Is ALPL p.Pro292Thr (c.874C>A) pathogenic?

ALPL p.Pro292Thr (c.874C>A) is classified Pathogenic/Likely pathogenic in ALPL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.5757); Ultra-rare (popmax 0.0164%, mid); Associated with hypophosphatasia.

What condition is associated with ALPL p.Pro292Thr (c.874C>A)?

ALPL p.Pro292Thr (c.874C>A) is associated with hypophosphatasia, adult hypophosphatasia, childhood hypophosphatasia (ClinVar).

How common is ALPL p.Pro292Thr (c.874C>A) in the general population?

ALPL p.Pro292Thr (c.874C>A) is ultra-rare (popmax 0.0164%, mid) (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.Pro292Thr (c.874C>A)?

AlphaMissense predicts likely pathogenic (score 0.5757) — an in-silico prediction, not a clinical call.

ALPL p.Pro292Thr

c.874C>A · rs765458125 · VCV1323883

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.5757 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.5757	likely pathogenic ✓ concordant with ClinVar
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -9.58	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	26.0	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00062% 10/1,613,754 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.005%	19,981
European (non-Finnish)	0.000508%	196,661

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.Pro292Thr
Coding: c.874C>A
MANE Select: NM_000478
dbSNP: rs765458125
Type: single nucleotide variant
Location: chr1:21573676 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 292: a β-strand; a UniProt-annotated variant site (in hops; 4% of wild-type activity)

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 childhood hypophosphatasia infantile hypophosphatasia

For Hypophosphatasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ALPL p.Pro292Leu Likely pathogenic ★★ same residue
ALPL p.Pro292Ser Pathogenic/Likely pathogenic ★★ same residue
ALPL p.Pro292= Benign ★★ same residue
ALPL p.Pro292_Asp294delinsLeu Likely pathogenic ★ 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

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-pro292thr (accessed [today's date]).

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