Is ALPL p.Val522Ala (c.1565T>C) pathogenic?

ALPL p.Val522Ala (c.1565T>C) is classified Benign in ALPL (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0774); Common (popmax 16.4%, sas) — too common for a highly-penetrant pathogenic allele; Associated with childhood hypophosphatasia.

What condition is associated with ALPL p.Val522Ala (c.1565T>C)?

ALPL p.Val522Ala (c.1565T>C) is associated with childhood hypophosphatasia, hypophosphatasia, adult hypophosphatasia (ClinVar).

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.Val522Ala (c.1565T>C)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

ALPL p.Val522Ala

Q: How common is ALPL p.Val522Ala (c.1565T>C) in the general population?

ALPL p.Val522Ala (c.1565T>C) is common (popmax 16.4%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1565T>C · rs34605986 · VCV193996

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 16.4%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

childhood hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -5.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.31	GERP -3.2
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	7.839	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 16.4% South Asian · 14,861/90,698 alleles

Filtering AF 16.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 16.1%

Overall 10.7% 170,290/1,597,356 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	16.4%	6
Amishnot grpmax-eligible	14.6%	7
European (non-Finnish)	11.5%	9
Remaining individualsnot grpmax-eligible	10.1%	10
Ashkenazi Jewishnot grpmax-eligible	9.63%	10
Middle Eastern	7.89%	13
Admixed American	7.41%	13
Finnishnot grpmax-eligible	6%	17
African / African-American	3.51%	29
East Asian	0.181%	552

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.Val522Ala
Coding: c.1565T>C
MANE Select: NM_000478
dbSNP: rs34605986
Type: single nucleotide variant
Location: chr1:21577638 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 522: a UniProt-annotated variant site (in)

Full ALPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

childhood hypophosphatasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypophosphatasia adult hypophosphatasia infantile hypophosphatasia

For Hypophosphatasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ALPL p.Val522Ile 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
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-val522ala (accessed [today's date]).

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