GP1BB p.Ser48Ter
c.143C>A · rs536874549 · VCV627237
ClinGen expert panel — Platelet Disorders VCEP
Likely Pathogenic for Bernard-Soulier syndrome. Applied ACMG criteria (verbatim):
PVS1_Strong PM2_Supporting PP4 PM3
Curation rationale (ClinGen, verbatim)
The c.143C>A (p.Ser48Ter) variant in GP1BB is a nonsense variant that is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient II:1 in PMID: 18825380) with this variant had aggregation absent for ristocetin and present for all other agonists as well as less than 10% expression of GPIba and GP9 measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome (PP4). This variant has been detected in at least two unrelated probands with Bernard-Soulier syndrome (PMID: 19484238). Both of these probands were homozygous for the variant (PM3). This variant is absent from gnomAD v4.1.0 (PM2_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: PVS1_Strong, PP4, PM3 and PM2_Supporting (VCEP specifications version 1).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | nonsense (stop-gain) | predicted loss-of-function |
|---|---|---|
| NMD | escapes | premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code |
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 2.1 | GERP 0.038, phastCons 1 |
| Overall | ||
| CADD | 36.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No allele count reported in gnomAD v4.1 (AN 1,533,114). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- GP1BB
- Protein
- p.Ser48Ter
- Coding
- c.143C>A
- MANE Select
- NM_000407
- dbSNP
- rs536874549
- Type
- single nucleotide variant
- Location
- chr22:19723986 (GRCh38)
- Gene constraint
- LOEUF 1.922 · pLI 0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 88.43 · 3 PDB
- Residue 48
- a turn; the lrrnt domain
Disease context
Bernard-Soulier syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: thrombocytopenia
For Bernard-Soulier syndrome (Orphanet):
- Inheritance
- Autosomal dominant, Autosomal recessive
- Onset
- All ages
Similar variants
- GP1BB p.Ser48Leu Uncertain significance ★ ⚠ same residue
- GP1BB p.Ser48= Likely benign ★ same residue
- GP1BB p.Asn89Asp Likely pathogenic ★★★ same condition
- GP1BB p.Asn89Thr Likely pathogenic ★★★ same condition
- GP1BB p.Cys141Ter Pathogenic ★★★ same condition
- GP1BB p.Cys147Ser Likely pathogenic ★★★ ⚠ same condition
- GP1BB p.Cys30Tyr Likely pathogenic ★★★ same condition
- GP1BB p.Cys32Ter Likely pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gp1bb-p-ser48ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown