Is ALPL p.Ala352= (c.1056G>A) pathogenic?

ALPL p.Ala352= (c.1056G>A) is classified Likely benign in ALPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-03). Ultra-rare (popmax 0.0173%, afr); Associated with adult hypophosphatasia.

What condition is associated with ALPL p.Ala352= (c.1056G>A)?

ALPL p.Ala352= (c.1056G>A) is associated with adult hypophosphatasia, childhood hypophosphatasia, infantile hypophosphatasia (ClinVar).

How common is ALPL p.Ala352= (c.1056G>A) in the general population?

ALPL p.Ala352= (c.1056G>A) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

ALPL p.Ala352=

c.1056G>A · rs774824768 · VCV1116252

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Conditions

adult hypophosphatasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -3.2
Overall
CADD	0.055	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0173% African / African-American · 13/74,932 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00155% 25/1,614,124 alleles · ultra-rare exomes 15/1,461,894 · genomes 10/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,764
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0032%	31,244
South Asian	0.0011%	91,084
European (non-Finnish)	0.000678%	147,507

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.Ala352=
Coding: c.1056G>A
MANE Select: NM_000478
dbSNP: rs774824768
Type: single nucleotide variant
Location: chr1:21575791 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 352: an α-helix

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.Ala352Val 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-ala352 (accessed [today's date]).

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