# NM_000478.6(ALPL):c.455G>A (p.Arg152His)

https://sugi.bio/variant/alpl-p-arg152his

## Summary

**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.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs149344982 · 22 submitters · 5 linked conditions · AlphaMissense likely benign · low-frequency (popmax 3.03%, sas)

## For patients & families {#patients}

This is a change in the ALPL gene that is classified as benign/likely benign — not considered disease-causing, submitted by 22 submitters, and is linked to adult hypophosphatasia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0028131/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALPL](https://sugi.bio/atlas/gene/ALPL/) |
| Protein change (HGVS p.) | p.Arg152His |
| Coding change (HGVS c.) | c.455G>A |
| MANE Select transcript | [NM_000478](https://www.ncbi.nlm.nih.gov/nuccore/NM_000478) |
| dbSNP | [rs149344982](https://www.ncbi.nlm.nih.gov/snp/rs149344982/) |
| Variant type | single nucleotide variant |
| Location | chr1:21563267-21563267 (GRCh38) |
| ClinVar | [VCV197679](https://www.ncbi.nlm.nih.gov/clinvar/variation/197679/) |

**All HGVS expressions:** `NC_000001.10:g.21889760G>A`, `NC_000001.11:g.21563267G>A`, `NG_008940.1:g.58903G>A`, `NM_000478.6:c.455G>A`, `NM_001127501.4:c.290G>A`, `NM_001177520.3:c.224G>A`, `NM_001369803.2:c.455G>A`, `NM_001369804.2:c.455G>A`, `NM_001369805.2:c.455G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0969)
- REVEL 0.262 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.219 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.243, GERP -2.94, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.24**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.83** across the covering region of the MANE Select transcript (21,554,082–21,577,645), spanning 23,563 bp. Chi-square p 6.1e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **3.03%** (sas) · FAF95 2.93% · FAF99 2.89% · 2,753/90,988 in the highest group · 20,661/1,612,314 alleles overall — low-frequency (popmax 3.03%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 3.03% | 33 |
| Middle Eastern | 2.37% | 42 |
| Remaining individuals (not grpmax-eligible) | 1.5% | 66 |
| European (non-Finnish) | 1.32% | 76 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.779% | 128 |
| Finnish (not grpmax-eligible) | 0.756% | 132 |
| Admixed American | 0.692% | 144 |
| African / African-American | 0.239% | 419 |
| Amish (not grpmax-eligible) | 0.11% | 908 |
| East Asian | 0.0201% | 4,985 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ALPL** population constraint: LOEUF 0.987, pLI 1.7059e-11, missense-Z 1.9112. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **ALPL-related autosomal dominant hypophosphatasia** — Definitive (AD)
- **ALPL-related autosomal recessive hypophosphatasia** — Definitive (AR)

## Protein context {#protein}

Residue **152** lies in 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).

AlphaFold model confidence (whole protein): pLDDT 93.74, 91% of residues very-high.

**5 experimental structure(s)** (PDB): [7YIV](https://www.rcsb.org/structure/7YIV), [7YIW](https://www.rcsb.org/structure/7YIW), [7YIX](https://www.rcsb.org/structure/7YIX), [9SH5](https://www.rcsb.org/structure/9SH5), [9S0V](https://www.rcsb.org/structure/9S0V).

## What this gene does {#gene-function}

*Describes the biological roles of ALPL (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ALPL's established molecular role includes alkaline phosphatase activity.


### Pathways affected {#pathways}

ALPL participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Post-translational modification: synthesis of GPI-anchored proteins](https://reactome.org/content/detail/R-HSA-163125) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** alkaline phosphatase activity, calcium ion binding, pyrophosphatase activity, pyridoxal phosphatase activity, phosphoethanolamine phosphatase activity.

**Biological process:** osteoblast differentiation, response to vitamin D, calcium ion homeostasis.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-01.

**Submitter consensus:** conflicting (19 Benign, 4 Likely benign, 1 not provided).

**Submission history:** 24 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Benign | criteria provided, single submitter | clinical testing | 2014-12-09 |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing |  |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2016-03-28 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2017-07-14 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-03-06 |
| GeneReviews | not provided | no classification provided | literature only |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2015-03-12 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-03-07 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2020-09-16 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-10-19 |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Benign | criteria provided, single submitter | clinical testing | 2021-12-18 |
| Fulgent Genetics, Fulgent Genetics | Benign | criteria provided, single submitter | clinical testing | 2021-07-07 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| JKU Lab, Dept of Paediatrics, Johannes Kepler University | Benign | criteria provided, single submitter | clinical testing | 2025-02-27 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-01 |
| Genomenon, Inc, Genomenon, Inc | Benign | criteria provided, single submitter | curation | 2025-08-29 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2023-01-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2026-03-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

## Associated conditions {#conditions}

[adult hypophosphatasia](https://sugi.bio/atlas/disease/adult-hypophosphatasia/), [hypophosphatasia](https://sugi.bio/atlas/disease/hypophosphatasia/), [osteogenesis imperfecta](https://sugi.bio/atlas/disease/osteogenesis-imperfecta/), [childhood hypophosphatasia](https://sugi.bio/atlas/disease/childhood-hypophosphatasia/), [infantile hypophosphatasia](https://sugi.bio/atlas/disease/infantile-hypophosphatasia/).

**Reported phenotype names (ClinVar):** Adult hypophosphatasia, not specified, Hypophosphatasia, not provided, Infantile hypophosphatasia, Childhood hypophosphatasia, Osteogenesis imperfecta, AllHighlyPenetrant, none provided, Phosphoethanol-aminuria.

## Similar variants {#similar}

Related ALPL variant pages (same residue, condition, or type): [ALPL p.Arg152=](/variant/alpl-p-arg152), [ALPL p.Arg152Cys](/variant/alpl-p-arg152cys), [ALPL p.Arg152Ser](/variant/alpl-p-arg152ser), [ALPL c.1190-2A>T](/variant/alpl-c-1190-minus-2a-t), [ALPL c.182-1G>A](/variant/alpl-c-182-minus-1g-a), [ALPL c.182-2A>G](/variant/alpl-c-182-minus-2a-g), [ALPL c.297+1G>A](/variant/alpl-c-297-plus-1g-a), [ALPL c.298-1G>A](/variant/alpl-c-298-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 197679). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*