# NM_139343.3(BIN1):c.1097T>C (p.Phe366Ser)

https://sugi.bio/variant/bin1-p-phe366ser

## Summary

**BIN1 p.Phe366Ser (c.1097T>C)** is classified **Uncertain significance** in BIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). AlphaMissense: likely benign (0.3393); Very rare (popmax 0.000175%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000175%, nfe)

## For patients & families {#patients}

This is a change in the BIN1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [BIN1](https://sugi.bio/atlas/gene/BIN1/) |
| Protein change (HGVS p.) | p.Phe366Ser |
| Coding change (HGVS c.) | c.1097T>C |
| MANE Select transcript | [NM_139343](https://www.ncbi.nlm.nih.gov/nuccore/NM_139343) |
| Variant type | single nucleotide variant |
| Location | chr2:127057507-127057507 (GRCh38) |
| ClinVar | [VCV4208953](https://www.ncbi.nlm.nih.gov/clinvar/variation/4208953/) |

**All HGVS expressions:** `LRG_873:g.54782T>C`, `LRG_873t1:c.1097T>C`, `NC_000002.11:g.127815083A>G`, `NC_000002.12:g.127057507A>G`, `NG_012042.1:g.54782T>C`, `NM_001320632.2:c.954+1504T>C`, `NM_001320633.2:c.1002+1504T>C`, `NM_001320634.1:c.837+1504T>C`, `NM_001320640.2:c.1097T>C`, `NM_001320641.2:c.1004T>C`, `NM_001320642.1:c.1016T>C`, `NM_004305.4:c.954+1504T>C`, `NM_139343.3:c.1097T>C`, `NM_139344.3:c.1002+1504T>C`, `NM_139345.3:c.1002+1504T>C`, `NM_139346.3:c.1049T>C`, `NM_139347.3:c.1004T>C`, `NM_139348.3:c.1004T>C`, `NM_139349.3:c.909+1504T>C`, `NM_139350.3:c.909+1504T>C`, `NM_139351.3:c.909+1504T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3393)
- REVEL 0.151 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.537 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.959, GERP 0.884, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.4**. 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 0.82** across the covering region of the MANE Select transcript (127,048,529–127,106,943), spanning 58,414 bp. Chi-square p 3.7e-07. 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 (A>T, Δ0.25 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 (gnomAD v4.1): grpmax **0.000175%** (nfe) · FAF95 2.9e-05% · FAF99 1.1e-05% · 2/1,144,586 in the highest group · 2/1,548,016 alleles overall — very rare (popmax 0.000175%, nfe).

*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}

**BIN1** population constraint: LOEUF 0.817, pLI 1.3843e-11, missense-Z 1.3433; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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):

- **centronuclear myopathy** — Definitive (AR)
- **centronuclear myopathy** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.61, 38% of residues very-high.

**7 experimental structure(s)** (PDB): [1MUZ](https://www.rcsb.org/structure/1MUZ), [1MV0](https://www.rcsb.org/structure/1MV0), [1MV3](https://www.rcsb.org/structure/1MV3), [2FIC](https://www.rcsb.org/structure/2FIC), [2RMY](https://www.rcsb.org/structure/2RMY), [2RND](https://www.rcsb.org/structure/2RND).

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

*Describes the biological roles of BIN1 (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:** BIN1's established molecular role includes protease binding.


### Pathways affected {#pathways}

BIN1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |

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

**Molecular function:** protease binding, lipid binding, aspartic-type endopeptidase inhibitor activity, identical protein binding, tau protein binding, actin filament binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, nucleus organization, endosome to lysosome transport, regulation of cell cycle process, T-tubule organization, positive regulation of apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-29.

**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 | 2025-06-29 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related BIN1 variant pages (same residue, condition, or type): [BIN1 p.Ala380Thr](/variant/bin1-p-ala380thr), [BIN1 p.Ala465Val](/variant/bin1-p-ala465val), [BIN1 p.Arg514His](/variant/bin1-p-arg514his), [BIN1 p.Arg66Trp](/variant/bin1-p-arg66trp), [BIN1 p.Asp394Gly](/variant/bin1-p-asp394gly), [BIN1 p.Asp530Asn](/variant/bin1-p-asp530asn), [BIN1 p.Asp570Glu](/variant/bin1-p-asp570glu), [BIN1 p.Asp93Tyr](/variant/bin1-p-asp93tyr).

### 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 4208953). 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.*