Is ALPL p.Arg152His (c.455G>A) pathogenic?

ALPL p.Arg152His (c.455G>A) is classified Benign/Likely benign in ALPL (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.0969); Low-frequency (popmax 3.03%, sas); Associated with adult hypophosphatasia.

What condition is associated with ALPL p.Arg152His (c.455G>A)?

ALPL p.Arg152His (c.455G>A) is associated with adult hypophosphatasia, hypophosphatasia, osteogenesis imperfecta (ClinVar).

How common is ALPL p.Arg152His (c.455G>A) in the general population?

ALPL p.Arg152His (c.455G>A) is low-frequency (popmax 3.03%, sas) (gnomAD).

What do computational predictors say about ALPL p.Arg152His (c.455G>A)?

AlphaMissense predicts likely benign (score 0.0969) — an in-silico prediction, not a clinical call.

ALPL p.Arg152His

c.455G>A · rs149344982 · VCV197679

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

AlphaMissense

likely benign

0.0969 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.03%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adult hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.0969	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -2.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	18.24	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 3.03% South Asian · 2,753/90,988 alleles

Filtering AF 2.93% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.89%

Overall 1.28% 20,661/1,612,314 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	3.03%	33
Middle Eastern	2.37%	42
Remaining individualsnot grpmax-eligible	1.5%	66
European (non-Finnish)	1.32%	76
Ashkenazi Jewishnot grpmax-eligible	0.779%	128
Finnishnot grpmax-eligible	0.756%	132
Admixed American	0.692%	144
African / African-American	0.239%	419
Amishnot grpmax-eligible	0.11%	908
East Asian	0.0201%	4,985

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.Arg152His
Coding: c.455G>A
MANE Select: NM_000478
dbSNP: rs149344982
Type: single nucleotide variant
Location: chr1:21563267 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 152: an α-helix; a disulfide bond; a UniProt-annotated variant site (in hops; uncertain significance); a UniProt-annotated variant site (in hops; benign; lethal form)

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

Disease context

adult hypophosphatasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypophosphatasia osteogenesis imperfecta childhood hypophosphatasia infantile hypophosphatasia

Similar variants

ALPL p.Arg152= Conflicting classifications of pathogenicity ★ same residue
ALPL p.Arg152Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ALPL p.Arg152Ser 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-arg152his (accessed [today's date]).

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