Is ALPL p.Ser403Cys (c.1207A>T) pathogenic?

ALPL p.Ser403Cys (c.1207A>T) is classified Likely pathogenic in ALPL (ClinVar, Single submitter, 2 submitters; last evaluated 2026-09-01). AlphaMissense: likely pathogenic (0.7286); Very rare (popmax 8.48e-05%, nfe); Associated with hypophosphatasia.

What condition is associated with ALPL p.Ser403Cys (c.1207A>T)?

ALPL p.Ser403Cys (c.1207A>T) is associated with hypophosphatasia (ClinVar).

How common is ALPL p.Ser403Cys (c.1207A>T) in the general population?

ALPL p.Ser403Cys (c.1207A>T) 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.Ser403Cys (c.1207A>T)?

AlphaMissense predicts likely pathogenic (score 0.7286) — an in-silico prediction, not a clinical call.

ALPL p.Ser403Cys

c.1207A>T · rs1216428237 · VCV446467

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7286 · 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	0.7286	likely pathogenic ✓ concordant with ClinVar
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -9.71	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	28.9	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) · 1/1,179,908 alleles

Overall 6.84e-05% 1/1,461,738 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.Ser403Cys
Coding: c.1207A>T
MANE Select: NM_000478
dbSNP: rs1216428237
Type: single nucleotide variant
Location: chr1:21576539 (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.Ser403Asn Uncertain significance ★★ ⚠ same residue
ALPL p.Ser403Arg Conflicting classifications of pathogenicity ★ ⚠ 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

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-ser403cys (accessed [today's date]).

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