# NM_006267.5(RANBP2):c.1209C>T (p.Ser403=)

https://sugi.bio/variant/ranbp2-p-ser403

## Summary

**RANBP2 p.Ser403= (c.1209C>T)** is classified **Benign/Likely benign** in RANBP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-17). Low-frequency (popmax 2.91%, afr); Associated with familial acute necrotizing encephalopathy.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs140275032 · 4 submitters · 1 linked condition · low-frequency (popmax 2.91%, afr)

## For patients & families {#patients}

This is a change in the RANBP2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters, 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.Ser403= |
| Coding change (HGVS c.) | c.1209C>T |
| MANE Select transcript | [NM_006267](https://www.ncbi.nlm.nih.gov/nuccore/NM_006267) |
| dbSNP | [rs140275032](https://www.ncbi.nlm.nih.gov/snp/rs140275032/) |
| Variant type | single nucleotide variant |
| Location | chr2:108749065-108749065 (GRCh38) |
| ClinVar | [VCV382435](https://www.ncbi.nlm.nih.gov/clinvar/variation/382435/) |

**All HGVS expressions:** `NC_000002.11:g.109365521C>T`, `NC_000002.12:g.108749065C>T`, `NG_012210.1:g.34585C>T`, `NM_006267.5:c.1209C>T`

## 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 -1.651, GERP -3.36 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.227**. 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>G, Δ0.57 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 **2.91%** (afr) · FAF95 2.8% · FAF99 2.76% · 2,175/74,832 in the highest group · 2,570/1,611,680 alleles overall — low-frequency (popmax 2.91%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 2.91% | 34 |
| Admixed American | 0.29% | 345 |
| Remaining individuals (not grpmax-eligible) | 0.241% | 415 |
| Middle Eastern | 0.181% | 554 |
| South Asian | 0.011% | 9,097 |
| European (non-Finnish) | 0.00449% | 22,261 |

*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}


**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. 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-17.

**Submitter consensus:** conflicting (3 Benign, 1 Likely benign).

**Submission history:** 4 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-03-29 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-01-17 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-03-17 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Familial acute necrotizing encephalopathy, not provided, ENCEPHALOPATHY, ACUTE, INFECTION-INDUCED, SUSCEPTIBILITY TO, 3, Susceptibility to Acute Necrotizing Encephalopathy 1, none provided.

## 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 382435). 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.*