Is ALPL p.Cys489Ter (c.1467C>A) pathogenic?

ALPL p.Cys489Ter (c.1467C>A) is classified Pathogenic in ALPL (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-01). Very rare (popmax 8.48e-05%, nfe); Associated with hypophosphatasia.

What condition is associated with ALPL p.Cys489Ter (c.1467C>A)?

ALPL p.Cys489Ter (c.1467C>A) is associated with hypophosphatasia (ClinVar).

How common is ALPL p.Cys489Ter (c.1467C>A) in the general population?

ALPL p.Cys489Ter (c.1467C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Hypophosphatasia inherited?

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

ALPL p.Cys489Ter

c.1467C>A · VCV4974795

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

hypophosphatasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	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 · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.61, phastCons 1
Overall
CADD	36.0	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 8.48e-05% European (non-Finnish) · 1/1,179,864 alleles

Overall 6.88e-05% 1/1,454,050 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.Cys489Ter
Coding: c.1467C>A
MANE Select: NM_000478
Type: single nucleotide variant
Location: chr1:21577540 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 489: a UniProt-annotated variant site (in hops; reduces alkaline phosphatase activity); a disulfide bond

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.Cys489Tyr Uncertain significance ★ same residue
ALPL p.Cys489Phe Pathogenic same residue
ALPL p.Cys489Ser Pathogenic ★ same residue
ALPL p.Cys489Arg Uncertain significance ★ ⚠ same residue
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

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-cys489ter (accessed [today's date]).

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