Is ALPL p.Arg450Cys (c.1348C>T) pathogenic?

ALPL p.Arg450Cys (c.1348C>T) is classified Pathogenic/Likely pathogenic in ALPL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-07). AlphaMissense: ambiguous (0.3639); Very rare (popmax 0.00934%, afr); Associated with hypophosphatasia.

What condition is associated with ALPL p.Arg450Cys (c.1348C>T)?

ALPL p.Arg450Cys (c.1348C>T) is associated with hypophosphatasia, adult hypophosphatasia, childhood hypophosphatasia (ClinVar).

How common is ALPL p.Arg450Cys (c.1348C>T) in the general population?

ALPL p.Arg450Cys (c.1348C>T) is very rare (popmax 0.00934%, afr) (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.Arg450Cys (c.1348C>T)?

AlphaMissense predicts ambiguous (score 0.3639) — an in-silico prediction, not a clinical call.

ALPL p.Arg450Cys

c.1348C>T · rs138690664 · VCV971527

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3639 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.3639	ambiguous
REVEL	0.756	pathogenic-leaning
SaProt	LLR -9.75	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.41, 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 0.00934% African / African-American · 7/74,932 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000744% 12/1,613,074 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,705
Admixed American	0.00333%	30,006
European (non-Finnish)	0.000254%	393,328

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.Arg450Cys
Coding: c.1348C>T
MANE Select: NM_000478
dbSNP: rs138690664
Type: single nucleotide variant
Location: chr1:21577421 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 450: a UniProt-annotated variant site (in hops; severe; 4% of activity); a UniProt-annotated variant site (in hops)

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.Arg450His Uncertain significance ★★ ⚠ same residue
ALPL p.Arg450Leu 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

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-arg450cys (accessed [today's date]).

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