# NM_016293.4(BIN2):c.362C>T (p.Ala121Val)

https://sugi.bio/variant/bin2-p-ala121val

## Summary

**BIN2 p.Ala121Val (c.362C>T)** is classified **Uncertain significance** in BIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely benign (0.1158); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## 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.Ala121Val |
| Coding change (HGVS c.) | c.362C>T |
| MANE Select transcript | [NM_016293](https://www.ncbi.nlm.nih.gov/nuccore/NM_016293) |
| Variant type | single nucleotide variant |
| Location | chr12:51302066-51302066 (GRCh38) |
| ClinVar | [VCV3480678](https://www.ncbi.nlm.nih.gov/clinvar/variation/3480678/) |

**All HGVS expressions:** `NC_000012.11:g.51695850G>A`, `NC_000012.12:g.51302066G>A`, `NM_001290007.2:c.284C>T`, `NM_001290008.2:c.312+620C>T`, `NM_001290009.2:c.-11C>T`, `NM_001364779.1:c.362C>T`, `NM_001364780.1:c.362C>T`, `NM_001364781.1:c.362C>T`, `NM_016293.4:c.362C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1158)
- REVEL 0.05 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.977 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.388, GERP -0.544, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.5**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.30 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **121** lies in the bar domain; an α-helix.

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.Ala121Val falls in the bar domain. 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 2024-10-20.

**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 | 2024-10-20 |

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

## Similar variants {#similar}

Related BIN2 variant pages (same residue, condition, or type): [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), [BIN2 p.Arg202Cys](/variant/bin2-p-arg202cys).

### 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 3480678). 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.*