# NM_000407.5(GP1BB):c.268C>T (p.Pro90Ser)

https://sugi.bio/variant/gp1bb-p-pro90ser

## Summary

**GP1BB p.Pro90Ser (c.268C>T)** is classified **Likely pathogenic** in GP1BB (ClinVar, Expert panel, 2 submitters; last evaluated 2025-02-18). AlphaMissense: ambiguous (0.5479); Very rare (popmax 0.0027%, sas); Associated with Bernard-Soulier syndrome.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs1197982563 · 2 submitters · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.0027%, sas)

## For patients & families {#patients}

This is a change in the GP1BB gene that is considered likely disease-causing, 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 | GP1BB 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 | [GP1BB](https://sugi.bio/atlas/gene/GP1BB/) |
| Protein change (HGVS p.) | p.Pro90Ser |
| Coding change (HGVS c.) | c.268C>T |
| MANE Select transcript | [NM_000407](https://www.ncbi.nlm.nih.gov/nuccore/NM_000407) |
| dbSNP | [rs1197982563](https://www.ncbi.nlm.nih.gov/snp/rs1197982563/) |
| Variant type | single nucleotide variant |
| Location | chr22:19724111-19724111 (GRCh38) |
| ClinVar | [VCV1691254](https://www.ncbi.nlm.nih.gov/clinvar/variation/1691254/) |

**All HGVS expressions:** `LRG_478:g.5569C>T`, `NC_000022.10:g.19711634C>T`, `NC_000022.11:g.19724111C>T`, `NG_007974.1:g.5569C>T`, `NM_000407.5:c.268C>T`, `NR_037611.1:n.4008C>T`, `NR_037612.1:n.2512C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.5479) — no call either way
- REVEL 0.771 (pathogenic-leaning)
- SaProt LLR -11.369 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense is indeterminate
- Conservation: phyloP 7.272, GERP 1.5, phastCons 1 — highly conserved
- CADD: **PHRED 28.9**. 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 1.03** across the covering region of the MANE Select transcript (19,723,570–19,724,461), spanning 891 bp. Chi-square p 0.61. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for GP1BB (54 scored positions, the nearest 94 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0027%** (sas) · FAF95 0.000449% · FAF99 0.000168% · 2/74,000 in the highest group · 3/1,443,012 alleles overall — very rare (popmax 0.0027%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0027% | 37,000 |
| Remaining individuals (not grpmax-eligible) | 0.00181% | 55,108 |

*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}

**GP1BB** population constraint: LOEUF 1.922, pLI 0.010404, missense-Z -2.9875; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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)

## Protein context {#protein}

Residue **90** lies in the lrrct domain.

AlphaFold model confidence (whole protein): pLDDT 88.43, 73% of residues very-high.

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

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

*Describes the biological roles of GP1BB (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:** GP1BB's established molecular role includes identical protein binding. p.Pro90Ser falls in the lrrct domain. In Reactome, GP1BB is annotated in disease pathway(s) including **Defective F9 activation**, **Defective binding of VWF variant to GPIb:IX:V**.

**Disease mechanism (Reactome):** GP1BB 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}

GP1BB 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}

**Molecular function:** identical protein binding.

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

## Clinical significance {#significance}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-02-18.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Likely Pathogenic).

**Submission history:** 2 submissions (2025); classifications have been stable.

**ClinGen expert panel:** Likely Pathogenic — Platelet Disorders VCEP (Bernard-Soulier syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PP4_Moderate`, `PM3_Supporting`, `PM2_Supporting`, `PM5_Supporting`, `PP3`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** NM_000407.5(GP1BB):c.268C>T is a missense variant (p.Pro90Ser), which has been reported in one homozygous proband with Bernard-Soulier syndrome. At least one patient (Patient BSS-8 in PMID:25539746) with this variant had aggregation absent for ristocetin and present for all other agonists, and flow cytometry revealed that the GPIbα and GPIX expression was severely reduced (<10% compared to controls), which is highly specific for Bernard-Soulier syndrome and with full gene sequencing and del/dup analysis of all BSS genes is specific to GP1bb (PP4_moderate). Additionally, the patient had macrothrombocytopenia and excessive mucocutaneous bleeding which is consistent with Bernard-Soulier syndrome. The Grpmax filtering allele frequency in gnomaDv4.1 is 0.000004490 (based on 2/74000 alleles) in the South Asian population, which is below the <0.0000651678 threshold for PM2_supporting. The computational predictor REVEL gives a score of 0.771, which is above the ClinGen PD VCEP PP3 threshold of >0.644 and predicts a damaging effect on GP1BB function (PP3). Another missense variant in the same codon has been reported in a patient with Bernard-Soulier syndrome c.269C>G (p.Pro90Arg) (PMID:21699652), it is classified Likely Pathogenic by the PD-VCEP (PM5_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3, PP4_moderate, PM2_supporting, PM5_supporting, and PM3_supporting (VCEP specifications version 1).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50040 · approved 2025-02-18 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/0759aa21-8414-40de-a1f3-20504a07daf1).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | Likely pathogenic | no assertion criteria provided | research |  |
| ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | Likely Pathogenic | reviewed by expert panel | curation | 2025-02-18 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Bernard Soulier syndrome, Platelet Glycoprotein 1b, Deficiency of, BLEEDING DISORDER, PLATELET-TYPE, 1, PLATELET GLYCOPROTEIN Ib DEFICIENCY, VON WILLEBRAND FACTOR RECEPTOR DEFICIENCY, GLYCOPROTEIN Ib, PLATELET, DEFICIENCY OF, Giant platelet syndrome, Hemorrhagiparous thrombocytic dystrophy, Giant platelet disease.

## Same-residue context {#hotspot}

Residue **90** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GP1BB p.Pro90Arg](/variant/gp1bb-p-pro90arg). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GP1BB variant pages (same residue, condition, or type): [GP1BB p.Pro90Arg](/variant/gp1bb-p-pro90arg), [GP1BB p.Pro90Leu](/variant/gp1bb-p-pro90leu), [GP1BB p.Asn89Asp](/variant/gp1bb-p-asn89asp), [GP1BB p.Asn89Thr](/variant/gp1bb-p-asn89thr), [GP1BB p.Cys141Ter](/variant/gp1bb-p-cys141ter), [GP1BB p.Cys147Ser](/variant/gp1bb-p-cys147ser), [GP1BB p.Cys30Tyr](/variant/gp1bb-p-cys30tyr), [GP1BB p.Cys32Ter](/variant/gp1bb-p-cys32ter).

### 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 1691254). 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.*