# NM_018688.6(BIN3):c.4A>T (p.Ser2Cys)

https://sugi.bio/variant/bin3-p-ser2cys

## Summary

**BIN3 p.Ser2Cys (c.4A>T)** is classified **Uncertain significance** in BIN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: likely pathogenic (0.6142); Very rare (popmax 0.00565%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00565%, nfe)

## For patients & families {#patients}

This is a change in the BIN3 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 | [BIN3](https://sugi.bio/atlas/gene/BIN3/) |
| Protein change (HGVS p.) | p.Ser2Cys |
| Coding change (HGVS c.) | c.4A>T |
| MANE Select transcript | [NM_018688](https://www.ncbi.nlm.nih.gov/nuccore/NM_018688) |
| Variant type | single nucleotide variant |
| Location | chr8:22669048-22669048 (GRCh38) |
| ClinVar | [VCV3824349](https://www.ncbi.nlm.nih.gov/clinvar/variation/3824349/) |

**All HGVS expressions:** `NC_000008.10:g.22526561T>A`, `NC_000008.11:g.22669048T>A`, `NG_113672.1:g.305T>A`, `NG_113672.2:g.328T>A`, `NM_001363046.2:c.-79A>T`, `NM_018688.6:c.4A>T`, `NR_156436.2:n.74A>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.6142)
- REVEL 0.273 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -12.519 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP 7.802, GERP 1.91, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.1**. 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 1.11** across the covering region of the MANE Select transcript (22,621,425–22,669,051), spanning 47,626 bp. Chi-square p 0.041. 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 (T>C, Δ0.34 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 **0.00565%** (nfe) · FAF95 0.00455% · FAF99 0.00415% · 66/1,168,910 in the highest group · 72/1,590,108 alleles overall — very rare (popmax 0.00565%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00565% | 17,711 |
| Remaining individuals (not grpmax-eligible) | 0.00488% | 20,502 |
| African / African-American | 0.00403% | 24,831 |

*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}

**BIN3** population constraint: LOEUF 1.45, pLI 6.6299e-16, missense-Z -0.68717. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.83, 85% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-10.

**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 | 2025-02-10 |

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

## Similar variants {#similar}

Related BIN3 variant pages (same residue, condition, or type): [BIN3 c.297+5C>T](/variant/bin3-c-297-plus-5c-t), [BIN3 p.Ala131Pro](/variant/bin3-p-ala131pro), [BIN3 p.Arg128Gln](/variant/bin3-p-arg128gln), [BIN3 p.Arg128Trp](/variant/bin3-p-arg128trp), [BIN3 p.Arg136Gly](/variant/bin3-p-arg136gly), [BIN3 p.Arg166Gln](/variant/bin3-p-arg166gln), [BIN3 p.Arg185Cys](/variant/bin3-p-arg185cys), [BIN3 p.Arg203Gln](/variant/bin3-p-arg203gln).

### 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 2026-07-14); 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 3824349). 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.*