# NM_134261.3(RORA):c.1268_1291delinsAT (p.Phe423fs)

https://sugi.bio/variant/rora-p-phe423fs

## Summary

**RORA p.Phe423fs (c.1268_1291delinsAT)** is classified **Pathogenic** in RORA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-12). No gnomAD frequency available for this variant; Associated with Inborn genetic diseases.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2541974207 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the RORA gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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.Phe423fs |
| Coding change (HGVS c.) | c.1268_1291delinsAT |
| MANE Select transcript | [NM_134261](https://www.ncbi.nlm.nih.gov/nuccore/NM_134261) |
| dbSNP | [rs2541974207](https://www.ncbi.nlm.nih.gov/snp/rs2541974207/) |
| Variant type | Indel |
| Location | chr15:60500962-60500985 (GRCh38) |
| ClinVar | [VCV2304091](https://www.ncbi.nlm.nih.gov/clinvar/variation/2304091/) |

**All HGVS expressions:** `NC_000015.10:g.60500962_60500985delinsAT`, `NC_000015.9:g.60793161_60793184delinsAT`, `NG_029246.1:g.733319_733342delinsAT`, `NG_029246.2:g.733317_733340delinsAT`, `NM_002943.4:c.1343_1366delinsAT`, `NM_134260.3:c.1367_1390delinsAT`, `NM_134261.3:c.1268_1291delinsAT`, `NM_134262.3:c.1103_1126delinsAT`

## 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 7.666, GERP 4.14, 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 9 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 indel 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 **423** 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.Phe423fs 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** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-12 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related RORA variant pages (same residue, condition, or type): [RORA p.Arg462Ter](/variant/rora-p-arg462ter), [RORA p.Ala7Ser](/variant/rora-p-ala7ser), [RORA p.Gln278His](/variant/rora-p-gln278his), [RORA p.Gly211Arg](/variant/rora-p-gly211arg), [RORA p.Lys151Gln](/variant/rora-p-lys151gln), [RORA p.Thr328Arg](/variant/rora-p-thr328arg), [RORA c.197-26379G>A](/variant/rora-c-197-minus-26379g-a), [RORA p.Asp21Gly](/variant/rora-p-asp21gly).

### 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 2304091). 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.*