# NM_030962.4(SBF2):c.192_193dup (p.Phe65fs)

https://sugi.bio/variant/sbf2-p-phe65fs

## Summary

**SBF2 p.Phe65fs (c.192_193dup)** is classified **Pathogenic** in SBF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-15). Very rare (popmax 0.000339%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1949709115 · 1 submitter · 1 linked condition · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the SBF2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Charcot-Marie-Tooth disease type 4.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012440/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.Phe65fs |
| Coding change (HGVS c.) | c.192_193dup |
| MANE Select transcript | [NM_030962](https://www.ncbi.nlm.nih.gov/nuccore/NM_030962) |
| dbSNP | [rs1949709115](https://www.ncbi.nlm.nih.gov/snp/rs1949709115/) |
| Variant type | Duplication |
| Location | chr11:10042929-10042930 (GRCh38) |
| ClinVar | [VCV942856](https://www.ncbi.nlm.nih.gov/clinvar/variation/942856/) |

**All HGVS expressions:** `LRG_267:g.256277_256278dup`, `LRG_267t1:c.192_193dup`, `NC_000011.10:g.10042930_10042931dup`, `NC_000011.9:g.10064477_10064478dup`, `NG_008074.1:g.256277_256278dup`, `NM_001386339.1:c.192_193dup`, `NM_001386342.1:c.192_193dup`, `NM_030962.4:c.192_193dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 9.33, GERP 1.95, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.591, pLI 5.3214e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 40**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,179,922 in the highest group · 5/1,614,046 alleles overall — very rare (popmax 0.000339%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,504 |
| European (non-Finnish) (grpmax) | 0.000339% | 294,981 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **65** lies in the udenn 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.Phe65fs falls in the udenn 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-09-15.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-09-15 |

## Associated conditions {#conditions}

[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 4, Charcot-Marie-Tooth disease, type IV, Charcot-Marie-Tooth, Type 4.

## Similar variants {#similar}

Related SBF2 variant pages (same residue, condition, or type): [SBF2 p.Phe65Leu](/variant/sbf2-p-phe65leu), [SBF2 c.142-14dup](/variant/sbf2-c-142-minus-14dup), [SBF2 p.Arg1433fs](/variant/sbf2-p-arg1433fs), [SBF2 p.Ser1397fs](/variant/sbf2-p-ser1397fs), [SBF2 p.Thr39fs](/variant/sbf2-p-thr39fs), [SBF2 c.620-10dup](/variant/sbf2-c-620-minus-10dup), [SBF2 p.Glu1230_Gln1231insProSerSerSerIleGlu](/variant/sbf2-p-glu1230-gln1231insproserserserileglu), [SBF2 c.862-12dup](/variant/sbf2-c-862-minus-12dup).

### 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 942856). 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.*