# NM_000478.6(ALPL):c.649_650insC (p.Val217fs)

https://sugi.bio/variant/alpl-p-val217fs

## Summary

**ALPL p.Val217fs (c.649_650insC)** is classified **Pathogenic** in ALPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-29). Very rare (popmax 0.00223%, eas); Associated with hypophosphatasia.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs781213038 · 2 submitters · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the ALPL gene that is 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.Val217fs |
| Coding change (HGVS c.) | c.649_650insC |
| MANE Select transcript | [NM_000478](https://www.ncbi.nlm.nih.gov/nuccore/NM_000478) |
| dbSNP | [rs781213038](https://www.ncbi.nlm.nih.gov/snp/rs781213038/) |
| Variant type | Insertion |
| Location | chr1:21568104-21568105 (GRCh38) |
| ClinVar | [VCV2671819](https://www.ncbi.nlm.nih.gov/clinvar/variation/2671819/) |

**All HGVS expressions:** `NC_000001.10:g.21894597_21894598insC`, `NC_000001.11:g.21568104_21568105insC`, `NG_008940.1:g.63740_63741insC`, `NG_008940.2:g.64122_64123insC`, `NM_000478.6:c.649_650insC`, `NM_001127501.4:c.484_485insC`, `NM_001177520.3:c.418_419insC`, `NM_001369803.2:c.649_650insC`, `NM_001369804.2:c.649_650insC`, `NM_001369805.2:c.649_650insC`

## 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 11.909, GERP 1.47, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — 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 7 of 12**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 39.0**. 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** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,858 in the highest group · 1/152,248 alleles overall — very rare (popmax 0.00223%, eas).

*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 **217** lies in a β-strand.

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 (2/2 Pathogenic).

**Submission history:** 2 submissions (2023–2025); 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 | 2023-12-05 |
| Genomenon, Inc, Genomenon, Inc | Pathogenic | criteria provided, single submitter | curation | 2025-08-29 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hypophosphatasia, Phosphoethanol-aminuria.

## Same-residue context {#hotspot}

Residue **217** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [ALPL p.Val217delinsAlaMet](/variant/alpl-p-val217delinsalamet), [ALPL p.Val217delinsAlaLys](/variant/alpl-p-val217delinsalalys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ALPL variant pages (same residue, condition, or type): [ALPL p.Val217delinsAlaLys](/variant/alpl-p-val217delinsalalys), [ALPL p.Val217Ala](/variant/alpl-p-val217ala), [ALPL p.Val217delinsAlaMet](/variant/alpl-p-val217delinsalamet), [ALPL p.Asn190Ter](/variant/alpl-p-asn190ter), [ALPL p.Leu512fs](/variant/alpl-p-leu512fs), [ALPL p.Met226fs](/variant/alpl-p-met226fs), [ALPL p.Tyr101fs](/variant/alpl-p-tyr101fs), [ALPL p.Ala485fs](/variant/alpl-p-ala485fs).

### 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 2671819). 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.*