# NM_030962.4(SBF2):c.777G>A (p.Pro259=)

https://sugi.bio/variant/sbf2-p-pro259

## Summary

**SBF2 p.Pro259= (c.777G>A)** is classified **Conflicting classifications of pathogenicity** in SBF2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-11). Rare (popmax 0.319%, afr); Associated with Charcot-Marie-Tooth disease type 4B2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs142261202 · 8 submitters · 3 linked conditions · rare (popmax 0.319%, afr)

## For patients & families {#patients}

This is a change in the SBF2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 8 submitters, and is linked to Charcot-Marie-Tooth disease type 4B2.

*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 |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SBF2 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Charcot-Marie-Tooth disease type 4B2** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Gait disturbance — Very frequent (99-80%)
- Abnormal foot morphology — Very frequent (99-80%)
- Areflexia of lower limbs — Very frequent (99-80%)
- Myelin outfoldings — Very frequent (99-80%)
- Poor fine motor coordination — Very frequent (99-80%)
- Decreased distal sensory nerve action potential — Very frequent (99-80%)
- Lower limb muscle weakness — Very frequent (99-80%)
- Distal upper limb muscle weakness — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009200/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SBF2](https://sugi.bio/atlas/gene/SBF2/) |
| Protein change (HGVS p.) | p.Pro259= |
| Coding change (HGVS c.) | c.777G>A |
| MANE Select transcript | [NM_030962](https://www.ncbi.nlm.nih.gov/nuccore/NM_030962) |
| dbSNP | [rs142261202](https://www.ncbi.nlm.nih.gov/snp/rs142261202/) |
| Variant type | single nucleotide variant |
| Location | chr11:10000998-10000998 (GRCh38) |
| ClinVar | [VCV301870](https://www.ncbi.nlm.nih.gov/clinvar/variation/301870/) |

**All HGVS expressions:** `LRG_267:g.298210G>A`, `LRG_267t1:c.777G>A`, `NC_000011.10:g.10000998C>T`, `NC_000011.9:g.10022545C>T`, `NG_008074.1:g.298210G>A`, `NM_001386339.1:c.777G>A`, `NM_001386342.1:c.777G>A`, `NM_030962.4:c.777G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.75) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.399, GERP -4.56 — fast-evolving / accelerated position
- CADD: **PHRED 21.6**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.75**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.75**, donor gain **0.00**.
- Pangolin: Δ**0.34** (gain), gain 0.34 / loss 0.10. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.319%** (afr) · FAF95 0.286% · FAF99 0.273% · 238/74,500 in the highest group · 347/1,594,900 alleles overall — rare (popmax 0.319%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.319% | 313 |
| Middle Eastern | 0.0829% | 1,206 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0746% | 1,340 |
| Remaining individuals (not grpmax-eligible) | 0.0275% | 3,640 |
| Admixed American | 0.0233% | 4,285 |
| South Asian | 0.00772% | 12,948 |
| European (non-Finnish) | 0.00378% | 26,428 |

*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}

**SBF2** population constraint: LOEUF 0.591, pLI 5.3214e-09, missense-Z 2.2041. *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 4B2** — Definitive (AR)

## Protein context {#protein}

Residue **259** lies in the cdenn domain.

AlphaFold model confidence (whole protein): pLDDT 73.74, 27% of residues very-high.

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

*Describes the biological roles of SBF2 (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:** SBF2's established molecular role includes guanyl-nucleotide exchange factor activity. p.Pro259= falls in the cdenn domain.


### Pathways affected {#pathways}

SBF2 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) | other |
| [Synthesis of PIPs at the plasma membrane](https://reactome.org/content/detail/R-HSA-1660499) | other |

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

**Molecular function:** guanyl-nucleotide exchange factor activity.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-11.

**Submitter consensus:** conflicting (3 Likely benign, 2 Uncertain significance, 1 Benign, 1 Uncertain Significance).

**Submission history:** 8 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Molecular Genetics Laboratory, London Health Sciences Centre | Likely benign | criteria provided, single submitter | clinical testing |  |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2018-03-06 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-07-11 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-11-11 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-01 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain Significance | criteria provided, single submitter | clinical testing | 2025-05-05 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease type 4B2](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-4b2/), [Charcot-Marie-Tooth disease](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease/), [Charcot-Marie-Tooth disease type 4](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-4/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease type 4B2, Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease, not provided, not specified, Inborn genetic diseases, Familial cancer of breast, AllHighlyPenetrant, CMT 4B2, Charcot-Marie-Tooth Neuropathy Type 4B2.

## Similar variants {#similar}

Related SBF2 variant pages (same residue, condition, or type): [SBF2 p.Pro259Leu](/variant/sbf2-p-pro259leu), [SBF2 c.1601-2A>G](/variant/sbf2-c-1601-minus-2a-g), [SBF2 c.3653-1G>A](/variant/sbf2-c-3653-minus-1g-a), [SBF2 p.Arg342Ter](/variant/sbf2-p-arg342ter), [SBF2 p.Arg356Ter](/variant/sbf2-p-arg356ter), [SBF2 p.Arg487Ter](/variant/sbf2-p-arg487ter), [SBF2 p.Arg77Ter](/variant/sbf2-p-arg77ter), [SBF2 c.1601-3T>G](/variant/sbf2-c-1601-minus-3t-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 301870). 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.*