# NM_006267.5(RANBP2):c.6039T>C (p.Phe2013=)

https://sugi.bio/variant/ranbp2-p-phe2013

## Summary

**RANBP2 p.Phe2013= (c.6039T>C)** is classified **Likely benign** in RANBP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-04). Absent from gnomAD v4.1; Associated with familial acute necrotizing encephalopathy.

**At a glance:** Likely benign · review: Single submitter · rsID rs2149280892 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the RANBP2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to familial acute necrotizing encephalopathy.

*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 dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Diagnostic panels | RANBP2 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Familial acute necrotizing encephalopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Coma — Very frequent (99-80%)
- Increased CSF protein concentration — Very frequent (99-80%)
- Acute encephalopathy — Very frequent (99-80%)
- Intellectual disability — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Spasticity — Frequent (79-30%)
- Dysarthria — Frequent (79-30%)
- Hypertonia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013232/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RANBP2](https://sugi.bio/atlas/gene/RANBP2/) |
| Protein change (HGVS p.) | p.Phe2013= |
| Coding change (HGVS c.) | c.6039T>C |
| MANE Select transcript | [NM_006267](https://www.ncbi.nlm.nih.gov/nuccore/NM_006267) |
| dbSNP | [rs2149280892](https://www.ncbi.nlm.nih.gov/snp/rs2149280892/) |
| Variant type | single nucleotide variant |
| Location | chr2:108766578-108766578 (GRCh38) |
| ClinVar | [VCV1139040](https://www.ncbi.nlm.nih.gov/clinvar/variation/1139040/) |

**All HGVS expressions:** `NC_000002.11:g.109383034T>C`, `NC_000002.12:g.108766578T>C`, `NG_012210.1:g.52098T>C`, `NM_006267.5:c.6039T>C`

## 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 0.317, GERP -0.661, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 7.481**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**RANBP2** population constraint: LOEUF 0.231, pLI 1, missense-Z 3.8313. *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):

- **Leigh syndrome** — Limited (AD)
- **familial acute necrotizing encephalopathy** — Moderate (AD)

## Protein context {#protein}

Residue **2013** lies in the ranbd1 2 domain; the '22 x 2 aa repeats of f-g' region.

**33 experimental structure(s)** (PDB): [1RRP](https://www.rcsb.org/structure/1RRP), [1XKE](https://www.rcsb.org/structure/1XKE), [1Z5S](https://www.rcsb.org/structure/1Z5S), [2LAS](https://www.rcsb.org/structure/2LAS), [3UIN](https://www.rcsb.org/structure/3UIN), [3UIO](https://www.rcsb.org/structure/3UIO) — incl. mutant structure 7MNM.

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

*Describes the biological roles of RANBP2 (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:** RANBP2's established molecular role includes SUMO transferase activity. p.Phe2013= falls in the ranbd1 2 domain. In Reactome, RANBP2 is annotated in disease pathway(s) including **Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)**, **HCMV Early Events**.

**Disease mechanism (Reactome):** RANBP2 loss or alteration is curated in [Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)](https://reactome.org/content/detail/R-HSA-5619107), [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690), [HCMV Late Events](https://reactome.org/content/detail/R-HSA-9610379).

### Pathways affected {#pathways}

RANBP2 participates in **37 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)](https://reactome.org/content/detail/R-HSA-5619107) | curated |
| ⚕ [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690) | curated |
| ⚕ [HCMV Late Events](https://reactome.org/content/detail/R-HSA-9610379) | curated |
| ⚕ [NEP/NS2 Interacts with the Cellular Export Machinery](https://reactome.org/content/detail/R-HSA-168333) | curated |
| ⚕ [NS1 Mediated Effects on Host Pathways](https://reactome.org/content/detail/R-HSA-168276) | curated |
| ⚕ [Rev-mediated nuclear export of HIV RNA](https://reactome.org/content/detail/R-HSA-165054) | curated |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| ⚕ [Transport of Ribonucleoproteins into the Host Nucleus](https://reactome.org/content/detail/R-HSA-168271) | curated |
| ⚕ [Viral Messenger RNA Synthesis](https://reactome.org/content/detail/R-HSA-168325) | curated |
| ⚕ [Vpr-mediated nuclear import of PICs](https://reactome.org/content/detail/R-HSA-180910) | curated |
| ⚕ [Nuclear import of Rev protein](https://reactome.org/content/detail/R-HSA-180746) | electronic |
| [Amplification  of signal from unattached  kinetochores via a MAD2  inhibitory signal](https://reactome.org/content/detail/R-HSA-141444) | curated |
| [EML4 and NUDC in mitotic spindle formation](https://reactome.org/content/detail/R-HSA-9648025) | curated |
| [IP3 and IP4 transport between cytosol and nucleus](https://reactome.org/content/detail/R-HSA-1855196) | curated |
| [IP6 and IP7 transport between cytosol and nucleus](https://reactome.org/content/detail/R-HSA-1855229) | curated |
| [IPs transport between nucleus and cytosol](https://reactome.org/content/detail/R-HSA-1855170) | curated |
| [ISG15 antiviral mechanism](https://reactome.org/content/detail/R-HSA-1169408) | curated |
| [Mitotic Prometaphase](https://reactome.org/content/detail/R-HSA-68877) | curated |
| [Nuclear Pore Complex (NPC) Disassembly](https://reactome.org/content/detail/R-HSA-3301854) | curated |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | curated |
| [Regulation of Glucokinase by Glucokinase Regulatory Protein](https://reactome.org/content/detail/R-HSA-170822) | curated |
| [Regulation of HSF1-mediated heat shock response](https://reactome.org/content/detail/R-HSA-3371453) | curated |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | curated |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | curated |
| [SUMOylation of RNA binding proteins](https://reactome.org/content/detail/R-HSA-4570464) | curated |
| [SUMOylation of SUMOylation proteins](https://reactome.org/content/detail/R-HSA-4085377) | curated |
| [SUMOylation of chromatin organization proteins](https://reactome.org/content/detail/R-HSA-4551638) | curated |
| [SUMOylation of ubiquitinylation proteins](https://reactome.org/content/detail/R-HSA-3232142) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [Transport of Mature mRNA Derived from an Intronless Transcript](https://reactome.org/content/detail/R-HSA-159231) | curated |
| [Transport of Mature mRNA derived from an Intron-Containing Transcript](https://reactome.org/content/detail/R-HSA-159236) | curated |
| [Transport of the SLBP Dependant Mature mRNA](https://reactome.org/content/detail/R-HSA-159230) | curated |
| [Transport of the SLBP independent Mature mRNA](https://reactome.org/content/detail/R-HSA-159227) | curated |
| [snRNP Assembly](https://reactome.org/content/detail/R-HSA-191859) | curated |
| [tRNA processing in the nucleus](https://reactome.org/content/detail/R-HSA-6784531) | curated |
| [SUMOylation of DNA replication proteins](https://reactome.org/content/detail/R-HSA-4615885) | electronic |

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

**Molecular function:** SUMO transferase activity, protein-macromolecule adaptor activity, small GTPase binding, SUMO ligase activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, NLS-bearing protein import into nucleus, protein sumoylation, nuclear export, centrosome localization.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-02-04.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-02-04 |

## Associated conditions {#conditions}

[familial acute necrotizing encephalopathy](https://sugi.bio/atlas/disease/familial-acute-necrotizing-encephalopathy/).

**Reported phenotype names (ClinVar):** Familial acute necrotizing encephalopathy, ENCEPHALOPATHY, ACUTE, INFECTION-INDUCED, SUSCEPTIBILITY TO, 3, Susceptibility to Acute Necrotizing Encephalopathy 1.

## Similar variants {#similar}

Related RANBP2 variant pages (same residue, condition, or type): [RANBP2 p.Thr585Met](/variant/ranbp2-p-thr585met), [RANBP2 c.406-2A>G](/variant/ranbp2-c-406-minus-2a-g), [RANBP2 p.Ala2564Ser](/variant/ranbp2-p-ala2564ser), [RANBP2 p.Ala3072Val](/variant/ranbp2-p-ala3072val), [RANBP2 p.Ala534Val](/variant/ranbp2-p-ala534val), [RANBP2 p.Ala836Val](/variant/ranbp2-p-ala836val), [RANBP2 p.Arg1096Gln](/variant/ranbp2-p-arg1096gln), [RANBP2 p.Arg1198Cys](/variant/ranbp2-p-arg1198cys).

### 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 1139040). 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.*