# NM_005060.4(RORC):c.1165C>T (p.Arg389Ter)

https://sugi.bio/variant/rorc-p-arg389ter

## Summary

**RORC p.Arg389Ter (c.1165C>T)** is classified **Likely pathogenic** in RORC (ClinVar, Single submitter, 1 submitter). Absent from gnomAD v4.1; Associated with autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1558164428 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the RORC gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy |
| Diagnostic panels | RORC is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017861/index) · [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.Arg389Ter |
| Coding change (HGVS c.) | c.1165C>T |
| MANE Select transcript | [NM_005060](https://www.ncbi.nlm.nih.gov/nuccore/NM_005060) |
| dbSNP | [rs1558164428](https://www.ncbi.nlm.nih.gov/snp/rs1558164428/) |
| Variant type | single nucleotide variant |
| Location | chr1:151813248-151813248 (GRCh38) |
| ClinVar | [VCV2585221](https://www.ncbi.nlm.nih.gov/clinvar/variation/2585221/) |

**All HGVS expressions:** `LRG_1322:g.23625C>T`, `LRG_1322t1:c.1165C>T`, `LRG_1322t2:c.1102C>T`, `NC_000001.10:g.151785724G>A`, `NC_000001.11:g.151813248G>A`, `NG_029118.1:g.23625C>T`, `NM_001001523.2:c.1102C>T`, `NM_005060.4:c.1165C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.20) — consistent with the pathogenic call
- Conservation: phyloP 8.395, GERP -3.8, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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 8 of 11**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 43.0**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.11**. Largest is donor loss, 9 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.11**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.26** (loss), gain 0.07 / loss 0.26. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

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

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.Arg389Ter falls in the nr lbd domain.


### 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neuberg Centre For Genomic Medicine, NCGM | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency](https://sugi.bio/atlas/disease/autosomal-recessive-mendelian-susceptibility-to-mycobacterial-diseases-due-to-complete-rorgamma-receptor-deficiency/).

**Reported phenotype names (ClinVar):** Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency, Immunodeficiency 42.

## Similar variants {#similar}

Related RORC variant pages (same residue, condition, or type): [RORC p.Arg10Gln](/variant/rorc-p-arg10gln), [RORC p.Arg13Trp](/variant/rorc-p-arg13trp), [RORC p.Arg208Gln](/variant/rorc-p-arg208gln), [RORC p.Arg237Ser](/variant/rorc-p-arg237ser), [RORC p.Arg257His](/variant/rorc-p-arg257his), [RORC p.Arg288Gln](/variant/rorc-p-arg288gln), [RORC p.Arg82Gln](/variant/rorc-p-arg82gln), [RORC p.Asn373Ser](/variant/rorc-p-asn373ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2585221). 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.*