# NM_033030.6(BOLL):c.515C>T (p.Ala172Val)

https://sugi.bio/variant/boll-p-ala172val

## Summary

**BOLL p.Ala172Val (c.515C>T)** is classified **Uncertain significance** in BOLL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-06). AlphaMissense: likely benign (0.1449); Very rare (popmax 0.000254%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the BOLL 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 | [BOLL](https://sugi.bio/atlas/gene/BOLL/) |
| Protein change (HGVS p.) | p.Ala172Val |
| Coding change (HGVS c.) | c.515C>T |
| MANE Select transcript | [NM_033030](https://www.ncbi.nlm.nih.gov/nuccore/NM_033030) |
| Variant type | single nucleotide variant |
| Location | chr2:197766569-197766569 (GRCh38) |
| ClinVar | [VCV3261348](https://www.ncbi.nlm.nih.gov/clinvar/variation/3261348/) |

**All HGVS expressions:** `NC_000002.11:g.198631293G>A`, `NC_000002.12:g.197766569G>A`, `NM_001284358.2:c.188C>T`, `NM_001284361.2:c.533C>T`, `NM_001284362.2:c.533C>T`, `NM_033030.6:c.515C>T`, `NM_197970.3:c.551C>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** (0.1449)
- REVEL 0.099 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.47 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 11.72, GERP 1.35, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.3**. 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 0.85** across the covering region of the MANE Select transcript (197,728,558–197,781,850), spanning 53,292 bp. Chi-square p 0.0053. 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>C, Δ0.21 acceptor loss), 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 **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,178,950 in the highest group · 3/1,460,416 alleles overall — very rare (popmax 0.000254%, 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}

**BOLL** population constraint: LOEUF 0.81, pLI 0.31354, missense-Z 0.71727. *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 **172** lies in the daz domain.

AlphaFold model confidence (whole protein): pLDDT 64.18, 25% of residues very-high.

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

*Describes the biological roles of BOLL (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:** BOLL's established molecular role includes translation activator activity. p.Ala172Val falls in the daz domain.


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

**Molecular function:** translation activator activity, identical protein binding.

**Biological process:** positive regulation of translational initiation, meiotic cell cycle.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-06.

**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 | 2024-04-06 |

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

## Similar variants {#similar}

Related BOLL variant pages (same residue, condition, or type): [BOLL p.Ala172Pro](/variant/boll-p-ala172pro), [BOLL p.Ala185Asp](/variant/boll-p-ala185asp), [BOLL p.Ala259Asp](/variant/boll-p-ala259asp), [BOLL p.Ala267Val](/variant/boll-p-ala267val), [BOLL p.Arg34Cys](/variant/boll-p-arg34cys), [BOLL p.Asp85Gly](/variant/boll-p-asp85gly), [BOLL p.Cys165Gly](/variant/boll-p-cys165gly), [BOLL p.Gln271His](/variant/boll-p-gln271his).

### 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 3261348). 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.*