# NM_002086.5(GRB2):c.619C>T (p.Arg207Cys)

https://sugi.bio/variant/grb2-p-arg207cys

## Summary

**GRB2 p.Arg207Cys (c.619C>T)** is classified **Uncertain significance** in GRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: ambiguous (0.4086); Very rare (popmax 0.00134%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the GRB2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [GRB2](https://sugi.bio/atlas/gene/GRB2/) |
| Protein change (HGVS p.) | p.Arg207Cys |
| Coding change (HGVS c.) | c.619C>T |
| MANE Select transcript | [NM_002086](https://www.ncbi.nlm.nih.gov/nuccore/NM_002086) |
| Variant type | single nucleotide variant |
| Location | chr17:75320403-75320403 (GRCh38) |
| ClinVar | [VCV4266715](https://www.ncbi.nlm.nih.gov/clinvar/variation/4266715/) |

**All HGVS expressions:** `NC_000017.10:g.73316484G>A`, `NC_000017.11:g.75320403G>A`, `NG_029556.1:g.90307C>T`, `NG_087138.1:g.701G>A`, `NG_087138.2:g.751G>A`, `NM_002086.5:c.619C>T`, `NM_203506.3:c.496C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4086) — no call either way
- REVEL 0.424 (indeterminate)
- SaProt LLR -6.408 (tolerated)
- Conservation: phyloP 11.767, GERP 1.87, phastCons 1 — highly conserved
- CADD: **PHRED 29.0**. 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 0.37** across the covering region of the MANE Select transcript (75,320,371–75,321,819), spanning 1,448 bp. Chi-square p 8.7e-15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00134%** (afr) · FAF95 0.000542% · FAF99 0.000428% · 1/74,886 in the highest group · 15/1,613,886 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00156% | 64,016 |
| African / African-American (grpmax) | 0.00134% | 74,886 |
| South Asian | 0.0011% | 91,068 |
| European (non-Finnish) | 0.00102% | 98,330 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**GRB2** population constraint: LOEUF 0.216, pLI 0.99988, missense-Z 3.8851. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **207** lies in the sh3 2 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 88.89, 68% of residues very-high.

**58 experimental structure(s)** (PDB): [1AZE](https://www.rcsb.org/structure/1AZE), [1BM2](https://www.rcsb.org/structure/1BM2), [1BMB](https://www.rcsb.org/structure/1BMB), [1CJ1](https://www.rcsb.org/structure/1CJ1), [1FHS](https://www.rcsb.org/structure/1FHS), [1FYR](https://www.rcsb.org/structure/1FYR) — incl. mutant structure 1AZE.

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

*Describes the biological roles of GRB2 (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:** GRB2's established molecular role includes phosphotyrosine residue binding. p.Arg207Cys falls in the sh3 2 domain. In Reactome, GRB2 is annotated in disease pathway(s) including **STAT5 activation downstream of FLT3 ITD mutants**, **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** GRB2 loss or alteration is curated in [STAT5 activation downstream of FLT3 ITD mutants](https://reactome.org/content/detail/R-HSA-9702518), [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370), [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530).

### Pathways affected {#pathways}

GRB2 participates in **97 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [STAT5 activation downstream of FLT3 ITD mutants](https://reactome.org/content/detail/R-HSA-9702518) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | other |
| ⚕ [Constitutive Signaling by EGFRvIII](https://reactome.org/content/detail/R-HSA-5637810) | other |
| ⚕ [Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants](https://reactome.org/content/detail/R-HSA-1236382) | other |
| ⚕ [Constitutive Signaling by Overexpressed ERBB2](https://reactome.org/content/detail/R-HSA-9634285) | other |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | other |
| ⚕ [InlB-mediated entry of Listeria monocytogenes into host cell](https://reactome.org/content/detail/R-HSA-8875360) | other |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | other |
| ⚕ [Signaling by ERBB2 ECD mutants](https://reactome.org/content/detail/R-HSA-9665348) | other |
| ⚕ [Signaling by ERBB2 KD Mutants](https://reactome.org/content/detail/R-HSA-9664565) | other |
| ⚕ [Signaling by ERBB2 TMD/JMD mutants](https://reactome.org/content/detail/R-HSA-9665686) | other |
| ⚕ [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302) | other |
| ⚕ [Signaling by FGFR2 in disease](https://reactome.org/content/detail/R-HSA-5655253) | other |
| ⚕ [Signaling by FGFR3 in disease](https://reactome.org/content/detail/R-HSA-5655332) | other |
| ⚕ [Signaling by FGFR4 in disease](https://reactome.org/content/detail/R-HSA-5655291) | other |
| ⚕ [Signaling by FLT3 ITD and TKD mutants](https://reactome.org/content/detail/R-HSA-9703648) | electronic |
| ⚕ [Signaling by FLT3 fusion proteins](https://reactome.org/content/detail/R-HSA-9703465) | other |
| ⚕ [Signaling by PDGFRA extracellular domain mutants](https://reactome.org/content/detail/R-HSA-9673770) | other |
| ⚕ [Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants](https://reactome.org/content/detail/R-HSA-9673767) | other |
| ⚕ [Signaling by cytosolic FGFR1 fusion mutants](https://reactome.org/content/detail/R-HSA-1839117) | other |
| ⚕ [Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants](https://reactome.org/content/detail/R-HSA-9670439) | other |
| [Signaling by LTK](https://reactome.org/content/detail/R-HSA-9842663) | curated |
| [Activated NTRK2 signals through FRS2 and FRS3](https://reactome.org/content/detail/R-HSA-9028731) | other |
| [Activated NTRK2 signals through PI3K](https://reactome.org/content/detail/R-HSA-9028335) | other |
| [Activated NTRK2 signals through RAS](https://reactome.org/content/detail/R-HSA-9026519) | other |
| [Activated NTRK3 signals through RAS](https://reactome.org/content/detail/R-HSA-9034864) | other |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | other |
| [CD28 dependent Vav1 pathway](https://reactome.org/content/detail/R-HSA-389359) | other |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | other |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | other |
| [Co-inhibition by BTLA](https://reactome.org/content/detail/R-HSA-9927353) | other |
| [DAP12 signaling](https://reactome.org/content/detail/R-HSA-2424491) | other |
| [Downstream signal transduction](https://reactome.org/content/detail/R-HSA-186763) | other |
| [EGFR Transactivation by Gastrin](https://reactome.org/content/detail/R-HSA-2179392) | other |
| [EGFR downregulation](https://reactome.org/content/detail/R-HSA-182971) | other |
| [Erythropoietin activates RAS](https://reactome.org/content/detail/R-HSA-9027284) | other |
| [FCERI mediated Ca+2 mobilization](https://reactome.org/content/detail/R-HSA-2871809) | other |
| [FCERI mediated MAPK activation](https://reactome.org/content/detail/R-HSA-2871796) | other |
| [FLT3 Signaling](https://reactome.org/content/detail/R-HSA-9607240) | other |
| [FRS-mediated FGFR1 signaling](https://reactome.org/content/detail/R-HSA-5654693) | other |
| [FRS-mediated FGFR2 signaling](https://reactome.org/content/detail/R-HSA-5654700) | other |
| [FRS-mediated FGFR3 signaling](https://reactome.org/content/detail/R-HSA-5654706) | other |
| [FRS-mediated FGFR4 signaling](https://reactome.org/content/detail/R-HSA-5654712) | other |
| [GAB1 signalosome](https://reactome.org/content/detail/R-HSA-180292) | other |
| [GRB2 events in EGFR signaling](https://reactome.org/content/detail/R-HSA-179812) | other |
| [GRB2 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1963640) | other |
| [GRB2:SOS provides linkage to MAPK signaling for Integrins ](https://reactome.org/content/detail/R-HSA-354194) | other |
| [Insulin receptor signalling cascade](https://reactome.org/content/detail/R-HSA-74751) | other |
| [Interleukin receptor SHC signaling](https://reactome.org/content/detail/R-HSA-912526) | other |
| [Interleukin-15 signaling](https://reactome.org/content/detail/R-HSA-8983432) | electronic |
| [Interleukin-3, Interleukin-5 and GM-CSF signaling](https://reactome.org/content/detail/R-HSA-512988) | other |
| [MET activates PI3K/AKT signaling](https://reactome.org/content/detail/R-HSA-8851907) | other |
| [MET activates PTPN11](https://reactome.org/content/detail/R-HSA-8865999) | other |
| [MET activates RAP1 and RAC1](https://reactome.org/content/detail/R-HSA-8875555) | other |
| [MET activates RAS signaling](https://reactome.org/content/detail/R-HSA-8851805) | other |
| [MET receptor recycling](https://reactome.org/content/detail/R-HSA-8875656) | other |
| [NCAM signaling for neurite out-growth](https://reactome.org/content/detail/R-HSA-375165) | other |
| [Negative regulation of FGFR1 signaling](https://reactome.org/content/detail/R-HSA-5654726) | other |
| [Negative regulation of FGFR2 signaling](https://reactome.org/content/detail/R-HSA-5654727) | other |
| [Negative regulation of FGFR3 signaling](https://reactome.org/content/detail/R-HSA-5654732) | other |
| [Negative regulation of FGFR4 signaling](https://reactome.org/content/detail/R-HSA-5654733) | other |
| [Negative regulation of MET activity](https://reactome.org/content/detail/R-HSA-6807004) | other |
| [PI-3K cascade:FGFR1](https://reactome.org/content/detail/R-HSA-5654689) | other |
| [PI-3K cascade:FGFR2](https://reactome.org/content/detail/R-HSA-5654695) | other |
| [PI-3K cascade:FGFR3](https://reactome.org/content/detail/R-HSA-5654710) | other |
| [PI-3K cascade:FGFR4](https://reactome.org/content/detail/R-HSA-5654720) | other |
| [PI3K Cascade](https://reactome.org/content/detail/R-HSA-109704) | other |
| [PI3K events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1963642) | other |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | other |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | other |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | other |
| [RET signaling](https://reactome.org/content/detail/R-HSA-8853659) | other |
| [RHO GTPases Activate WASPs and WAVEs](https://reactome.org/content/detail/R-HSA-5663213) | other |
| [RHOU GTPase cycle](https://reactome.org/content/detail/R-HSA-9013420) | other |
| [Regulation of KIT signaling](https://reactome.org/content/detail/R-HSA-1433559) | other |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | other |
| [Regulation of signaling by CBL](https://reactome.org/content/detail/R-HSA-912631) | other |
| [Role of LAT2/NTAL/LAB on calcium mobilization](https://reactome.org/content/detail/R-HSA-2730905) | other |
| [SHC-mediated cascade:FGFR1](https://reactome.org/content/detail/R-HSA-5654688) | other |
| [SHC-mediated cascade:FGFR2](https://reactome.org/content/detail/R-HSA-5654699) | other |
| [SHC-mediated cascade:FGFR3](https://reactome.org/content/detail/R-HSA-5654704) | other |
| [SHC-mediated cascade:FGFR4](https://reactome.org/content/detail/R-HSA-5654719) | other |
| [SHC-related events triggered by IGF1R](https://reactome.org/content/detail/R-HSA-2428933) | other |
| [SHC1 events in EGFR signaling](https://reactome.org/content/detail/R-HSA-180336) | other |
| [SHC1 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1250196) | other |
| [SHC1 events in ERBB4 signaling](https://reactome.org/content/detail/R-HSA-1250347) | other |
| [SOS-mediated signalling](https://reactome.org/content/detail/R-HSA-112412) | other |
| [STAT5 Activation](https://reactome.org/content/detail/R-HSA-9645135) | other |
| [Signal attenuation](https://reactome.org/content/detail/R-HSA-74749) | other |
| [Signal regulatory protein family interactions](https://reactome.org/content/detail/R-HSA-391160) | other |
| [Signaling by CSF1 (M-CSF) in myeloid cells](https://reactome.org/content/detail/R-HSA-9680350) | other |
| [Signaling by CSF3 (G-CSF)](https://reactome.org/content/detail/R-HSA-9674555) | electronic |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | other |
| [Signalling to RAS](https://reactome.org/content/detail/R-HSA-167044) | other |
| [Spry regulation of FGF signaling](https://reactome.org/content/detail/R-HSA-1295596) | other |
| [Tie2 Signaling](https://reactome.org/content/detail/R-HSA-210993) | other |

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

**Molecular function:** phosphotyrosine residue binding, RNA binding, guanyl-nucleotide exchange factor adaptor activity, epidermal growth factor receptor binding, neurotrophin TRKA receptor binding, SH3 domain binding.

**Biological process:** epidermal growth factor receptor signaling pathway, insulin receptor signaling pathway, actin cytoskeleton organization, receptor internalization, T cell activation, natural killer cell mediated cytotoxicity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-24.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-24 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related GRB2 variant pages (same residue, condition, or type): [GRB2 p.His79=](/variant/grb2-p-his79), [GRB2 p.Ala82Ser](/variant/grb2-p-ala82ser), [GRB2 p.Arg215Trp](/variant/grb2-p-arg215trp), [GRB2 p.Asn126Ser](/variant/grb2-p-asn126ser), [GRB2 p.Asp133Asn](/variant/grb2-p-asp133asn), [GRB2 p.Asp23Asn](/variant/grb2-p-asp23asn), [GRB2 p.Glu87Asp](/variant/grb2-p-glu87asp).

### 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 4266715). 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.*