# NM_002972.4(SBF1):c.3318G>A (p.Pro1106=)

https://sugi.bio/variant/sbf1-p-pro1106

## Summary

**SBF1 p.Pro1106= (c.3318G>A)** is classified **Likely benign** in SBF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-06). Very rare (popmax 0.00534%, afr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs758415526 · 2 submitters · very rare (popmax 0.00534%, afr)

## For patients & families {#patients}

This is a change in the SBF1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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 | [SBF1](https://sugi.bio/atlas/gene/SBF1/) |
| Protein change (HGVS p.) | p.Pro1106= |
| Coding change (HGVS c.) | c.3318G>A |
| MANE Select transcript | [NM_002972](https://www.ncbi.nlm.nih.gov/nuccore/NM_002972) |
| dbSNP | [rs758415526](https://www.ncbi.nlm.nih.gov/snp/rs758415526/) |
| Variant type | single nucleotide variant |
| Location | chr22:50460125-50460125 (GRCh38) |
| ClinVar | [VCV752686](https://www.ncbi.nlm.nih.gov/clinvar/variation/752686/) |

**All HGVS expressions:** `NC_000022.10:g.50898554C>T`, `NC_000022.11:g.50460125C>T`, `NG_041810.1:g.19947G>A`, `NM_001365819.1:c.3321G>A`, `NM_002972.4:c.3318G>A`

## 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 -11.493, GERP -3.9 — fast-evolving / accelerated position
- CADD: **PHRED 2.843**. 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 (C>A, Δ0.37 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 **0.00534%** (afr) · FAF95 0.00175% · FAF99 0.00104% · 4/74,914 in the highest group · 14/1,612,642 alleles overall — very rare (popmax 0.00534%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00534% | 18,728 |
| Admixed American | 0.00333% | 29,998 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,239 |
| East Asian | 0.00223% | 44,888 |
| European (non-Finnish) | 0.000424% | 235,998 |

*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}

**SBF1** population constraint: LOEUF 0.381, pLI 1, missense-Z 0.05106. *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):

- **Charcot-Marie-Tooth disease type 4B3** — Moderate (AR)

## Protein context {#protein}

Residue **1106** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 74.72, 33% of residues very-high.

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

*Describes the biological roles of SBF1 (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:** SBF1's established molecular role includes guanyl-nucleotide exchange factor activity. p.Pro1106= falls in the disordered region.


### Pathways affected {#pathways}

SBF1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAB GEFs exchange GTP for GDP on RABs](https://reactome.org/content/detail/R-HSA-8876198) | curated |
| [Synthesis of PIPs at the ER membrane](https://reactome.org/content/detail/R-HSA-1483248) | curated |

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

**Molecular function:** guanyl-nucleotide exchange factor activity, protein-membrane adaptor activity.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-06.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-06 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-01-02 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## Same-residue context {#hotspot}

Residue **1106** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SBF1 p.Pro1106fs](/variant/sbf1-p-pro1106fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SBF1 variant pages (same residue, condition, or type): [SBF1 p.Pro1106Leu](/variant/sbf1-p-pro1106leu), [SBF1 p.Pro1106fs](/variant/sbf1-p-pro1106fs), [SBF1 c.3826+1G>A](/variant/sbf1-c-3826-plus-1g-a), [SBF1 p.Met417Val](/variant/sbf1-p-met417val), [SBF1 c.1431+6A>T](/variant/sbf1-c-1431-plus-6a-t), [SBF1 c.1636+4C>T](/variant/sbf1-c-1636-plus-4c-t), [SBF1 c.1899+3G>A](/variant/sbf1-c-1899-plus-3g-a), [SBF1 c.2643+6C>T](/variant/sbf1-c-2643-plus-6c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 752686). 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.*