# NM_005060.4(RORC):c.1089T>C (p.Val363=)

https://sugi.bio/variant/rorc-p-val363

## Summary

**RORC p.Val363= (c.1089T>C)** is classified **Benign/Likely benign** in RORC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). Rare (popmax 0.205%, sas); Associated with autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs199641073 · 2 submitters · 1 linked condition · rare (popmax 0.205%, sas)

## For patients & families {#patients}

This is a change in the RORC gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters, 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.Val363= |
| Coding change (HGVS c.) | c.1089T>C |
| MANE Select transcript | [NM_005060](https://www.ncbi.nlm.nih.gov/nuccore/NM_005060) |
| dbSNP | [rs199641073](https://www.ncbi.nlm.nih.gov/snp/rs199641073/) |
| Variant type | single nucleotide variant |
| Location | chr1:151813324-151813324 (GRCh38) |
| ClinVar | [VCV1167416](https://www.ncbi.nlm.nih.gov/clinvar/variation/1167416/) |

**All HGVS expressions:** `LRG_1322:g.23549T>C`, `LRG_1322t1:c.1089T>C`, `LRG_1322t2:c.1026T>C`, `NC_000001.10:g.151785800A>G`, `NC_000001.11:g.151813324A>G`, `NG_029118.1:g.23549T>C`, `NM_001001523.2:c.1026T>C`, `NM_005060.4:c.1089T>C`

## 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 -1.301, GERP -3.8 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.629**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.43 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.205%** (sas) · FAF95 0.181% · FAF99 0.172% · 187/91,070 in the highest group · 197/1,614,114 alleles overall — rare (popmax 0.205%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.205% | 487 |
| Middle Eastern | 0.0165% | 6,062 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,812 |
| European (non-Finnish) | 8.47e-05% | 1,179,990 |

*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 **363** 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.Val363= 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-12.

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

**Submission history:** 2 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-06-12 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-08 |

## 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, not specified, Immunodeficiency 42, AllHighlyPenetrant.

## 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 2026-10-14); 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 1167416). 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.*