Is ALPL p.Val217fs (c.649_650insC) pathogenic?

ALPL p.Val217fs (c.649650insC) is classified Pathogenic in ALPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-29). Very rare (popmax 0.00223%, eas); Associated with hypophosphatasia.

What condition is associated with ALPL p.Val217fs (c.649_650insC)?

ALPL p.Val217fs (c.649_650insC) is associated with hypophosphatasia (ClinVar).

How common is ALPL p.Val217fs (c.649_650insC) in the general population?

ALPL p.Val217fs (c.649_650insC) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Hypophosphatasia inherited?

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

ALPL p.Val217fs

c.649_650insC · rs781213038 · VCV2671819

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

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 7 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,858 alleles

Overall 0.000657% 1/152,248 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.Val217fs
Coding: c.649_650insC
MANE Select: NM_000478
dbSNP: rs781213038
Type: Insertion
Location: chr1:21568104 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 217: 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

For Hypophosphatasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ALPL p.Val217delinsAlaLys Pathogenic/Likely pathogenic ★★ same residue
ALPL p.Val217Ala Uncertain significance ★★ ⚠ same residue
ALPL p.Val217delinsAlaMet Pathogenic ★ same residue
ALPL p.Asn190Ter Pathogenic ★★ same condition
ALPL p.Leu512fs Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Met226fs Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Tyr101fs Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Ala485fs 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-val217fs (accessed [today's date]).

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