1-21563225-G-C

Variant names:

• chr1-21563225-G-C
• rs140167865
• NM_000478.6:c.413G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PM2 PP2 PP5_Very_Strong BP4

The NM_000478.6(ALPL):​c.413G>C​(p.Arg138Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.85
• 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 12 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000478.6
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 1-21563225-G-C is Pathogenic according to our data. Variant chr1-21563225-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2676516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35796678). . Strength limited to SUPPORTING due to the PP5.

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.413G>C	p.Arg138Pro	missense	Exon 5 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.413G>C	p.Arg138Pro	missense	Exon 5 of 12	NP_001356732.1
	ALPL	NM_001369804.2		c.413G>C	p.Arg138Pro	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.413G>C	p.Arg138Pro	missense	Exon 5 of 12	ENSP00000363973.3
	ALPL	ENST00000374832.5	TSL:2	c.413G>C	p.Arg138Pro	missense	Exon 5 of 12	ENSP00000363965.1
	ALPL	ENST00000540617.5	TSL:2	c.248G>C	p.Arg83Pro	missense	Exon 4 of 11	ENSP00000442672.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Adult hypophosphatasia Pathogenic:1

Aug 24, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypophosphatasia Pathogenic:1

Aug 29, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

ALPL c.413G>C is a missense variant that changes the amino acid at residue 138 from Arginine to Proline. This variant has been observed in at least one proband affected with hypophosphatasia (PMID:30508915). It has been observed in trans with a pathogenic variant (PMID:30508915). At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:32160374). It is absent or not present at a significant frequency in gnomAD. In conclusion, we classify ALPL p.Arg138Pro (c.413G>C) as a pathogenic variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.041	T
MutationAssessor	Benign	-0.85	N
PhyloP100		1.9
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.46
Sift	Benign	0.047	D
Sift4G	Benign	0.075	T
Polyphen		0.81	P
Vest4		0.30
MutPred		0.53		Loss of MoRF binding (P = 0.0312)
MVP		0.86
MPC		1.1
ClinPred		0.64	D
GERP RS		1.0
Varity_R		0.29
gMVP		0.92
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs140167865; hg19: chr1-21889718;