ALPL variants. Premature tooth loss was present in 63% (17/27); 19% (5/27) were missing eight or more teeth.

PMID: 34164522 Su et al., 2021
6 ALPL variants were identified in 5 HPP children: proband 1: c.346G>A (p.A116T); proband 2: c.346G>A (p.A116T)/deletions from c.1097 to c.1099 CCT (p.T366_S367deli) compound heterozygous variant; proband 3: insertion of G from c.1014 to c.1015 (p.H338fs)/c.1446C>A (p.H482Q) compound heterozygous variant; proband 4: c.920C>T (p.P307L); and proband 5: c.883A>G (p.M295V).
4/5 probands had no dental phenotype, proband 3 presented with "Premature loss of baby teeth & irregular tooth alignment". Father of proband 1 (no ALPL variant) had caries & premature tooth loss at age 32. Little evidence of a dental phenotype in this group.

PMID: 31760938 Mao et al., 2019
Three forms of recessive HPP were identified in four unrelated patients from four different Chinese families, including one lethal infantile (patient 1), two childhood (patient 2 and 3) and one odonto HPP (patient 4). Patient 2 and 3 presented premature loss of deciduous teeth, muscle weakness and bone pain, whereas patient 4 had early loss of deciduous teeth only. Six variants in the ALPL gene were identified (5 missense and 1 frameshift).

PMID: 19500388 Fauvert et al., 2009
Cohort of individuals with ALPL variants and hypophosphatasia. Reported 39 patients with ALPL variants (mono and bi allelic) and odontohypophosphatasia - patients with only dental manifestations.

ALPL is associated with 4 disease entities in OMIM including AD, AR Odontohypophosphatasia, MIM:146300 (accessed 27th Feb 2026).

Created: 27 Feb 2026, 11:40 a.m. | Last Modified: 27 Feb 2026, 11:40 a.m.

Panel Version: 4.26

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Odontohypophosphatasia, OMIM:146300; hypophosphatasia, MONDO:0018570

Publications

• 19500388
• 34164522
• 36101824
• 39983296

Green List (high evidence)

According to the review of ALPL literature, PMID: 39872235
"78.8% of adults with pediatric-onset HPP have dental involvement vs 42.6% of those with adult-onset HPP."
"clinical observations can include enamel hypoplasia and discoloration (possibly contributing to increased caries prevalence), delayed tooth eruption, tooth mobility, and malocclusion (misalignment of upper and lower teeth due to incorrect positions along the dental arches)"

(Note that enamel hypoplasia, although it can mean just specific teeth being affected, is also a term often used to reflect amelogenesis imperfecta in the presence of diseases affecting other organ systems, this is because the original definition of amelogenesis imperfecta excluded it being part of syndromic diseases, this is now changing)

According to Chavez et al.'s ALPL review PMID: 32758526
"Ameloblasts, odontoblasts, cementoblasts, osteoblasts, and periodontal ligament (PDL) cells express TNAP (encoded by ALPL) ( (Bowden and Foster, 2019, Zweifler et al., 2015), indicating the enzyme may function in all aspects of dental and periodontal mineralization."

ALPL is also included on the panel used by Fulgent genetics to screen patients with amelogenesis imperfecta
https://fulgentgenetics.com/Amelogenesis-Imperfecta
Sources: Literature, Expert Review

Created: 12 Jan 2026, 3:35 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal