# NM_017813.5(BPNT2):c.563A>G (p.Lys188Arg)

https://sugi.bio/variant/bpnt2-p-lys188arg

## Summary

**BPNT2 p.Lys188Arg (c.563A>G)** is classified **Uncertain significance** in BPNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.1009); Very rare (popmax 0.00879%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00879%, sas)

## For patients & families {#patients}

This is a change in the BPNT2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BPNT2](https://sugi.bio/atlas/gene/BPNT2/) |
| Protein change (HGVS p.) | p.Lys188Arg |
| Coding change (HGVS c.) | c.563A>G |
| MANE Select transcript | [NM_017813](https://www.ncbi.nlm.nih.gov/nuccore/NM_017813) |
| Variant type | single nucleotide variant |
| Location | chr8:56978133-56978133 (GRCh38) |
| ClinVar | [VCV4214973](https://www.ncbi.nlm.nih.gov/clinvar/variation/4214973/) |

**All HGVS expressions:** `NC_000008.10:g.57890692T>C`, `NC_000008.11:g.56978133T>C`, `NG_031926.1:g.20739A>G`, `NM_017813.5:c.563A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1009)
- REVEL 0.395 (indeterminate)
- SaProt LLR -5.323 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor gain** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 6.169, GERP 1.75, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.7**. 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 0.97** across the covering region of the MANE Select transcript (56,963,796–56,993,585), spanning 29,789 bp. Chi-square p 0.51. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.05**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.21**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.21**.
- Population frequency (gnomAD v4.1): grpmax **0.00879%** (sas) · FAF95 0.00437% · FAF99 0.00312% · 8/90,964 in the highest group · 9/1,456,128 alleles overall — very rare (popmax 0.00879%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00879% | 11,370 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,312 |

*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}

**BPNT2** population constraint: LOEUF 0.619, pLI 0.78838, missense-Z -0.43186; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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):

- **chondrodysplasia with joint dislocations, gPAPP type** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.55, 70% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of BPNT2 (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.*


### Pathways affected {#pathways}

BPNT2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cytosolic sulfonation of small molecules](https://reactome.org/content/detail/R-HSA-156584) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-01.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-01 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related BPNT2 variant pages (same residue, condition, or type): [BPNT2 p.Arg187Ter](/variant/bpnt2-p-arg187ter), [BPNT2 c.-155C>G](/variant/bpnt2-c-minus-155c-g), [BPNT2 c.*4264G>A](/variant/bpnt2-c-star-4264g-a), [BPNT2 c.*5193A>G](/variant/bpnt2-c-star-5193a-g), [BPNT2 p.Ala218Ser](/variant/bpnt2-p-ala218ser), [BPNT2 p.Arg187Gln](/variant/bpnt2-p-arg187gln), [BPNT2 p.Arg243Cys](/variant/bpnt2-p-arg243cys), [BPNT2 p.Arg243His](/variant/bpnt2-p-arg243his).

### 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 4214973). 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.*