# NM_014314.4(RIGI):c.558G>T (p.Trp186Cys)

https://sugi.bio/variant/rigi-p-trp186cys

## Summary

**RIGI p.Trp186Cys (c.558G>T)** is classified **Uncertain significance** in RIGI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-06). AlphaMissense: likely pathogenic (0.8422); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs765471170 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the RIGI gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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 | [RIGI](https://sugi.bio/atlas/gene/RIGI/) |
| Protein change (HGVS p.) | p.Trp186Cys |
| Coding change (HGVS c.) | c.558G>T |
| MANE Select transcript | [NM_014314](https://www.ncbi.nlm.nih.gov/nuccore/NM_014314) |
| dbSNP | [rs765471170](https://www.ncbi.nlm.nih.gov/snp/rs765471170/) |
| Variant type | single nucleotide variant |
| Location | chr9:32492404-32492404 (GRCh38) |
| ClinVar | [VCV1506930](https://www.ncbi.nlm.nih.gov/clinvar/variation/1506930/) |

**All HGVS expressions:** `NC_000009.11:g.32492402C>A`, `NC_000009.12:g.32492404C>A`, `NG_046918.1:g.38921G>T`, `NM_001385907.1:c.558G>T`, `NM_001385909.1:c.558G>T`, `NM_001385910.1:c.117G>T`, `NM_001385912.1:c.-38-984G>T`, `NM_001385913.1:c.543G>T`, `NM_001385914.1:c.117G>T`, `NM_014314.3:c.558G>T`, `NM_014314.4:c.558G>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.8422)
- REVEL 0.296 (indeterminate)
- SaProt LLR -4.437 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- SpliceAI predicts **donor loss** (Δ 0.31) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.508, GERP -0.858, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.0**. 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.*
- Regional missense constraint: **o/e 1.04** across the covering region of the MANE Select transcript (32,489,353–32,526,166), spanning 36,813 bp. Chi-square p 0.5. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.31**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 13 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  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**0.22** (loss), gain 0.00 / loss 0.22. 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 (gnomAD v4.1): grpmax **0.00133%** (afr) · FAF95 0.000359% · FAF99 0.00026% · 1/74,908 in the highest group · 12/1,614,018 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,243 |
| African / African-American (grpmax) | 0.00133% | 74,908 |
| European (non-Finnish) | 0.000763% | 131,116 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.40, 52% of residues very-high.

**44 experimental structure(s)** (PDB): [2LWD](https://www.rcsb.org/structure/2LWD), [2LWE](https://www.rcsb.org/structure/2LWE), [2QFB](https://www.rcsb.org/structure/2QFB), [2QFD](https://www.rcsb.org/structure/2QFD), [2RMJ](https://www.rcsb.org/structure/2RMJ), [2YKG](https://www.rcsb.org/structure/2YKG) — incl. mutant structure 2LWE.

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

*Describes the biological roles of RIGI (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:** RIGI's established molecular role includes RNA helicase activity. In Reactome, RIGI is annotated in disease pathway(s) including **Evasion by RSV of host interferon responses**, **RSV-host interactions**.

**Disease mechanism (Reactome):** RIGI loss or alteration is curated in [Evasion by RSV of host interferon responses](https://reactome.org/content/detail/R-HSA-9833109), [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110), [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916).

### Pathways affected {#pathways}

RIGI participates in **15 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Evasion by RSV of host interferon responses](https://reactome.org/content/detail/R-HSA-9833109) | curated |
| ⚕ [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110) | curated |
| ⚕ [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916) | curated |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| [DDX58/IFIH1-mediated induction of interferon-alpha/beta](https://reactome.org/content/detail/R-HSA-168928) | curated |
| [ISG15 antiviral mechanism](https://reactome.org/content/detail/R-HSA-1169408) | curated |
| [Modulation of host responses by IFN-stimulated genes](https://reactome.org/content/detail/R-HSA-9909505) | curated |
| [NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10](https://reactome.org/content/detail/R-HSA-933543) | curated |
| [OAS antiviral response](https://reactome.org/content/detail/R-HSA-8983711) | curated |
| [Ovarian tumor domain proteases](https://reactome.org/content/detail/R-HSA-5689896) | curated |
| [TRAF3-dependent IRF activation pathway](https://reactome.org/content/detail/R-HSA-918233) | curated |
| [TRAF6 mediated IRF7 activation](https://reactome.org/content/detail/R-HSA-933541) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [Negative regulators of DDX58/IFIH1 signaling](https://reactome.org/content/detail/R-HSA-936440) | electronic |
| [TRAF6 mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-933542) | electronic |

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

**Molecular function:** RNA helicase activity, double-stranded RNA binding, single-stranded RNA binding, GTP binding, zinc ion binding, ATP hydrolysis activity.

**Biological process:** positive regulation of defense response to virus by host, cytoplasmic pattern recognition receptor signaling pathway, detection of virus, positive regulation of gene expression, regulation of cell migration, positive regulation of granulocyte macrophage colony-stimulating factor production.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-06.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-03-28 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related RIGI variant pages (same residue, condition, or type): [RIGI p.Ala436Val](/variant/rigi-p-ala436val), [RIGI p.Ala537Ser](/variant/rigi-p-ala537ser), [RIGI p.Ala537Thr](/variant/rigi-p-ala537thr), [RIGI p.Ala774Thr](/variant/rigi-p-ala774thr), [RIGI p.Arg109Cys](/variant/rigi-p-arg109cys), [RIGI p.Arg34Gly](/variant/rigi-p-arg34gly), [RIGI p.Arg664His](/variant/rigi-p-arg664his), [RIGI p.Arg767Cys](/variant/rigi-p-arg767cys).

### 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 1506930). 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.*