Is ALPL p.Asp156Tyr (c.466G>T) pathogenic?

ALPL p.Asp156Tyr (c.466G>T) is classified Uncertain significance in ALPL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-09-01). AlphaMissense: likely benign (0.1908); Very rare (popmax 0.00144%, nfe); Associated with hypophosphatasia.

What condition is associated with ALPL p.Asp156Tyr (c.466G>T)?

ALPL p.Asp156Tyr (c.466G>T) is associated with hypophosphatasia (ClinVar).

How common is ALPL p.Asp156Tyr (c.466G>T) in the general population?

ALPL p.Asp156Tyr (c.466G>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

How is Hypophosphatasia inherited?

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

What do computational predictors say about ALPL p.Asp156Tyr (c.466G>T)?

AlphaMissense predicts likely benign (score 0.1908) — an in-silico prediction, not a clinical call.

ALPL p.Asp156Tyr

c.466G>T · rs1397418141 · VCV2664471

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1908 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.1908	likely benign
REVEL	0.749	pathogenic-leaning
SaProt	LLR -12.87	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.39	donor gain · deltas
Constraint at this position
Conservation	phyloP 5.2	GERP -3.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,176,538 alleles

Filtering AF 0.00088% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00072%

Overall 0.00117% 17/1,458,884 alleles · very rare

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.Asp156Tyr
Coding: c.466G>T
MANE Select: NM_000478
dbSNP: rs1397418141
Type: single nucleotide variant
Location: chr1:21563278 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 156: a turn; a disulfide bond

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.Asp156= Likely benign ★★ same residue
ALPL p.Asp156Asn Uncertain significance ★ ⚠ same residue
ALPL p.Asp156Gly 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

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-asp156tyr (accessed [today's date]).

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