# NM_000174.5(GP9):c.212T>C (p.Phe71Ser)

https://sugi.bio/variant/gp9-p-phe71ser

## Summary

**GP9 p.Phe71Ser (c.212T>C)** is classified **Pathogenic** in GP9 (ClinVar, Expert panel, 6 submitters; last evaluated 2026-03-17). AlphaMissense: likely pathogenic (0.9716); Very rare (popmax 0.00329%, sas); Associated with Bernard-Soulier syndrome.

**At a glance:** Pathogenic · review: Expert panel · rsID rs121918037 · 6 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00329%, sas)

## For patients & families {#patients}

This is a change in the GP9 gene that is considered disease-causing, submitted by 6 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.Phe71Ser |
| Coding change (HGVS c.) | c.212T>C |
| MANE Select transcript | [NM_000174](https://www.ncbi.nlm.nih.gov/nuccore/NM_000174) |
| dbSNP | [rs121918037](https://www.ncbi.nlm.nih.gov/snp/rs121918037/) |
| Variant type | single nucleotide variant |
| Location | chr3:129061951-129061951 (GRCh38) |
| ClinVar | [VCV13531](https://www.ncbi.nlm.nih.gov/clinvar/variation/13531/) |

**All HGVS expressions:** `LRG_477:g.6150T>C`, `LRG_477t1:c.212T>C`, `NC_000003.11:g.128780794T>C`, `NC_000003.12:g.129061951T>C`, `NG_008715.1:g.6150T>C`, `NM_000174.5:c.212T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9716) — concordant with the pathogenic call
- REVEL 0.634 (indeterminate)
- SaProt LLR -13.738 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 7.487, GERP 1.53, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in GP9 (of 1,016 modeled).
- CADD: **PHRED 24.4**. 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 0.94** across the covering region of the MANE Select transcript (129,061,740–129,062,270), spanning 530 bp. Chi-square p 0.38. 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 GP9 (111 scored positions, the nearest 15 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 **0.00329%** (sas) · FAF95 0.000875% · FAF99 0.000443% · 3/91,084 in the highest group · 18/1,613,770 alleles overall — very rare (popmax 0.00329%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00329% | 30,361 |
| East Asian | 0.00223% | 44,894 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,478 |
| African / African-American | 0.00133% | 74,932 |
| European (non-Finnish) | 0.00102% | 98,325 |

*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}

Residue **71** lies in a UniProt-annotated variant site (in bss); a turn.

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}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2026-03-17.

**Submitter consensus:** unanimous (6/6 Pathogenic).

**Submission history:** 6 submissions (1997–2026); classifications have been stable.

**ClinGen expert panel:** Pathogenic — Platelet Disorders VCEP (Bernard-Soulier syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PP1_Moderate`, `PS3_Supporting`, `PM5_Supporting`, `PM3_Strong`, `PP4`.
*Considered but not met:* `PP3`, `BP4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.212C>T variant in GP9 is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 71. This variant has been detected in at least 16 probands with Bernard-Soulier syndrome. This variant has been detected in at least 8 probands with supporting laboratory results described in the literature (PM3_Strong). Two of these probands were compound heterozygous for this variant and another variant (c.266G>A [p.Cys89Tyr], c.182A>G [p.Asn61Ser]) (PMID:24934643). Six of these probands were homozygous for the variant, with at least 3 of these confirmed using parental testing or other methods (PMIDs: 9163595, 432024, 21173099, 21699652, 25539746). At least one patient (proband in PMID: 9432024) with this variant had aggregation absent for ristocetin and present for all other agonists and flow cytometry with less than 10% expression of GPIba, which is highly specific for Bernard-Soulier syndrome (PP4). The variant has been reported to segregate with Bernard-Soulier syndrome in the proband plus two affected family members, all with the homozygous genotype (PP1_moderate; PMID:17763149). Another missense variant in the same codon has been reported in a patient with Bernard-Soulier syndrome c.212T>G, p.Phe71Cys (PMID:21699652), classified likely pathogenic by the ClinGen PD VCEP (PM5_supporting). The highest minor allele frequency in gnomaDv4.1 is 0.00003294 (3/91084 alleles) in the South Asian genetic ancestry group, which is below the <0.0000329 threshold for PM2_supporting. Surface expression of GP1Ba measured by flow cytometry in CHO-K1 cells transiently co-transfected with the c.212T>C variant in GP9 and wild type GP1Bb showed decreased expression at ~17% (<25%) WT levels, indicating that this variant impacts protein function (PMID:10527407; PS3_Supporting).   In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4, PM3_strong, PM2_Supporting, PS3_Supporting, PP1_Moderate, PM5_supporting (VCEP specifications version 1).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50040 · approved 2026-03-17 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/7f4f85a2-aada-40d5-8d5f-540a8dd10bdf).*
*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 |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1997-05-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-25 |
| NIHR Bioresource Rare Diseases, University of Cambridge | Pathogenic | criteria provided, single submitter | research | 2019-02-01 |
| ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-21 |
| ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | Pathogenic | reviewed by expert panel | curation | 2026-03-17 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **71** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GP9 p.Phe71Cys](/variant/gp9-p-phe71cys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GP9 variant pages (same residue, condition, or type): [GP9 p.Phe71Cys](/variant/gp9-p-phe71cys), [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).

### 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 13531). 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.*