Is ALPL p.Arg168fs (c.501_503delinsC) pathogenic?

ALPL p.Arg168fs (c.501503delinsC) is classified Likely pathogenic in ALPL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). Absent from gnomAD; Associated with adult hypophosphatasia.

What condition is associated with ALPL p.Arg168fs (c.501_503delinsC)?

ALPL p.Arg168fs (c.501_503delinsC) is associated with adult hypophosphatasia (ClinVar).

How common is ALPL p.Arg168fs (c.501_503delinsC) in the general population?

ALPL p.Arg168fs (c.501_503delinsC) is absent from gnomAD (gnomAD).

ALPL p.Arg168fs

c.501_503delinsC · rs2545303484 · VCV3241947

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 6 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -5.8	GERP -3.9

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ALPL
Protein: p.Arg168fs
Coding: c.501_503delinsC
MANE Select: NM_000478
dbSNP: rs2545303484
Type: Indel
Location: chr1:21564069 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 168: a β-strand; a disulfide bond

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

Similar variants

ALPL p.Leu8fs Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Thr134His Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Val217delinsAlaLys Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Ala500fs 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.Arg168= Likely benign ★ same residue
ALPL c.1190-2A>T 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-arg168fs (accessed [today's date]).

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