# NM_000478.6(ALPL):c.963G>A (p.Arg321=)

https://sugi.bio/variant/alpl-p-arg321

## Summary

**ALPL p.Arg321= (c.963G>A)** is classified **Likely benign** in ALPL (ClinVar, Single submitter, 2 submitters; last evaluated 2023-10-12). Very rare (popmax 0.0011%, sas); Associated with hypophosphatasia.

**At a glance:** Likely benign · review: Single submitter · rsID rs757111696 · 2 submitters · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the ALPL gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Clinical trials | 43 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ALPL is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Hypophosphatasia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the dentition — Very frequent (99-80%)
- Large fontanelles — Very frequent (99-80%)
- Abnormal rib morphology — Very frequent (99-80%)
- Narrow chest — Very frequent (99-80%)
- Abnormal metaphysis morphology — Very frequent (99-80%)
- Skin dimple over apex of long bone angulation — Very frequent (99-80%)
- Craniosynostosis — Very frequent (99-80%)
- Failure to thrive in infancy — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006734/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.Arg321= |
| Coding change (HGVS c.) | c.963G>A |
| MANE Select transcript | [NM_000478](https://www.ncbi.nlm.nih.gov/nuccore/NM_000478) |
| dbSNP | [rs757111696](https://www.ncbi.nlm.nih.gov/snp/rs757111696/) |
| Variant type | single nucleotide variant |
| Location | chr1:21573765-21573765 (GRCh38) |
| ClinVar | [VCV991460](https://www.ncbi.nlm.nih.gov/clinvar/variation/991460/) |

**All HGVS expressions:** `NC_000001.10:g.21900258G>A`, `NC_000001.11:g.21573765G>A`, `NG_008940.1:g.69401G>A`, `NM_000478.6:c.963G>A`, `NM_001127501.4:c.798G>A`, `NM_001177520.3:c.732G>A`, `NM_001369803.2:c.963G>A`, `NM_001369804.2:c.963G>A`, `NM_001369805.2:c.963G>A`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.066, GERP -0.716, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.67**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.51 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/91,084 in the highest group · 1/1,461,868 alleles overall — very rare (popmax 0.0011%, sas).

*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}


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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-12.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2020–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-08-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-12 |

## Associated conditions {#conditions}

[hypophosphatasia](https://sugi.bio/atlas/disease/hypophosphatasia/).

**Reported phenotype names (ClinVar):** Hypophosphatasia, not provided, Phosphoethanol-aminuria, none provided.

## Similar variants {#similar}

Related ALPL variant pages (same residue, condition, or type): [ALPL p.Arg321Trp](/variant/alpl-p-arg321trp), [ALPL p.Arg321Gln](/variant/alpl-p-arg321gln), [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), [ALPL c.472+1G>A](/variant/alpl-c-472-plus-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 991460). 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.*