Is ALPL p.Arg272Cys (c.814C>T) pathogenic?

ALPL p.Arg272Cys (c.814C>T) is classified Pathogenic in ALPL (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-09-03). AlphaMissense: likely pathogenic (0.6078); Very rare (popmax 0.00381%, nfe); Associated with ALPL-related disorder.

What condition is associated with ALPL p.Arg272Cys (c.814C>T)?

ALPL p.Arg272Cys (c.814C>T) is associated with ALPL-related disorder, hypophosphatasia, adult hypophosphatasia (ClinVar).

How common is ALPL p.Arg272Cys (c.814C>T) in the general population?

ALPL p.Arg272Cys (c.814C>T) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about ALPL p.Arg272Cys (c.814C>T)?

AlphaMissense predicts likely pathogenic (score 0.6078) — an in-silico prediction, not a clinical call.

ALPL p.Arg272Cys

c.814C>T · rs121918020 · VCV13684

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.6078 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALPL-related disorder

Computational evidence

Protein change
AlphaMissense	0.6078	likely pathogenic ✓ concordant with ClinVar
REVEL	0.923	moderately pathogenic-leaning
SaProt	LLR -14.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	32.0	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 0.00381% European (non-Finnish) · 45/1,180,038 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00291% 47/1,614,004 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00381%	26,223
East Asian	0.00223%	44,882
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Arg272Cys
Coding: c.814C>T
MANE Select: NM_000478
dbSNP: rs121918020
Type: single nucleotide variant
Location: chr1:21570326 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 272: an α-helix; a UniProt-annotated variant site (in hops; 6.8% of wild-type activity); a UniProt-annotated variant site (in hops)

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

Disease context

ALPL-related disorder

Also linked: hypophosphatasia adult hypophosphatasia childhood hypophosphatasia infantile hypophosphatasia

Similar variants

ALPL p.Arg272His Pathogenic/Likely pathogenic ★★ ⚠ same residue
ALPL p.Arg272Leu Pathogenic/Likely pathogenic ★★ same residue
ALPL p.Arg272fs Pathogenic/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
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-arg272cys (accessed [today's date]).

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