# NM_005060.4(RORC):c.14del (p.Pro5fs)

https://sugi.bio/variant/rorc-p-pro5fs

## Summary

**RORC p.Pro5fs (c.14del)** is classified **Uncertain significance** in RORC (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-15). Very rare (popmax 0.000254%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the RORC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [RORC](https://sugi.bio/atlas/gene/RORC/) |
| Protein change (HGVS p.) | p.Pro5fs |
| Coding change (HGVS c.) | c.14del |
| MANE Select transcript | [NM_005060](https://www.ncbi.nlm.nih.gov/nuccore/NM_005060) |
| Variant type | Deletion |
| Location | chr1:151831751-151831751 (GRCh38) |
| ClinVar | [VCV4911107](https://www.ncbi.nlm.nih.gov/clinvar/variation/4911107/) |

**All HGVS expressions:** `LRG_1322:g.5122del`, `LRG_1322t1:c.14del`, `NC_000001.10:g.151804230del`, `NC_000001.11:g.151831754del`, `NG_029118.1:g.5122del`, `NM_005060.4:c.14del`

## 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 3.199, GERP 0.269, 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 0.351, 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 1 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 (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,944 in the highest group · 3/1,609,988 alleles overall — very rare (popmax 0.000254%, nfe).

*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}

**RORC** population constraint: LOEUF 0.351, pLI 1, missense-Z 2.8954. *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 **5** lies in the 'modulating' region.

AlphaFold model confidence (whole protein): pLDDT 75.42, 57% of residues very-high.

**162 experimental structure(s)** (PDB): [3B0W](https://www.rcsb.org/structure/3B0W), [3KYT](https://www.rcsb.org/structure/3KYT), [3L0J](https://www.rcsb.org/structure/3L0J), [3L0L](https://www.rcsb.org/structure/3L0L), [4NB6](https://www.rcsb.org/structure/4NB6), [4NIE](https://www.rcsb.org/structure/4NIE) — incl. mutant structure 5X8Q.

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

*Describes the biological roles of RORC (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:** RORC's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. p.Pro5fs falls in the modulating region.


### Pathways affected {#pathways}

RORC participates in **6 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 |
| [Expression of BMAL (ARNTL), CLOCK, and NPAS2](https://reactome.org/content/detail/R-HSA-9931509) | 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 |
| [RUNX3 Regulates Immune Response and Cell Migration](https://reactome.org/content/detail/R-HSA-8949275) | other |

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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription repressor activity, RNA polymerase II-specific, oxysterol binding, ligand-modulated transcription factor activity, sequence-specific double-stranded DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, cellular response to sterol, T-helper 17 cell differentiation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-12-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-12-15 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related RORC variant pages (same residue, condition, or type): [RORC p.Pro5Arg](/variant/rorc-p-pro5arg), [RORC p.Arg69fs](/variant/rorc-p-arg69fs), [RORC p.Glu303fs](/variant/rorc-p-glu303fs), [RORC c.821_933+84del](/variant/rorc-c-821-933-plus-84del), [RORC c.1174+9del](/variant/rorc-c-1174-plus-9del), [RORC c.298+16_298+17del](/variant/rorc-c-298-plus-16-298-plus-17del).

### 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 4911107). 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.*