Is ALPL p.Gly425= (c.1275C>T) pathogenic?

ALPL p.Gly425= (c.1275C>T) is classified Conflicting classifications of pathogenicity in ALPL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-06). Very rare (popmax 0.00576%, nfe); Associated with adult hypophosphatasia.

What condition is associated with ALPL p.Gly425= (c.1275C>T)?

ALPL p.Gly425= (c.1275C>T) is associated with adult hypophosphatasia, childhood hypophosphatasia, infantile hypophosphatasia (ClinVar).

How common is ALPL p.Gly425= (c.1275C>T) in the general population?

ALPL p.Gly425= (c.1275C>T) is very rare (popmax 0.00576%, nfe) (gnomAD).

ALPL p.Gly425=

c.1275C>T · rs748883680 · VCV1082268

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00576%, nfe)

Conditions

adult 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 -8.2	GERP -3.6
Overall
CADD	4.174	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00576% European (non-Finnish) · 68/1,179,896 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00423%

Overall 0.00483% 78/1,613,746 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00576%	17,351
African / African-American	0.00534%	18,715
South Asian	0.00439%	22,766
Admixed American	0.00333%	29,992

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.Gly425=
Coding: c.1275C>T
MANE Select: NM_000478
dbSNP: rs748883680
Type: single nucleotide variant
Location: chr1:21576607 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 425: a β-strand

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

Disease context

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

Also linked: childhood hypophosphatasia infantile hypophosphatasia

Similar variants

ALPL p.Gly425Asp Uncertain significance ★★ ⚠ same residue
ALPL c.1190-2A>T Pathogenic ★★ same condition
ALPL c.298-1G>A Pathogenic ★★ same condition
ALPL c.62-1G>C Pathogenic/Likely pathogenic ★★ same condition
ALPL c.648+1G>A Pathogenic ★★ same condition
ALPL c.648+1G>T Pathogenic ★★ same condition
ALPL c.649-1G>A Pathogenic/Likely pathogenic ★★ same condition
ALPL c.862+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-gly425 (accessed [today's date]).

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