# NM_000478.6(ALPL):c.393C>T (p.Ser131=)

https://sugi.bio/variant/alpl-p-ser131

## Summary

**ALPL p.Ser131= (c.393C>T)** is classified **Likely benign** in ALPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-02). Ultra-rare (popmax 0.0165%, mid); Associated with adult hypophosphatasia.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs2148158625 · 2 submitters · 3 linked conditions · ultra-rare (popmax 0.0165%, mid)

## 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 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.Ser131= |
| Coding change (HGVS c.) | c.393C>T |
| MANE Select transcript | [NM_000478](https://www.ncbi.nlm.nih.gov/nuccore/NM_000478) |
| dbSNP | [rs2148158625](https://www.ncbi.nlm.nih.gov/snp/rs2148158625/) |
| Variant type | single nucleotide variant |
| Location | chr1:21563205-21563205 (GRCh38) |
| ClinVar | [VCV1113340](https://www.ncbi.nlm.nih.gov/clinvar/variation/1113340/) |

**All HGVS expressions:** `NC_000001.10:g.21889698C>T`, `NC_000001.11:g.21563205C>T`, `NG_008940.1:g.58841C>T`, `NM_000478.6:c.393C>T`, `NM_001127501.4:c.228C>T`, `NM_001177520.3:c.162C>T`, `NM_001369803.2:c.393C>T`, `NM_001369804.2:c.393C>T`, `NM_001369805.2:c.393C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.52) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -9.061, GERP -3.86 — fast-evolving / accelerated position
- CADD: **PHRED 17.25**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.52**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.52**.
- Pangolin: Δ**0.26** (gain), gain 0.26 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · 1/6,062 in the highest group · 4/1,613,946 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| East Asian | 0.00223% | 44,878 |
| South Asian | 0.0011% | 91,080 |
| European (non-Finnish) | 8.47e-05% | 1,180,022 |

*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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-12-02.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2021–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-12-02 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-03 |

## Associated conditions {#conditions}

[adult hypophosphatasia](https://sugi.bio/atlas/disease/adult-hypophosphatasia/), [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 provided, Childhood hypophosphatasia, Infantile hypophosphatasia, none provided.

## Same-residue context {#hotspot}

Residue **131** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ALPL p.Ser131fs](/variant/alpl-p-ser131fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ALPL variant pages (same residue, condition, or type): [ALPL p.Ser131fs](/variant/alpl-p-ser131fs), [ALPL p.Ser131Arg](/variant/alpl-p-ser131arg), [ALPL c.1190-2A>T](/variant/alpl-c-1190-minus-2a-t), [ALPL c.298-1G>A](/variant/alpl-c-298-minus-1g-a), [ALPL c.62-1G>C](/variant/alpl-c-62-minus-1g-c), [ALPL c.648+1G>A](/variant/alpl-c-648-plus-1g-a), [ALPL c.648+1G>T](/variant/alpl-c-648-plus-1g-t), [ALPL c.649-1G>A](/variant/alpl-c-649-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 1113340). 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.*