# NM_000478.6(ALPL):c.558G>A (p.Trp186Ter)

https://sugi.bio/variant/alpl-p-trp186ter

## Summary

**ALPL p.Trp186Ter (c.558G>A)** is classified **Pathogenic** in ALPL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-29). Very rare (popmax 8.47e-05%, nfe); Associated with hypophosphatasia.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs2148161624 · 3 submitters · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the ALPL gene that is considered disease-causing, submitted by 3 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.Trp186Ter |
| Coding change (HGVS c.) | c.558G>A |
| MANE Select transcript | [NM_000478](https://www.ncbi.nlm.nih.gov/nuccore/NM_000478) |
| dbSNP | [rs2148161624](https://www.ncbi.nlm.nih.gov/snp/rs2148161624/) |
| Variant type | single nucleotide variant |
| Location | chr1:21564126-21564126 (GRCh38) |
| ClinVar | [VCV1073912](https://www.ncbi.nlm.nih.gov/clinvar/variation/1073912/) |

**All HGVS expressions:** `NC_000001.10:g.21890619G>A`, `NC_000001.11:g.21564126G>A`, `NG_008940.1:g.59762G>A`, `NM_000478.6:c.558G>A`, `NM_001127501.4:c.393G>A`, `NM_001177520.3:c.327G>A`, `NM_001369803.2:c.558G>A`, `NM_001369804.2:c.558G>A`, `NM_001369805.2:c.558G>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.82, GERP 0.84, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.987, pLI 1.7059e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 12**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 42.0**. 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: **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 **8.47e-05%** (nfe) · 1/1,180,016 in the highest group · 2/1,461,796 alleles overall — very rare (popmax 8.47e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00156% | 63,974 |
| European (non-Finnish) (grpmax) | 8.47e-05% | 1,180,016 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **186** lies in a disulfide bond.

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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-29.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| JKU Lab, Dept of Paediatrics, Johannes Kepler University | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-13 |
| Genomenon, Inc, Genomenon, Inc | Pathogenic | criteria provided, single submitter | curation | 2025-08-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-09 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **186** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ALPL p.Trp186fs](/variant/alpl-p-trp186fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ALPL variant pages (same residue, condition, or type): [ALPL p.Trp186fs](/variant/alpl-p-trp186fs), [ALPL p.Trp186Arg](/variant/alpl-p-trp186arg), [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 1073912). 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.*