Is ALPL p.Ser521Arg (c.1563C>G) pathogenic?

ALPL p.Ser521Arg (c.1563C>G) is classified Uncertain significance in ALPL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.2037); Ultra-rare (popmax 0.0179%, eas); Associated with hypophosphatasia.

What condition is associated with ALPL p.Ser521Arg (c.1563C>G)?

ALPL p.Ser521Arg (c.1563C>G) is associated with hypophosphatasia, adult hypophosphatasia, childhood hypophosphatasia (ClinVar).

How common is ALPL p.Ser521Arg (c.1563C>G) in the general population?

ALPL p.Ser521Arg (c.1563C>G) is ultra-rare (popmax 0.0179%, eas) (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.Ser521Arg (c.1563C>G)?

AlphaMissense predicts likely benign (score 0.2037) — an in-silico prediction, not a clinical call.

ALPL p.Ser521Arg

c.1563C>G · rs370978556 · VCV2199960

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2037 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.2037	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.25	GERP -2.1, phastCons 0.007
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	9.676	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0179% East Asian · 8/44,782 alleles

Filtering AF 0.00885% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00642%

Overall 0.00113% 18/1,598,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0179%	5,598
Remaining individualsnot grpmax-eligible	0.0161%	6,229

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.Ser521Arg
Coding: c.1563C>G
MANE Select: NM_000478
dbSNP: rs370978556
Type: single nucleotide variant
Location: chr1:21577636 (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

Also linked: adult hypophosphatasia childhood hypophosphatasia infantile hypophosphatasia

For Hypophosphatasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ALPL p.Ser521Asn Uncertain significance ★★ ⚠ same residue
ALPL p.Ser521fs Likely pathogenic ★ same residue
ALPL p.Ser521= 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

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-ser521arg (accessed [today's date]).

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