# NM_199173.6(BGLAP):c.254A>G (p.Asp85Gly)

https://sugi.bio/variant/bglap-p-asp85gly

## Summary

**BGLAP p.Asp85Gly (c.254A>G)** is classified **Uncertain significance** in BGLAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.7162); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BGLAP 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 | [BGLAP](https://sugi.bio/atlas/gene/BGLAP/) |
| Protein change (HGVS p.) | p.Asp85Gly |
| Coding change (HGVS c.) | c.254A>G |
| MANE Select transcript | [NM_199173](https://www.ncbi.nlm.nih.gov/nuccore/NM_199173) |
| Variant type | single nucleotide variant |
| Location | chr1:156243113-156243113 (GRCh38) |
| ClinVar | [VCV4206749](https://www.ncbi.nlm.nih.gov/clinvar/variation/4206749/) |

**All HGVS expressions:** `NC_000001.10:g.156212904A>G`, `NC_000001.11:g.156243113A>G`, `NG_047015.1:g.5954A>G`, `NM_001199661.1:c.*30A>G`, `NM_001199662.1:c.*118A>G`, `NM_001199663.1:c.*30A>G`, `NM_001199664.1:c.*118A>G`, `NM_199173.6:c.254A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.7162)
- REVEL 0.63 (indeterminate)
- SaProt LLR -9.332 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 10.786, GERP 0.66, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.2**. 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 0.89** across the covering region of the MANE Select transcript (156,242,232–156,243,159), spanning 927 bp. Chi-square p 0.22. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 17 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**BGLAP** population constraint: LOEUF 1.795, pLI 1.0032e-06, missense-Z 0.34834. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **85** lies in the gla domain.

AlphaFold model confidence (whole protein): pLDDT 76.66, 39% of residues very-high.

**9 experimental structure(s)** (PDB): [13IB](https://www.rcsb.org/structure/13IB), [8XS1](https://www.rcsb.org/structure/8XS1), [9BUR](https://www.rcsb.org/structure/9BUR), [9BUX](https://www.rcsb.org/structure/9BUX), [9L23](https://www.rcsb.org/structure/9L23), [9MQB](https://www.rcsb.org/structure/9MQB) — incl. mutant structure 9MQB.

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

*Describes the biological roles of BGLAP (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}

BGLAP participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Gamma-carboxylation of protein precursors](https://reactome.org/content/detail/R-HSA-159740) | curated |
| [Removal of aminoterminal propeptides from gamma-carboxylated proteins](https://reactome.org/content/detail/R-HSA-159782) | curated |
| [Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus](https://reactome.org/content/detail/R-HSA-159763) | curated |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** osteoblast differentiation, response to vitamin D.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-04.

**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 | 2025-08-04 |

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

## Similar variants {#similar}

Related BGLAP variant pages (same residue, condition, or type): [BGLAP p.Ala23Val](/variant/bglap-p-ala23val), [BGLAP p.Arg94Trp](/variant/bglap-p-arg94trp), [BGLAP p.Asp81Glu](/variant/bglap-p-asp81glu), [BGLAP p.Gly27Ser](/variant/bglap-p-gly27ser), [BGLAP p.Gly88Ser](/variant/bglap-p-gly88ser), [BGLAP p.Gly98Ser](/variant/bglap-p-gly98ser), [BGLAP p.Ile87Met](/variant/bglap-p-ile87met), [BGLAP p.Leu15Phe](/variant/bglap-p-leu15phe).

### 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 4206749). 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.*