Is ALPL p.Pro280Thr (c.838C>A) pathogenic?

ALPL p.Pro280Thr (c.838C>A) is classified Uncertain significance in ALPL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-20). AlphaMissense: likely benign (0.0937); Very rare (popmax 0.00153%, nfe); Associated with childhood hypophosphatasia.

What condition is associated with ALPL p.Pro280Thr (c.838C>A)?

ALPL p.Pro280Thr (c.838C>A) is associated with childhood hypophosphatasia, adult hypophosphatasia, infantile hypophosphatasia (ClinVar).

How common is ALPL p.Pro280Thr (c.838C>A) in the general population?

ALPL p.Pro280Thr (c.838C>A) is very rare (popmax 0.00153%, 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.Pro280Thr (c.838C>A)?

AlphaMissense predicts likely benign (score 0.0937) — an in-silico prediction, not a clinical call.

ALPL p.Pro280Thr

c.838C>A · VCV3580091

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

childhood hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.0937	likely benign
REVEL	0.439	indeterminate
SaProt	LLR -10.40	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	19.51	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 0.00153% European (non-Finnish) · 18/1,180,040 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00118% 19/1,614,016 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00153%	65,558
African / African-American	0.00133%	74,910

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.Pro280Thr
Coding: c.838C>A
MANE Select: NM_000478
Type: single nucleotide variant
Location: chr1:21570350 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 280: an α-helix

Full ALPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

childhood 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 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
ALPL c.997+1G>T 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-pro280thr (accessed [today's date]).

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