# NM_000174.5(GP9):c.438G>A (p.Pro146=)

https://sugi.bio/variant/gp9-p-pro146

## Summary

**GP9 p.Pro146= (c.438G>A)** is classified **Conflicting classifications of pathogenicity** in GP9 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-09). Ultra-rare (popmax 0.0275%, sas); Associated with Bernard-Soulier syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs767278544 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0275%, sas)

## For patients & families {#patients}

This is a change in the GP9 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Bernard-Soulier syndrome.

*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 |
| Diagnostic panels | GP9 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Bernard-Soulier syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Impaired ristocetin-induced platelet aggregation — Obligate (100%)
- Abnormal bleeding — Very frequent (99-80%)
- Giant platelets — Very frequent (99-80%)
- Decreased platelet glycoprotein Ib-IX-V — Very frequent (99-80%)
- Macrothrombocytopenia — Very frequent (99-80%)
- Menorrhagia — Frequent (79-30%)
- Petechiae — Frequent (79-30%)
- Gastrointestinal hemorrhage — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002470/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GP9](https://sugi.bio/atlas/gene/GP9/) |
| Protein change (HGVS p.) | p.Pro146= |
| Coding change (HGVS c.) | c.438G>A |
| MANE Select transcript | [NM_000174](https://www.ncbi.nlm.nih.gov/nuccore/NM_000174) |
| dbSNP | [rs767278544](https://www.ncbi.nlm.nih.gov/snp/rs767278544/) |
| Variant type | single nucleotide variant |
| Location | chr3:129062177-129062177 (GRCh38) |
| ClinVar | [VCV343221](https://www.ncbi.nlm.nih.gov/clinvar/variation/343221/) |

**All HGVS expressions:** `LRG_477:g.6376G>A`, `NC_000003.11:g.128781020G>A`, `NC_000003.12:g.129062177G>A`, `NG_008715.1:g.6376G>A`, `NM_000174.5:c.438G>A`

## 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 -6.039, GERP -2.5 — fast-evolving / accelerated position
- CADD: **PHRED 0.172**. 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** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0275%** (sas) · FAF95 0.0189% · FAF99 0.016% · 24/87,426 in the highest group · 46/1,575,630 alleles overall — ultra-rare (popmax 0.0275%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0275% | 3,643 |
| African / African-American | 0.00404% | 24,761 |
| Remaining individuals (not grpmax-eligible) | 0.00327% | 30,542 |
| European (non-Finnish) | 0.00146% | 68,542 |

*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}


Curated gene–disease validity (ClinGen):

- **Bernard-Soulier syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.43, 61% of residues very-high.

**2 experimental structure(s)** (PDB): [3REZ](https://www.rcsb.org/structure/3REZ), [8WFS](https://www.rcsb.org/structure/8WFS) — incl. mutant structure 3REZ.

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

*Describes the biological roles of GP9 (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:** GP9 participates in disease-associated pathways. In Reactome, GP9 is annotated in disease pathway(s) including **Defective F9 activation**, **Defective binding of VWF variant to GPIb:IX:V**.

**Disease mechanism (Reactome):** GP9 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}

GP9 participates in **10 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 |
| [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:** blood coagulation, intrinsic pathway, positive regulation of platelet activation, release of sequestered calcium ion into cytosol.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-06-09.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-09 |

## Associated conditions {#conditions}

[Bernard-Soulier syndrome](https://sugi.bio/atlas/disease/bernard-soulier-syndrome/).

**Reported phenotype names (ClinVar):** Bernard Soulier syndrome, not provided, none provided, GLYCOPROTEIN Ib, PLATELET, DEFICIENCY OF, Giant platelet syndrome, Hemorrhagiparous thrombocytic dystrophy, Giant platelet disease, PLATELET GLYCOPROTEIN Ib DEFICIENCY, VON WILLEBRAND FACTOR RECEPTOR DEFICIENCY, BLEEDING DISORDER, PLATELET-TYPE, 1.

## Similar variants {#similar}

Related GP9 variant pages (same residue, condition, or type): [GP9 p.Asn61Ser](/variant/gp9-p-asn61ser), [GP9 p.Cys135Tyr](/variant/gp9-p-cys135tyr), [GP9 p.Cys24Arg](/variant/gp9-p-cys24arg), [GP9 p.Cys38Arg](/variant/gp9-p-cys38arg), [GP9 p.Cys89Tyr](/variant/gp9-p-cys89tyr), [GP9 p.Leu56Pro](/variant/gp9-p-leu56pro), [GP9 p.Leu7Pro](/variant/gp9-p-leu7pro), [GP9 p.Phe71Cys](/variant/gp9-p-phe71cys).

### 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 343221). 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.*