Is ALPL p.Asn430Ser (c.1289A>G) pathogenic?

ALPL p.Asn430Ser (c.1289A>G) is classified Pathogenic in ALPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1993); Very rare (popmax 8.48e-05%, nfe); Associated with hypophosphatasia.

What condition is associated with ALPL p.Asn430Ser (c.1289A>G)?

ALPL p.Asn430Ser (c.1289A>G) is associated with hypophosphatasia (ClinVar).

How common is ALPL p.Asn430Ser (c.1289A>G) in the general population?

ALPL p.Asn430Ser (c.1289A>G) 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.

What do computational predictors say about ALPL p.Asn430Ser (c.1289A>G)?

AlphaMissense predicts likely benign (score 0.1993) — an in-silico prediction, not a clinical call.

ALPL p.Asn430Ser

c.1289A>G · VCV4086889

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1993 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.1993	likely benign ⚠ discordant with ClinVar
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -10.22	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,710 alleles

Overall 0.000658% 1/152,012 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.Asn430Ser
Coding: c.1289A>G
MANE Select: NM_000478
Type: single nucleotide variant
Location: chr1:21576621 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB

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.Asn430= Likely benign ★ 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
ALPL c.298-1G>A Pathogenic ★★ same condition
ALPL c.472+1G>A Pathogenic ★★ same condition
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-asn430ser (accessed [today's date]).

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