# NM_000419.5(ITGA2B):c.786C>T (p.Phe262=)

https://sugi.bio/variant/itga2b-p-phe262

## Summary

**ITGA2B p.Phe262= (c.786C>T)** is classified **Likely benign** in ITGA2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). Very rare (popmax 0.00533%, afr); Associated with Glanzmann thrombasthenia.

**At a glance:** Likely benign · review: Single submitter · rsID rs1341886951 · 1 submitter · 1 linked condition · very rare (popmax 0.00533%, afr)

## For patients & families {#patients}

This is a change in the ITGA2B gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Glanzmann thrombasthenia.

*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 recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Clinical trials | 14 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ITGA2B is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Glanzmann thrombasthenia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Prolonged bleeding time — Very frequent (99-80%)
- Spontaneous, recurrent epistaxis — Very frequent (99-80%)
- Gingival bleeding — Frequent (79-30%)
- Bruising susceptibility — Frequent (79-30%)
- Prolonged bleeding after surgery — Frequent (79-30%)
- Prolonged bleeding following circumcision — Frequent (79-30%)
- Menorrhagia — Occasional (29-5%)
- Purpura — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002478/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ITGA2B](https://sugi.bio/atlas/gene/ITGA2B/) |
| Protein change (HGVS p.) | p.Phe262= |
| Coding change (HGVS c.) | c.786C>T |
| MANE Select transcript | [NM_000419](https://www.ncbi.nlm.nih.gov/nuccore/NM_000419) |
| dbSNP | [rs1341886951](https://www.ncbi.nlm.nih.gov/snp/rs1341886951/) |
| Variant type | single nucleotide variant |
| Location | chr17:44384961-44384961 (GRCh38) |
| ClinVar | [VCV2726738](https://www.ncbi.nlm.nih.gov/clinvar/variation/2726738/) |

**All HGVS expressions:** `LRG_479:g.9545C>T`, `LRG_479t1:c.786C>T`, `NC_000017.10:g.42462329G>A`, `NC_000017.11:g.44384961G>A`, `NG_008331.1:g.9545C>T`, `NM_000419.5:c.786C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.14, GERP -2.07 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.986**. 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 deltas (raw): acceptor loss **0.02**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss, 13 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.24** (loss), gain 0.01 / loss 0.24. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00533%** (afr) · FAF95 0.00174% · FAF99 0.00104% · 4/75,042 in the highest group · 4/1,461,838 alleles overall — very rare (popmax 0.00533%, afr).

*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}

**ITGA2B** population constraint: LOEUF 0.763, pLI 9.1914e-19, missense-Z 1.3317. *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):

- **platelet-type bleeding disorder 16** — Definitive (AD)
- **Glanzmann thrombasthenia** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.00, 71% of residues very-high.

**80 experimental structure(s)** (PDB): [11YB](https://www.rcsb.org/structure/11YB), [1DPK](https://www.rcsb.org/structure/1DPK), [1DPQ](https://www.rcsb.org/structure/1DPQ), [1KUP](https://www.rcsb.org/structure/1KUP), [1KUZ](https://www.rcsb.org/structure/1KUZ), [1M8O](https://www.rcsb.org/structure/1M8O) — incl. mutant structure 1DPQ.

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

*Describes the biological roles of ITGA2B (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:** ITGA2B's established molecular role includes identical protein binding. In Reactome, ITGA2B is annotated in disease pathway(s) including **Paradoxical activation of RAF signaling by kinase inactive BRAF**, **Signaling by BRAF and RAF1 fusions**.

**Disease mechanism (Reactome):** ITGA2B loss or alteration is curated in [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952), [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223).

### Pathways affected {#pathways}

ITGA2B participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | curated |
| [Fibrin formation](https://reactome.org/content/detail/R-HSA-9769733) | curated |
| [GRB2:SOS provides linkage to MAPK signaling for Integrins ](https://reactome.org/content/detail/R-HSA-354194) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |
| [Integrin signaling](https://reactome.org/content/detail/R-HSA-354192) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function](https://reactome.org/content/detail/R-HSA-8936459) | curated |
| [Signal transduction by L1](https://reactome.org/content/detail/R-HSA-445144) | curated |
| [p130Cas linkage to MAPK signaling for integrins](https://reactome.org/content/detail/R-HSA-372708) | curated |

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

**Molecular function:** identical protein binding, molecular adaptor activity.

**Biological process:** integrin-mediated signaling pathway, cell-cell adhesion mediated by integrin, heterotypic cell-cell adhesion.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-16 |

## Associated conditions {#conditions}

[Glanzmann thrombasthenia](https://sugi.bio/atlas/disease/glanzmann-thrombasthenia/).

**Reported phenotype names (ClinVar):** Glanzmann thrombasthenia, Glanzmann's thrombasthenia, BLEEDING DISORDER, PLATELET-TYPE, 2, THROMBASTHENIA OF GLANZMANN AND NAEGELI, Thrombasthenia, PLATELET GLYCOPROTEIN IIb-IIIa DEFICIENCY.

## Similar variants {#similar}

Related ITGA2B variant pages (same residue, condition, or type): [ITGA2B c.1210+105A>G](/variant/itga2b-c-1210-plus-105a-g), [ITGA2B c.1210+5G>A](/variant/itga2b-c-1210-plus-5g-a), [ITGA2B c.1211-1G>C](/variant/itga2b-c-1211-minus-1g-c), [ITGA2B c.1544+1G>A](/variant/itga2b-c-1544-plus-1g-a), [ITGA2B c.1545-1G>A](/variant/itga2b-c-1545-minus-1g-a), [ITGA2B c.1600+1G>A](/variant/itga2b-c-1600-plus-1g-a), [ITGA2B c.1752+2T>C](/variant/itga2b-c-1752-plus-2t-c), [ITGA2B c.1753-1G>A](/variant/itga2b-c-1753-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 2726738). 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.*