Is ALPL p.Phe328del (c.978CTT[2]) pathogenic?

ALPL p.Phe328del (c.978CTT[2]) is classified Pathogenic/Likely pathogenic in ALPL (ClinVar, Multiple submitters, 14 submitters; last evaluated 2025-11-26). Ultra-rare (popmax 0.0111%, eas); Associated with hypophosphatasia.

What condition is associated with ALPL p.Phe328del (c.978CTT[2])?

ALPL p.Phe328del (c.978CTT[2]) is associated with hypophosphatasia, osteogenesis imperfecta, ALPL-related autosomal recessive hypophosphatasia (ClinVar).

How common is ALPL p.Phe328del (c.978CTT[2]) in the general population?

ALPL p.Phe328del (c.978CTT[2]) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

How is Hypophosphatasia inherited?

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

ALPL p.Phe328del

c.978CTT[2] · rs753338851 · VCV654922

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

hypophosphatasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Overall
CADD	19.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,898 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00291% 47/1,614,076 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,980
South Asian	0.00329%	30,359
European (non-Finnish)	0.00322%	31,054
African / African-American	0.00133%	74,932

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.Phe328del
Coding: c.978CTT[2]
MANE Select: NM_000478
dbSNP: rs753338851
Type: Microsatellite
Location: chr1:21573780 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 328: a β-strand

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: osteogenesis imperfecta ALPL-related autosomal recessive hypophosphatasia adult hypophosphatasia childhood hypophosphatasia infantile hypophosphatasia

For Hypophosphatasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ALPL c.69_74del Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Ala498fs Likely pathogenic ★★ same condition
ALPL p.His79fs Likely pathogenic ★★ same condition
ALPL p.Leu372fs Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Ser310fs Pathogenic ★★ same condition
ALPL p.Ser364fs Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Ser368del Pathogenic ★★ same condition
ALPL p.Ser394fs 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-phe328del (accessed [today's date]).

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