# NM_000173.7(GP1BA):c.813C>T (p.Pro271=)

https://sugi.bio/variant/gp1ba-p-pro271

## Summary

**GP1BA p.Pro271= (c.813C>T)** is classified **Likely benign** in GP1BA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-20). Ultra-rare (popmax 0.0164%, mid).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the GP1BA gene that is classified as likely benign — not considered disease-causing, 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 | [GP1BA](https://sugi.bio/atlas/gene/GP1BA/) |
| Protein change (HGVS p.) | p.Pro271= |
| Coding change (HGVS c.) | c.813C>T |
| MANE Select transcript | [NM_000173](https://www.ncbi.nlm.nih.gov/nuccore/NM_000173) |
| Variant type | single nucleotide variant |
| Location | chr17:4933417-4933417 (GRCh38) |
| ClinVar | [VCV4932786](https://www.ncbi.nlm.nih.gov/clinvar/variation/4932786/) |

**All HGVS expressions:** `LRG_480:g.6123C>T`, `LRG_480t1:c.813C>T`, `NC_000017.10:g.4836712C>T`, `NC_000017.11:g.4933417C>T`, `NG_008767.2:g.6123C>T`, `NM_000173.7:c.813C>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 (below), not from a missing predictor score.
- Conservation: phyloP -12.398, GERP -3.39 — fast-evolving / accelerated position
- CADD: **PHRED 0.083**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0164%** (mid) · FAF95 0.00231% · FAF99 0.00202% · 1/6,084 in the highest group · 44/1,613,740 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,084 |
| Admixed American | 0.00333% | 29,999 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,231 |
| European (non-Finnish) | 0.00314% | 31,886 |
| East Asian | 0.00223% | 44,894 |
| South Asian | 0.0011% | 91,090 |

*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}

**GP1BA** population constraint: LOEUF 1.289, pLI 0.099846, missense-Z 1.4512. *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):

- **Bernard-Soulier syndrome** — Definitive (AR)
- **platelet-type von Willebrand disease** — Definitive (AD)

## Protein context {#protein}

Residue **271** lies in the lrrct domain.

AlphaFold model confidence (whole protein): pLDDT 64.65, 38% of residues very-high.

**22 experimental structure(s)** (PDB): [1GWB](https://www.rcsb.org/structure/1GWB), [1M0Z](https://www.rcsb.org/structure/1M0Z), [1M10](https://www.rcsb.org/structure/1M10), [1OOK](https://www.rcsb.org/structure/1OOK), [1P8V](https://www.rcsb.org/structure/1P8V), [1P9A](https://www.rcsb.org/structure/1P9A).

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

*Describes the biological roles of GP1BA (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:** p.Pro271= falls in the lrrct domain. In Reactome, GP1BA is annotated in disease pathway(s) including **Defective F9 activation**, **Defective binding of VWF variant to GPIb:IX:V**.

**Disease mechanism (Reactome):** GP1BA loss or alteration is curated in [Defective F9 activation](https://reactome.org/content/detail/R-HSA-9673221), [Defective binding of VWF variant to GPIb:IX:V](https://reactome.org/content/detail/R-HSA-9846298), [Enhanced binding of GP1BA variant to VWF multimer:collagen ](https://reactome.org/content/detail/R-HSA-9845620).

### Pathways affected {#pathways}

GP1BA participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective F9 activation](https://reactome.org/content/detail/R-HSA-9673221) | curated |
| ⚕ [Defective binding of VWF variant to GPIb:IX:V](https://reactome.org/content/detail/R-HSA-9846298) | curated |
| ⚕ [Enhanced binding of GP1BA variant to VWF multimer:collagen ](https://reactome.org/content/detail/R-HSA-9845620) | curated |
| [Amplification and propagation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769743) | curated |
| [FXIIa, PKa-dependent activation of coagulation pathway](https://reactome.org/content/detail/R-HSA-9935598) | curated |
| [GP1b-IX-V activation signalling](https://reactome.org/content/detail/R-HSA-430116) | curated |
| [Platelet Adhesion to exposed collagen](https://reactome.org/content/detail/R-HSA-75892) | curated |
| [Platelet Aggregation (Plug Formation)](https://reactome.org/content/detail/R-HSA-76009) | curated |
| [RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function](https://reactome.org/content/detail/R-HSA-8936459) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140837) | other |

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

**Biological process:** cell adhesion, blood coagulation, blood coagulation, intrinsic pathway, positive regulation of platelet activation, fibrinolysis, release of sequestered calcium ion into cytosol.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-20.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-20 |

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

## Similar variants {#similar}

Related GP1BA variant pages (same residue, condition, or type): [GP1BA p.Cys225Arg](/variant/gp1ba-p-cys225arg), [GP1BA p.Cys81Arg](/variant/gp1ba-p-cys81arg), [GP1BA p.Gln346Ter](/variant/gp1ba-p-gln346ter), [GP1BA p.Glu347Ter](/variant/gp1ba-p-glu347ter), [GP1BA p.Leu145Pro](/variant/gp1ba-p-leu145pro), [GP1BA p.Ser267Ter](/variant/gp1ba-p-ser267ter), [GP1BA p.Ser486Ter](/variant/gp1ba-p-ser486ter), [GP1BA p.Trp223Gly](/variant/gp1ba-p-trp223gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4932786). 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.*