# NM_016293.4(BIN2):c.1531G>A (p.Gly511Arg)

https://sugi.bio/variant/bin2-p-gly511arg

## Summary

**BIN2 p.Gly511Arg (c.1531G>A)** is classified **Uncertain significance** in BIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: likely benign (0.0876); Very rare (popmax 0.00223%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the BIN2 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 | [BIN2](https://sugi.bio/atlas/gene/BIN2/) |
| Protein change (HGVS p.) | p.Gly511Arg |
| Coding change (HGVS c.) | c.1531G>A |
| MANE Select transcript | [NM_016293](https://www.ncbi.nlm.nih.gov/nuccore/NM_016293) |
| Variant type | single nucleotide variant |
| Location | chr12:51288173-51288173 (GRCh38) |
| ClinVar | [VCV3824346](https://www.ncbi.nlm.nih.gov/clinvar/variation/3824346/) |

**All HGVS expressions:** `NC_000012.11:g.51681957C>T`, `NC_000012.12:g.51288173C>T`, `NM_001290007.2:c.1453G>A`, `NM_001290008.2:c.1435G>A`, `NM_001290009.2:c.1159G>A`, `NM_001364779.1:c.1528G>A`, `NM_001364780.1:c.1516-3386G>A`, `NM_001364781.1:c.1369G>A`, `NM_016293.4:c.1531G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0876)
- REVEL 0.161 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.182 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.39, GERP -2.53 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 14.5**. 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 0.87** across the covering region of the MANE Select transcript (51,281,502–51,324,102), spanning 42,600 bp. Chi-square p 0.00047. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,880 in the highest group · 2/1,461,584 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,880 |
| European (non-Finnish) | 8.48e-05% | 1,179,793 |

*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}

**BIN2** population constraint: LOEUF 0.766, pLI 6.5356e-06, missense-Z 1.7208. *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 **511** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 66.40, 39% of residues very-high.

**2 experimental structure(s)** (PDB): [4AVM](https://www.rcsb.org/structure/4AVM), [4I1Q](https://www.rcsb.org/structure/4I1Q).

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

*Describes the biological roles of BIN2 (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:** BIN2's established molecular role includes phospholipid binding. p.Gly511Arg falls in the disordered region. In Reactome, BIN2 is annotated in disease pathway(s) including **Signaling by membrane-tethered fusions of PDGFRA or PDGFRB**.

**Disease mechanism (Reactome):** BIN2 loss or alteration is curated in [Signaling by membrane-tethered fusions of PDGFRA or PDGFRB](https://reactome.org/content/detail/R-HSA-9673768).

### Pathways affected {#pathways}

BIN2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by membrane-tethered fusions of PDGFRA or PDGFRB](https://reactome.org/content/detail/R-HSA-9673768) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

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

**Molecular function:** phospholipid binding.

**Biological process:** phagocytosis, engulfment, cell chemotaxis, podosome assembly, plasma membrane tubulation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-08.

**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 | 2025-01-08 |

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

## Similar variants {#similar}

Related BIN2 variant pages (same residue, condition, or type): [BIN2 p.Ala121Val](/variant/bin2-p-ala121val), [BIN2 p.Ala130Thr](/variant/bin2-p-ala130thr), [BIN2 p.Ala158Thr](/variant/bin2-p-ala158thr), [BIN2 p.Ala344Val](/variant/bin2-p-ala344val), [BIN2 p.Ala384Thr](/variant/bin2-p-ala384thr), [BIN2 p.Arg123Lys](/variant/bin2-p-arg123lys), [BIN2 p.Arg138Thr](/variant/bin2-p-arg138thr), [BIN2 p.Arg142Trp](/variant/bin2-p-arg142trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 3824346). 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.*