# NM_139343.3(BIN1):c.1473T>C (p.Pro491=)

https://sugi.bio/variant/bin1-p-pro491

## Summary

**BIN1 p.Pro491= (c.1473T>C)** is classified **Conflicting classifications of pathogenicity** in BIN1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-08). Rare (popmax 0.196%, eas); Associated with myopathy, centronuclear, 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs779756862 · 2 submitters · 1 linked condition · rare (popmax 0.196%, eas)

## For patients & families {#patients}

This is a change in the BIN1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to myopathy, centronuclear, 2.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Diagnostic panels | BIN1 is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Autosomal recessive centronuclear myopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- High palate — Frequent (79-30%)
- Retrognathia — Frequent (79-30%)
- Motor delay — Frequent (79-30%)
- Generalized hypotonia — Frequent (79-30%)
- Respiratory insufficiency — Frequent (79-30%)
- Waddling gait — Frequent (79-30%)
- Progressive muscle weakness — Frequent (79-30%)
- Gowers sign — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015208/index) · [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.Pro491= |
| Coding change (HGVS c.) | c.1473T>C |
| MANE Select transcript | [NM_139343](https://www.ncbi.nlm.nih.gov/nuccore/NM_139343) |
| dbSNP | [rs779756862](https://www.ncbi.nlm.nih.gov/snp/rs779756862/) |
| Variant type | single nucleotide variant |
| Location | chr2:127050901-127050901 (GRCh38) |
| ClinVar | [VCV331045](https://www.ncbi.nlm.nih.gov/clinvar/variation/331045/) |

**All HGVS expressions:** `LRG_873:g.61388T>C`, `LRG_873t1:c.1473T>C`, `NC_000002.11:g.127808477A>G`, `NC_000002.12:g.127050901A>G`, `NG_012042.1:g.61388T>C`, `NM_001320632.2:c.966T>C`, `NM_001320633.2:c.1104T>C`, `NM_001320634.1:c.849T>C`, `NM_001320640.2:c.1233T>C`, `NM_001320641.2:c.1380T>C`, `NM_001320642.1:c.1392T>C`, `NM_004305.4:c.1056T>C`, `NM_139343.3:c.1473T>C`, `NM_139344.3:c.1344T>C`, `NM_139345.3:c.1212T>C`, `NM_139346.3:c.1185T>C`, `NM_139347.3:c.1248T>C`, `NM_139348.3:c.1140T>C`, `NM_139349.3:c.1119T>C`, `NM_139350.3:c.1011T>C`, `NM_139351.3:c.921T>C`

## 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 -2.185, GERP -3.96 — fast-evolving / accelerated position
- CADD: **PHRED 5.246**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.50 acceptor 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 **0.196%** (eas) · FAF95 0.163% · FAF99 0.151% · 88/44,880 in the highest group · 103/1,613,964 alleles overall — rare (popmax 0.196%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.196% | 510 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,929 |
| South Asian | 0.00878% | 11,384 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-09-08.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-08 |

## Associated conditions {#conditions}

[myopathy, centronuclear, 2](https://sugi.bio/atlas/disease/myopathy-centronuclear-2/).

**Reported phenotype names (ClinVar):** Myopathy, centronuclear, 2, MYOTUBULAR MYOPATHY, AUTOSOMAL RECESSIVE.

## Similar variants {#similar}

Related BIN1 variant pages (same residue, condition, or type): [BIN1 p.Pro491fs](/variant/bin1-p-pro491fs), [BIN1 p.Arg145Cys](/variant/bin1-p-arg145cys), [BIN1 p.Arg234Cys](/variant/bin1-p-arg234cys), [BIN1 c.165+6T>C](/variant/bin1-c-165-plus-6t-c), [BIN1 c.-163T>C](/variant/bin1-c-minus-163t-c), [BIN1 p.Ala104Ser](/variant/bin1-p-ala104ser), [BIN1 p.Ala289Thr](/variant/bin1-p-ala289thr), [BIN1 p.Ala289Val](/variant/bin1-p-ala289val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 331045). 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.*