# NM_001098671.2(RASGRP2):c.1195_1196dup (p.Pro401fs)

https://sugi.bio/variant/rasgrp2-p-pro401fs

## Summary

**RASGRP2 p.Pro401fs (c.1195_1196dup)** is classified **Pathogenic** in RASGRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2496499928 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the RASGRP2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RASGRP2](https://sugi.bio/atlas/gene/RASGRP2/) |
| Protein change (HGVS p.) | p.Pro401fs |
| Coding change (HGVS c.) | c.1195_1196dup |
| MANE Select transcript | [NM_001098671](https://www.ncbi.nlm.nih.gov/nuccore/NM_001098671) |
| dbSNP | [rs2496499928](https://www.ncbi.nlm.nih.gov/snp/rs2496499928/) |
| Variant type | Duplication |
| Location | chr11:64735641-64735642 (GRCh38) |
| ClinVar | [VCV2737271](https://www.ncbi.nlm.nih.gov/clinvar/variation/2737271/) |

**All HGVS expressions:** `LRG_100:g.14814_14815dup`, `LRG_100t1:c.1195_1196dup`, `NC_000011.10:g.64735643_64735644dup`, `NC_000011.9:g.64503115_64503116dup`, `NG_007574.1:g.14814_14815dup`, `NM_001098670.2:c.1195_1196dup`, `NM_001098671.2:c.1195_1196dup`, `NM_001318398.2:c.760_761dup`, `NM_153819.2:c.1194_1195dup`

## 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 -0.37, GERP -2, phastCons 0.002 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.854, pLI 4.1031e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 17**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**RASGRP2** population constraint: LOEUF 0.854, pLI 4.1031e-10, missense-Z 1.8284. *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 18** — Definitive (AR)

## Protein context {#protein}

Residue **401** lies in a UniProt-annotated variant site (in bdplt18); a UniProt-annotated variant site (in bdplt18; lack of mutant protein in platelets from a patient homozygous for the mutation); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 77.48, 44% of residues very-high.

**2 experimental structure(s)** (PDB): [2MA2](https://www.rcsb.org/structure/2MA2), [6AXF](https://www.rcsb.org/structure/6AXF).

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

*Describes the biological roles of RASGRP2 (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:** RASGRP2's established molecular role includes guanyl-nucleotide exchange factor activity. p.Pro401fs falls in the disordered region.


### Pathways affected {#pathways}

RASGRP2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Integrin signaling](https://reactome.org/content/detail/R-HSA-354192) | curated |
| [Rap1 signalling](https://reactome.org/content/detail/R-HSA-392517) | curated |
| [Effects of PIP2 hydrolysis](https://reactome.org/content/detail/R-HSA-114508) | electronic |
| [FCERI mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-2871837) | electronic |

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

**Molecular function:** guanyl-nucleotide exchange factor activity.

**Biological process:** positive regulation of GTPase activity, cellular response to calcium ion.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-04.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-04 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related RASGRP2 variant pages (same residue, condition, or type): [RASGRP2 p.Asn69fs](/variant/rasgrp2-p-asn69fs), [RASGRP2 p.Asp91Ter](/variant/rasgrp2-p-asp91ter), [RASGRP2 c.372-3dup](/variant/rasgrp2-c-372-minus-3dup), [RASGRP2 c.1591+47_1591+48dup](/variant/rasgrp2-c-1591-plus-47-1591-plus-48dup), [RASGRP2 c.1591+48dup](/variant/rasgrp2-c-1591-plus-48dup), [RASGRP2 c.813+218_813+219dup](/variant/rasgrp2-c-813-plus-218-813-plus-219dup), [RASGRP2 p.Arg494fs](/variant/rasgrp2-p-arg494fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2737271). 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.*