# NM_134261.3(RORA):c.1019del (p.Arg340fs)

https://sugi.bio/variant/rora-p-arg340fs

## Summary

**RORA p.Arg340fs (c.1019del)** is classified **Pathogenic/Likely pathogenic** in RORA (ClinVar, No assertion criteria, 2 submitters; last evaluated 2018-07-27). No gnomAD frequency available for this variant; Associated with Severe intellectual deficiency.

**At a glance:** Pathogenic/Likely pathogenic · review: No assertion criteria · rsID rs1057518981 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the RORA gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to Severe intellectual deficiency.

*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:** [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.Arg340fs |
| Coding change (HGVS c.) | c.1019del |
| MANE Select transcript | [NM_134261](https://www.ncbi.nlm.nih.gov/nuccore/NM_134261) |
| dbSNP | [rs1057518981](https://www.ncbi.nlm.nih.gov/snp/rs1057518981/) |
| Variant type | Deletion |
| Location | chr15:60503591-60503591 (GRCh38) |
| ClinVar | [VCV374220](https://www.ncbi.nlm.nih.gov/clinvar/variation/374220/) |

**All HGVS expressions:** `NC_000015.10:g.60503591del`, `NC_000015.9:g.60795790del`, `NG_029246.1:g.730713del`, `NM_002943.4:c.1094del`, `NM_134260.2:c.1118delG`, `NM_134260.3:c.1118del`, `NM_134261.3:c.1019del`, `NM_134262.3:c.854del`

## 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 6.677, GERP 4.39, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.207, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 11**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **340** lies in the nr lbd domain; an α-helix.

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.Arg340fs falls in the nr lbd domain.


### 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}

**Pathogenic/Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2018-07-27.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2018); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2018-07-27 |
| Laboratory of Molecular Genetics, CHU Rennes | Likely pathogenic | no assertion criteria provided | clinical testing |  |

## Associated conditions {#conditions}

[Severe intellectual deficiency](https://sugi.bio/atlas/disease/severe-intellectual-deficiency/), [intellectual developmental disorder with or without epilepsy or cerebellar ataxia](https://sugi.bio/atlas/disease/intellectual-developmental-disorder-with-or-without-epilepsy-or-cerebellar-ataxia/).

**Reported phenotype names (ClinVar):** Severe intellectual deficiency, Intellectual developmental disorder with or without epilepsy or cerebellar ataxia.

## Similar variants {#similar}

Related RORA variant pages (same residue, condition, or type): [RORA c.1075+2del](/variant/rora-c-1075-plus-2del), [RORA p.Asn187fs](/variant/rora-p-asn187fs), [RORA p.Gln332_Tyr333insTer](/variant/rora-p-gln332-tyr333inster), [RORA p.Ile449fs](/variant/rora-p-ile449fs), [RORA c.1183+7_1183+10del](/variant/rora-c-1183-plus-7-1183-plus-10del), [RORA c.196+51382_196+51385del](/variant/rora-c-196-plus-51382-196-plus-51385del), [RORA p.Arg340Cys](/variant/rora-p-arg340cys), [RORA p.Arg500Ter](/variant/rora-p-arg500ter).

### 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 374220). 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.*