ALPL p.Ser521fs
c.1560_1561delinsT · VCV4854274
Likely pathogenic
Single submitter
Classification
Likely pathogenic
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
Consequence
frameshift
predicted LoF
gnomAD v4.1
Rare
Conditions
1
infantile 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 | escapes | premature termination codon in the last exon (12 of 12) — the truncated protein is likely expressed. PVS1 input, not an applied code |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 0.53 | GERP -2.1, phastCons 0.14 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Variant & gene context
- Gene
- ALPL
- Protein
- p.Ser521fs
- Coding
- c.1560_1561delinsT
- MANE Select
- NM_000478
- Type
- Indel
- Location
- chr1:21577633 (GRCh38)
- Gene constraint
- LOEUF 0.987 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 93.74 · 5 PDB
Disease context
infantile hypophosphatasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Hypophosphatasia (Orphanet):
- Inheritance
- Autosomal dominant, Autosomal recessive
- Onset
- All ages
Similar variants
- ALPL p.Ser521Arg Uncertain significance ★★ ⚠ same residue
- ALPL p.Ser521Asn Uncertain significance ★★ ⚠ same residue
- ALPL p.Thr134His Pathogenic/Likely pathogenic ★★ same condition
- ALPL p.Val217delinsAlaLys Pathogenic/Likely pathogenic ★★ same condition
- ALPL c.863-12_863-7delinsGGTCCCCGGTCCC Uncertain significance ★ same condition
- ALPL p.Phe327Gly Conflicting classifications of pathogenicity ★ same condition
- ALPL p.Ser521= Likely benign ★ same residue
- ALPL c.62-1G>C 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-ser521fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown