# NM_001378074.1(BOC):c.694A>G (p.Ile232Val)

https://sugi.bio/variant/boc-p-ile232val

## Summary

**BOC p.Ile232Val (c.694A>G)** is classified **Uncertain significance** in BOC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). AlphaMissense: likely benign (0.2179); Ultra-rare (popmax 0.0117%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs367568060 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0117%, amr)

## For patients & families {#patients}

This is a change in the BOC 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 | [BOC](https://sugi.bio/atlas/gene/BOC/) |
| Protein change (HGVS p.) | p.Ile232Val |
| Coding change (HGVS c.) | c.694A>G |
| MANE Select transcript | [NM_001378074](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378074) |
| dbSNP | [rs367568060](https://www.ncbi.nlm.nih.gov/snp/rs367568060/) |
| Variant type | single nucleotide variant |
| Location | chr3:113272436-113272436 (GRCh38) |
| ClinVar | [VCV2382088](https://www.ncbi.nlm.nih.gov/clinvar/variation/2382088/) |

**All HGVS expressions:** `NC_000003.11:g.112991283A>G`, `NC_000003.12:g.113272436A>G`, `NM_001301861.2:c.694A>G`, `NM_001378073.1:c.694A>G`, `NM_001378074.1:c.694A>G`, `NM_001378075.1:c.694A>G`, `NM_001387919.1:c.694A>G`, `NM_001387920.1:c.694A>G`, `NM_001387921.1:c.694A>G`, `NM_001387924.1:c.694A>G`, `NM_001387925.1:c.694A>G`, `NM_001387926.1:c.694A>G`, `NM_001387927.1:c.694A>G`, `NM_001387928.1:c.694A>G`, `NM_001387929.1:c.694A>G`, `NM_001387930.1:c.694A>G`, `NM_033254.4:c.694A>G`, `NR_170866.1:n.1273A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2179)
- REVEL 0.047 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.812 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.63, GERP -2.64, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 15.49**. 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 (113,249,803–113,286,859), spanning 37,056 bp. Chi-square p 1.8e-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, Δ0.43 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 **0.0117%** (amr) · FAF95 0.00986% · FAF99 0.00921% · 7/60,020 in the highest group · 149/1,613,824 alleles overall — ultra-rare (popmax 0.0117%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0117% | 8,574 |
| European (non-Finnish) | 0.0114% | 8,739 |
| African / African-American | 0.00533% | 18,749 |
| East Asian | 0.00223% | 44,846 |
| South Asian | 0.0022% | 45,533 |

*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}

**BOC** population constraint: LOEUF 0.789, pLI 8.5065e-16, missense-Z 2.2833. *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 63.98, 11% of residues very-high.

**3 experimental structure(s)** (PDB): [3N1G](https://www.rcsb.org/structure/3N1G), [3N1M](https://www.rcsb.org/structure/3N1M), [3N1P](https://www.rcsb.org/structure/3N1P).

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

*Describes the biological roles of BOC (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.*


### Pathways affected {#pathways}

BOC participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of SMO](https://reactome.org/content/detail/R-HSA-5635838) | curated |
| [Ligand-receptor interactions](https://reactome.org/content/detail/R-HSA-5632681) | electronic |
| [Myogenesis](https://reactome.org/content/detail/R-HSA-525793) | other |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-27.

**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 | 2024-11-27 |

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

## Similar variants {#similar}

Related BOC variant pages (same residue, condition, or type): [BOC p.Ala715=](/variant/boc-p-ala715), [BOC p.Lys884Asn](/variant/boc-p-lys884asn), [BOC p.Pro829Arg](/variant/boc-p-pro829arg), [BOC p.Pro913Ser](/variant/boc-p-pro913ser), [BOC p.Ala226Thr](/variant/boc-p-ala226thr), [BOC p.Ala424Thr](/variant/boc-p-ala424thr), [BOC p.Ala470Val](/variant/boc-p-ala470val), [BOC p.Ala503Val](/variant/boc-p-ala503val).

### 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 2382088). 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.*