Is ALPL p.Arg272fs (c.814del) pathogenic?

ALPL p.Arg272fs (c.814del) is classified Pathogenic/Likely pathogenic in ALPL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-18). Very rare (popmax 0.000593%, nfe); Associated with adult hypophosphatasia.

What condition is associated with ALPL p.Arg272fs (c.814del)?

ALPL p.Arg272fs (c.814del) is associated with adult hypophosphatasia, hypophosphatasia (ClinVar).

How common is ALPL p.Arg272fs (c.814del) in the general population?

ALPL p.Arg272fs (c.814del) is very rare (popmax 0.000593%, nfe) (gnomAD).

ALPL p.Arg272fs

c.814del · rs2545324402 · VCV1916165

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

adult hypophosphatasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,012 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,461,868 alleles · very rare

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.Arg272fs
Coding: c.814del
MANE Select: NM_000478
dbSNP: rs2545324402
Type: Deletion
Location: chr1:21570325 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 272: an α-helix; a UniProt-annotated variant site (in hops; 6.8% of wild-type activity); a UniProt-annotated variant site (in hops)

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

Disease context

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

Also linked: hypophosphatasia

Similar variants

ALPL p.Arg272Cys Pathogenic ★★ same residue
ALPL p.Arg272His Pathogenic/Likely pathogenic ★★ ⚠ same residue
ALPL p.Arg272Leu Pathogenic/Likely pathogenic ★★ same residue
ALPL c.793-30_793-11del Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Ala492fs Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Arg138fs Pathogenic ★★ same condition
ALPL p.Asn16fs Pathogenic ★★ same condition
ALPL p.Asn190del Pathogenic/Likely 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-arg272fs (accessed [today's date]).

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