Is ALPL p.Asp216= (c.648C>T) pathogenic?

ALPL p.Asp216= (c.648C>T) is classified Conflicting classifications of pathogenicity in ALPL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-12-03). Very rare (popmax 0.00667%, amr); Associated with hypophosphatasia.

What condition is associated with ALPL p.Asp216= (c.648C>T)?

ALPL p.Asp216= (c.648C>T) is associated with hypophosphatasia (ClinVar).

How common is ALPL p.Asp216= (c.648C>T) in the general population?

ALPL p.Asp216= (c.648C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

How is Hypophosphatasia inherited?

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

ALPL p.Asp216=

c.648C>T · rs201739155 · VCV295545

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

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 -0.81	GERP -3.9, phastCons 0.001
Overall
CADD	3.146	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,996 alleles

Filtering AF 0.00426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.00459% 74/1,613,400 alleles · very rare exomes 67/1,461,254 · genomes 7/152,146 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0064%	15,618
European (non-Finnish)	0.00534%	18,729
African / African-American	0.00267%	37,459
South Asian	0.0011%	91,082

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.Asp216=
Coding: c.648C>T
MANE Select: NM_000478
dbSNP: rs201739155
Type: single nucleotide variant
Location: chr1:21564216 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 216: 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

For Hypophosphatasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ALPL p.Asp216Gly Uncertain significance ★ ⚠ 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
ALPL c.62-1G>C 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-asp216 (accessed [today's date]).

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