Is ALPL p.Ala176= (c.528C>T) pathogenic?

ALPL p.Ala176= (c.528C>T) is classified Likely benign in ALPL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-26). Very rare (popmax 0.00347%, nfe); Associated with childhood hypophosphatasia.

What condition is associated with ALPL p.Ala176= (c.528C>T)?

ALPL p.Ala176= (c.528C>T) is associated with childhood hypophosphatasia, hypophosphatasia, adult hypophosphatasia (ClinVar).

How common is ALPL p.Ala176= (c.528C>T) in the general population?

ALPL p.Ala176= (c.528C>T) is very rare (popmax 0.00347%, nfe) (gnomAD).

How is Hypophosphatasia inherited?

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

ALPL p.Ala176=

c.528C>T · rs758330265 · VCV755336

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Conditions

childhood hypophosphatasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.9
Overall
CADD	1.189	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00347% European (non-Finnish) · 41/1,180,018 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00291% 47/1,613,966 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00347%	28,781
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Remaining individualsnot grpmax-eligible	0.0032%	31,241
African / African-American	0.00267%	37,466
Admixed American	0.00167%	60,000

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.Ala176=
Coding: c.528C>T
MANE Select: NM_000478
dbSNP: rs758330265
Type: single nucleotide variant
Location: chr1:21564096 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 176: a turn; a disulfide bond; a UniProt-annotated variant site (in hops; 30% of alkaline phosphatase activity)

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.Ala176Thr Pathogenic/Likely pathogenic ★★ same residue
ALPL p.Ala176Val Likely pathogenic ★★ 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-ala176 (accessed [today's date]).

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