Is ALPL p.Phe94= (c.282C>T) pathogenic?

ALPL p.Phe94= (c.282C>T) is classified Likely benign in ALPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-24). Very rare (popmax 0.00665%, sas); Associated with adult hypophosphatasia.

What condition is associated with ALPL p.Phe94= (c.282C>T)?

ALPL p.Phe94= (c.282C>T) is associated with adult hypophosphatasia, childhood hypophosphatasia, infantile hypophosphatasia (ClinVar).

How common is ALPL p.Phe94= (c.282C>T) in the general population?

ALPL p.Phe94= (c.282C>T) is very rare (popmax 0.00665%, sas) (gnomAD).

ALPL p.Phe94=

c.282C>T · rs746608270 · VCV1152675

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00665%, sas)

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 -5.9	GERP -3.3
Overall
CADD	8.542	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00665% South Asian · 6/90,282 alleles

Filtering AF 0.00288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00197%

Overall 0.00118% 19/1,610,756 alleles · very rare exomes 15/1,458,620 · genomes 4/152,136 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00665%	15,047
Admixed American	0.00168%	59,686
European (non-Finnish)	0.00102%	98,219

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.Phe94=
Coding: c.282C>T
MANE Select: NM_000478
dbSNP: rs746608270
Type: single nucleotide variant
Location: chr1:21561197 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 94: 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.Phe94Ser 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-phe94 (accessed [today's date]).

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