# NM_134261.3(RORA):c.136C>A (p.Arg46Ser)

https://sugi.bio/variant/rora-p-arg46ser

## Summary

**RORA p.Arg46Ser (c.136C>A)** is classified **Conflicting classifications of pathogenicity** in RORA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-11-01). AlphaMissense: likely benign (0.3342); Very rare (popmax 0.0035%, nfe); Associated with neurofibromatosis type 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.0035%, nfe)

## For patients & families {#patients}

This is a change in the RORA gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to neurofibromatosis type 1.

*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) | Infancy, Neonatal |
| Prevalence | 1-5 / 10 000 (United Kingdom) |
| Clinical trials | 176 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | RORA is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Neurofibromatosis type 1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the nervous system — Very frequent (99-80%)
- Delayed puberty — Very frequent (99-80%)
- Melanocytic nevus — Very frequent (99-80%)
- Multiple lipomas — Very frequent (99-80%)
- Intellectual disability, mild — Very frequent (99-80%)
- Specific learning disability — Very frequent (99-80%)
- Subcutaneous nodule — Very frequent (99-80%)
- Meningioma — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007866/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RORA](https://sugi.bio/atlas/gene/RORA/) |
| Protein change (HGVS p.) | p.Arg46Ser |
| Coding change (HGVS c.) | c.136C>A |
| MANE Select transcript | [NM_134261](https://www.ncbi.nlm.nih.gov/nuccore/NM_134261) |
| Variant type | single nucleotide variant |
| Location | chr15:61229083-61229083 (GRCh38) |
| ClinVar | [VCV4074930](https://www.ncbi.nlm.nih.gov/clinvar/variation/4074930/) |

**All HGVS expressions:** `NC_000015.10:g.61229083G>T`, `NC_000015.9:g.61521282G>T`, `NG_029246.1:g.5221C>A`, `NG_029246.2:g.5219C>A`, `NM_134261.3:c.136C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.3342)
- REVEL 0.376 (indeterminate)
- SaProt LLR -5.712 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- SpliceAI predicts **donor gain** (Δ 0.76) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 8.967, GERP 2.72, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.4**. 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.*
- Regional missense constraint: **o/e 1.29** across the covering region of the MANE Select transcript (60,678,663–61,229,218), spanning 550,555 bp. Chi-square p 0.0056. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.76**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.76**.
- Pangolin: Δ**0.32** (gain), gain 0.32 / loss 0.11. 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 **0.0035%** (nfe) · FAF95 0.00264% · FAF99 0.00232% · 40/1,142,096 in the highest group · 41/1,536,968 alleles overall — very rare (popmax 0.0035%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0035% | 28,552 |
| African / African-American | 0.0014% | 71,222 |

*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}

**RORA** population constraint: LOEUF 0.207, pLI 1, missense-Z 2.3246. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **46** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 76.40, 57% of residues very-high.

**3 experimental structure(s)** (PDB): [1N83](https://www.rcsb.org/structure/1N83), [1S0X](https://www.rcsb.org/structure/1S0X), [4S15](https://www.rcsb.org/structure/4S15).

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

*Describes the biological roles of RORA (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:** RORA's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding. p.Arg46Ser falls in the disordered region.


### Pathways affected {#pathways}

RORA participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [Nuclear Receptor transcription pathway](https://reactome.org/content/detail/R-HSA-383280) | curated |
| [SUMOylation of intracellular receptors](https://reactome.org/content/detail/R-HSA-4090294) | curated |
| [Expression of BMAL (ARNTL), CLOCK, and NPAS2](https://reactome.org/content/detail/R-HSA-9931509) | electronic |
| [Heme signaling](https://reactome.org/content/detail/R-HSA-9707616) | electronic |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | electronic |
| [Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes](https://reactome.org/content/detail/R-HSA-9931510) | electronic |
| [RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression](https://reactome.org/content/detail/R-HSA-9933387) | electronic |

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

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, transcription coregulator binding, transcription corepressor binding, transcription coactivator binding, DNA binding.

**Biological process:** angiogenesis, regulation of DNA-templated transcription, positive regulation of vascular endothelial growth factor production, intracellular receptor signaling pathway, cellular response to sterol, muscle cell differentiation.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2022-11-01.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2020–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-04-29 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-01 |

## Associated conditions {#conditions}

[neurofibromatosis type 1](https://sugi.bio/atlas/disease/neurofibromatosis-type-1/).

**Reported phenotype names (ClinVar):** Neurofibromatosis, type 1, not specified, Peripheral type neurofibromatosis, VON RECKLINGHAUSEN DISEASE, Neurofibromatosis, type I, NEUROFIBROMATOSIS, TYPE I, SOMATIC, AllHighlyPenetrant.

## Similar variants {#similar}

Related RORA variant pages (same residue, condition, or type): [RORA p.Arg462Ter](/variant/rora-p-arg462ter), [RORA p.Arg500Ter](/variant/rora-p-arg500ter), [RORA p.Ala11Val](/variant/rora-p-ala11val), [RORA p.Ala358Thr](/variant/rora-p-ala358thr), [RORA p.Ala7Ser](/variant/rora-p-ala7ser), [RORA p.Arg170His](/variant/rora-p-arg170his), [RORA p.Arg462Gln](/variant/rora-p-arg462gln), [RORA p.Arg47Thr](/variant/rora-p-arg47thr).

### 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 4074930). 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.*