1-21563234-C-T

Variant names:

• chr1-21563234-C-T
• rs916300043
• NM_000478.6:c.422C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM5 PP2 PP3_Strong PP5

The NM_000478.6(ALPL):​c.422C>T​(p.Thr141Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T141N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.12
• Publications: 1 publications found

Genes affected

ALPL (HGNC:438): (alkaline phosphatase, biomineralization associated) 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]

ALPL Gene-Disease associations (from GenCC):

• adult hypophosphatasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• childhood hypophosphatasia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, ClinGen, Orphanet
• hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
• infantile hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia
• odontohypophosphatasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• perinatal lethal hypophosphatasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21563234-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 551980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 220 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 1.2672 (below the threshold of 3.09). Trascript score misZ: 1.9021 (below the threshold of 3.09). GenCC associations: The gene is linked to adult hypophosphatasia, infantile hypophosphatasia, odontohypophosphatasia, childhood hypophosphatasia, hypophosphatasia, perinatal lethal hypophosphatasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 1-21563234-C-T is Pathogenic according to our data. Variant chr1-21563234-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1465466.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000478.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	NM_000478.6	MANE Select	c.422C>T	p.Thr141Ile	missense	Exon 5 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.422C>T	p.Thr141Ile	missense	Exon 5 of 12	NP_001356732.1
	ALPL	NM_001369804.2		c.422C>T	p.Thr141Ile	missense	Exon 5 of 12	NP_001356733.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	ENST00000374840.8	TSL:1 MANE Select	c.422C>T	p.Thr141Ile	missense	Exon 5 of 12	ENSP00000363973.3
	ALPL	ENST00000374832.5	TSL:2	c.422C>T	p.Thr141Ile	missense	Exon 5 of 12	ENSP00000363965.1
	ALPL	ENST00000540617.5	TSL:2	c.257C>T	p.Thr86Ile	missense	Exon 4 of 11	ENSP00000442672.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461492 Hom.: 0 Cov.: 37 AF XY: 0.0000124 AC XY: 9 AN XY: 727048

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypophosphatasia Pathogenic:2

Jul 31, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALPL c.422C>T (p.Thr141Ile) results in a non-conservative amino acid change located in the Alkaline phosphatase domain (IPR001952) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 250596 control chromosomes (gnomAD). c.422C>T has been reported in the literature in two individuals affected with Hypophosphatasia (example, DelAngel_2020). A GWAS study using UK Biobank participants suggest the variant was associated with phenotypes of abnormlal Alkaline phosphatase (Backman_2021). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as likely pathogenic/pathogenic by our lab (c.422C>A, p.Thr141Asn), supporting the critical relevance of codon 141 to ALPL protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 61% of normal activity in vitro (DelAngel_2020). The following publications have been ascertained in the context of this evaluation (PMID: 34662886, 32160374). ClinVar contains an entry for this variant (Variation ID: 1465466). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Aug 29, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

ALPL c.422C>T is a missense variant that changes the amino acid at residue 141 from Threonine to Isoleucine. This variant has been observed in at least one proband affected with hypophosphatasia (PMID:32973344;32811521). Functional studies have been reported;however, the significance of the findings remain unclear (PMID:32160374). It is absent or not present at a significant frequency in gnomAD. In silico models agree that this variant is possibly or probably damaging. In conclusion, we classify ALPL p.Thr141Ile (c.422C>T) as a likely pathogenic variant.

not provided Pathogenic:1

Apr 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 141 of the ALPL protein (p.Thr141Ile). This variant disrupts the p.Thr141 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been observed in individuals with ALPL-related conditions (PMID: 25731960), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects ALPL function (PMID: 32160374). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALPL protein function. This missense change has been observed in individuals with hypophosphatasia (PMID: 32160374, 32811521). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.83		Loss of disorder (P = 0.0287)
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.51
gMVP		0.92
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs916300043; hg19: chr1-21889727;