Is ALPL p.Thr373= (c.1119C>T) pathogenic?

ALPL p.Thr373= (c.1119C>T) is classified Benign/Likely benign in ALPL (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Low-frequency (popmax 2.7%, afr); Associated with hypophosphatasia.

What condition is associated with ALPL p.Thr373= (c.1119C>T)?

ALPL p.Thr373= (c.1119C>T) is associated with hypophosphatasia, osteogenesis imperfecta (ClinVar).

How common is ALPL p.Thr373= (c.1119C>T) in the general population?

ALPL p.Thr373= (c.1119C>T) is low-frequency (popmax 2.7%, afr) (gnomAD).

How is Hypophosphatasia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ALPL p.Thr373=

c.1119C>T · rs112335417 · VCV295548

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.7%, afr)

Conditions

hypophosphatasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -3.2
Overall
CADD	3.127	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.7% African / African-American · 2,026/75,048 alleles

Filtering AF 2.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.56%

Overall 0.145% 2,348/1,614,232 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.7%	37
Remaining individualsnot grpmax-eligible	0.189%	530
Admixed American	0.153%	652
Middle Eastern	0.099%	1,010
South Asian	0.0132%	7,591
East Asian	0.00891%	11,220
European (non-Finnish)	0.00763%	13,112

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ALPL
Protein: p.Thr373=
Coding: c.1119C>T
MANE Select: NM_000478
dbSNP: rs112335417
Type: single nucleotide variant
Location: chr1:21575854 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 373: a β-strand

Full ALPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypophosphatasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: osteogenesis imperfecta

For Hypophosphatasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ALPL c.1190-2A>T Pathogenic ★★ same condition
ALPL c.182-1G>A Pathogenic/Likely pathogenic ★★ same condition
ALPL c.182-2A>G Pathogenic/Likely pathogenic ★★ same condition
ALPL c.297+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALPL c.298-1G>A Pathogenic ★★ same condition
ALPL c.472+1G>A Pathogenic ★★ same condition
ALPL c.62-1G>C Pathogenic/Likely pathogenic ★★ same condition
ALPL c.648+1G>A Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/alpl-p-thr373 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown