# NM_000478.6(ALPL):c.212G>C (p.Arg71Pro)

https://sugi.bio/variant/alpl-p-arg71pro

## Summary

**ALPL p.Arg71Pro (c.212G>C)** is classified **Pathogenic/Likely pathogenic** in ALPL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-09-02). AlphaMissense: likely pathogenic (0.9984); Very rare (popmax 0.00263%, nfe); Associated with hypophosphatasia.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs121918003 · 6 submitters · 3 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00263%, nfe)

## For patients & families {#patients}

This is a change in the ALPL gene that is considered likely disease-causing, submitted by 6 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.Arg71Pro |
| Coding change (HGVS c.) | c.212G>C |
| MANE Select transcript | [NM_000478](https://www.ncbi.nlm.nih.gov/nuccore/NM_000478) |
| dbSNP | [rs121918003](https://www.ncbi.nlm.nih.gov/snp/rs121918003/) |
| Variant type | single nucleotide variant |
| Location | chr1:21561127-21561127 (GRCh38) |
| ClinVar | [VCV13665](https://www.ncbi.nlm.nih.gov/clinvar/variation/13665/) |

**All HGVS expressions:** `NC_000001.10:g.21887620G>C`, `NC_000001.11:g.21561127G>C`, `NG_008940.1:g.56763G>C`, `NM_000478.6:c.212G>C`, `NM_001127501.4:c.47G>C`, `NM_001177520.3:c.66+382G>C`, `NM_001369803.2:c.212G>C`, `NM_001369804.2:c.212G>C`, `NM_001369805.2:c.212G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9984) — concordant with the pathogenic call
- REVEL 0.992 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.454 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.804, GERP 1.77, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in ALPL (of 3,100 modeled).
- CADD: **PHRED 34.0**. 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.*
- 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.26 acceptor 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 **0.00263%** (nfe) · FAF95 0.00188% · FAF99 0.00164% · 31/1,179,558 in the highest group · 31/1,460,496 alleles overall — very rare (popmax 0.00263%, nfe).

*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 **71** lies in an α-helix; a UniProt-annotated variant site (in hops; abolished alkaline phosphatase activity); a UniProt-annotated variant site (in hops; loss of alkaline phosphatase activity); a UniProt-annotated variant site (in hppc; severe allele).

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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-02.

**Submitter consensus:** conflicting (4 Likely pathogenic, 2 Pathogenic).

**Submission history:** 6 submissions (1992–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1992-10-15 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-12-12 |
| Genomenon, Inc, Genomenon, Inc | Pathogenic | criteria provided, single submitter | curation | 2025-08-29 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-10-10 |
| Laboratory of Genetics, Children's Clinical University Hospital Latvia | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-02-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-09-02 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **71** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [ALPL p.Arg71His](/variant/alpl-p-arg71his), [ALPL p.Arg71Cys](/variant/alpl-p-arg71cys), [ALPL p.Arg71Ser](/variant/alpl-p-arg71ser), [ALPL p.Arg71Gly](/variant/alpl-p-arg71gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ALPL variant pages (same residue, condition, or type): [ALPL p.Arg71Cys](/variant/alpl-p-arg71cys), [ALPL p.Arg71Gly](/variant/alpl-p-arg71gly), [ALPL p.Arg71His](/variant/alpl-p-arg71his), [ALPL p.Arg71Ser](/variant/alpl-p-arg71ser), [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).

### 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 13665). 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.*