# NM_014314.4(RIGI):c.1825C>T (p.Pro609Ser)

https://sugi.bio/variant/rigi-p-pro609ser

## Summary

**RIGI p.Pro609Ser (c.1825C>T)** is classified **Uncertain significance** in RIGI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-07). AlphaMissense: ambiguous (0.3803); Very rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1298839859 · 2 submitters · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.01%, amr)

## 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.Pro609Ser |
| Coding change (HGVS c.) | c.1825C>T |
| MANE Select transcript | [NM_014314](https://www.ncbi.nlm.nih.gov/nuccore/NM_014314) |
| dbSNP | [rs1298839859](https://www.ncbi.nlm.nih.gov/snp/rs1298839859/) |
| Variant type | single nucleotide variant |
| Location | chr9:32477081-32477081 (GRCh38) |
| ClinVar | [VCV2776667](https://www.ncbi.nlm.nih.gov/clinvar/variation/2776667/) |

**All HGVS expressions:** `NC_000009.11:g.32477079G>A`, `NC_000009.12:g.32477081G>A`, `NG_046918.1:g.54244C>T`, `NM_001385907.1:c.1819C>T`, `NM_001385909.1:c.1825C>T`, `NM_001385910.1:c.1384C>T`, `NM_001385912.1:c.1216C>T`, `NM_001385913.1:c.1810C>T`, `NM_001385914.1:c.1381C>T`, `NM_014314.3:c.1825C>T`, `NM_014314.4:c.1825C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.3803) — no call either way
- REVEL 0.164 (moderately benign-leaning)
- SaProt LLR -7.91 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate
- Conservation: phyloP 7.072, GERP 0.443, phastCons 1 — highly conserved
- CADD: **PHRED 22.7**. 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 1.05** across the covering region of the MANE Select transcript (32,467,888–32,480,248), spanning 12,360 bp. Chi-square p 0.59. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for RIGI (729 scored positions, the nearest 6 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.01%** (amr) · FAF95 0.00428% · FAF99 0.00295% · 6/60,028 in the highest group · 8/1,614,080 alleles overall — very rare (popmax 0.01%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.01% | 10,005 |
| European (non-Finnish) | 0.00017% | 589,971 |

*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}

Residue **609** lies in an α-helix; the 'interaction with zc3hav1' region.

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. p.Pro609Ser falls in the interaction with zc3hav1 region. 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 2024-10-07.

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

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-09 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-07 |

## 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 2776667). 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.*