Is ALPL p.Ser368del (c.1098CTC[1]) pathogenic?

ALPL p.Ser368del (c.1098CTC[1]) is classified Pathogenic in ALPL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-09-01). Very rare (popmax 0.00446%, eas); Associated with hypophosphatasia.

What condition is associated with ALPL p.Ser368del (c.1098CTC[1])?

ALPL p.Ser368del (c.1098CTC[1]) is associated with hypophosphatasia, adult hypophosphatasia, infantile hypophosphatasia (ClinVar).

How common is ALPL p.Ser368del (c.1098CTC[1]) in the general population?

ALPL p.Ser368del (c.1098CTC[1]) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Hypophosphatasia inherited?

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

ALPL p.Ser368del

c.1098CTC[1] · rs1558557341 · VCV545020

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, 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 11	GERP 1.6, phastCons 1

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,836 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000342% 5/1,461,892 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,418
European (non-Finnish)	0.000254%	393,309

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.Ser368del
Coding: c.1098CTC[1]
MANE Select: NM_000478
dbSNP: rs1558557341
Type: Microsatellite
Location: chr1:21575832 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 368: a turn

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: adult hypophosphatasia infantile hypophosphatasia

For Hypophosphatasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ALPL p.Ser368Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
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.Phe328del Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Ser310fs Pathogenic ★★ same condition
ALPL p.Ser364fs 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-ser368del (accessed [today's date]).

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